WO2002046465A2 - Method for identification of genes involved in specific diseases - Google Patents

Method for identification of genes involved in specific diseases Download PDF

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WO2002046465A2
WO2002046465A2 PCT/GB2001/005458 GB0105458W WO0246465A2 WO 2002046465 A2 WO2002046465 A2 WO 2002046465A2 GB 0105458 W GB0105458 W GB 0105458W WO 0246465 A2 WO0246465 A2 WO 0246465A2
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polypeptide
nucleic acid
hypoxia
recited
gene
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PCT/GB2001/005458
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French (fr)
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WO2002046465A3 (en
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Jonathan White
Christopher Robert Mundy
Neil Raymond Ward
David Krige
Susan Mary Kingsman
Robert Alan Harris
William Nigel Rayner
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Oxford Biomedica (Uk) Limited
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Priority claimed from GB0030076A external-priority patent/GB0030076D0/en
Priority claimed from GB0103156A external-priority patent/GB0103156D0/en
Priority claimed from GB0125666A external-priority patent/GB0125666D0/en
Application filed by Oxford Biomedica (Uk) Limited filed Critical Oxford Biomedica (Uk) Limited
Priority to AU2002220920A priority Critical patent/AU2002220920A1/en
Priority to US10/170,385 priority patent/US20030203372A1/en
Publication of WO2002046465A2 publication Critical patent/WO2002046465A2/en
Publication of WO2002046465A3 publication Critical patent/WO2002046465A3/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • This invention relates to novel methods for the identification of genes and gene products that are implicated in certain disease states.
  • the invention also relates to novel genes and gene products identified using these m ethods. All publications, patents and patent applications cited herein are incorporated in full by reference.
  • transcriptome is meant the exact set of transcripts that are expressed in a cell.
  • the em erging field of nucleic acid arrays is one field in which a large num ber of powerful tools are being generated for the study of transcriptom e variation between different tissue types.
  • any m ethods currently em ployed utilise established cell lines. Because these cells have been manipulated to allow their immortalisation in cell culture, the physiological situation in these cells is not considered by the present inventors to be generally representative of the authentic situation in equivalent cells in vivo. Furtherm ore, m ost of these methods tend to utilise a global strategy for intervention, often ignoring the intricacies in gene expression that exist between different tissues. There thus rem ains a great need for the establishm ent of novel m ethods for the analysis of gene expression.
  • a method for the identification of a gene that is implicated in a specific disease or physiological condition comprising the steps of: a) comparing: i) the transcriptom e or proteome of a first specialised cell type that is implicated in the disease or condition under first and second experim ental conditions; with ii) the transcriptome or proteome of a second specialised cell type under said first and said second experim ental conditions; and b) identifying as a gene implicated in the disease or physiological condition, a gene that is differentially regulated in the two specialised cell types under the first and second experimental conditions.
  • V arious groups have previously investigated mechanism s of physiological regulation, by comparing gene expression levels in the presence and absence of a physiological stim ulus or challenge.
  • Genes identified in a particular cell type as being expressed at different levels under different conditions are implicated as components of a pathway that is responsive to the altered conditions, or that is regulated differently under the altered conditions.
  • these m ethods exhibit a tendency to ignore patterns of gene expression that are physiologically relevant. This inclination is considered to result from a prejudice in the art that dictates that cells respond to changes in certain physiological conditions in a generic fashion, rather than in a cell specific fashion.
  • B y "implicated in a specific disease or physiological condition" is meant that the gene has been found to possess a distinct role in a pathway that is involved in susceptibility to, generation of or m aintenance of a particular disease phenotype or physiological condition.
  • any point in any pathw ay may be the unique point at w hich a cell departs from the normal physiological response and generates a disease phenotype.
  • the effect that is m anifested as a disease is the result of a m utation event, in which a mutation occurs in the sequence of a gene encoding a protein that functions in a relevant physiological pathway.
  • m ethods There are num erous examples of diseases and conditions that m ay be studied using the m ethod of the invention. Such pathological conditions include those that result from a change in the intrinsic nature of a cell (usually genetic) or from a change in the cellular microenvironm ent, either of which m ight be recapitulated in a laboratory setting.
  • the m ethods may be applied to any disease or condition that is manifested in, or is generated in a specific cell type.
  • Examples of such conditions include changes in the cellular microenvironment, exposure to hormones, growth factors, cytokines, chem okines, inflamm atory agents, toxins, m etabolites, pH, pharm aceutical agents, hypoxia, anoxia, ischemia, im balance of any plasm a-borne nutrient [including glucose, am ino acids, co-factors, m ineral salts, proteins and lipids], osm otic stress, temperature [hypo and hyper- thermia], mechanical stress, irradiation [ionising or non-ionising], cell-extracellular m atrix interactions, cell-cell interactions, accumulations of foreign or pathological extracellular components, intracellular and extracellular pathogens [including bacteria, viruses, fungi and mycoplasma] and genetic perturbations [both epigenetic or m ediated by mutation or polymorphism].
  • diseases include cardiovascular disease, atherosclerosis, inflamm atory conditions (including rheum atoid arthritis), cancer, ischemic disease, asthm a, hem atopoietic disorders, neurological diseases including Parkinson's and Alzheimer' s diseases, infectious disease and allergies.
  • hypoxia is intended to refer to an environment of reduced oxygen tension, as compared to the norm al physiological environment for a particular organism , which is termed "normoxia” .
  • non-moxia an environment of reduced oxygen tension
  • the prejudice in this technical field presents the view that there is a general, ubiquitous response to hypoxia, mediated prim arily at the level of m RNA (transcriptional initiation and post- transcriptional stabilisation).
  • tissue oxygenation plays a significant regulatory role in both apoptosis and in angiogenesis (Bouck et al, 1996, Adv . Cancer Res. 69:135-174; Bunn et al, 1996, Physiol. Rev. 76:839-885 ; Dor et al, 1997 , Trends Cardiovasc. M ed., 7 :289-294; Carmeliet et al, 1998, Nature 394:485-490). Apoptosis (see Duke et al, 1996, Sci.
  • Angiogenesis i.e. blood vessel growth, vascularization
  • hypooxygenated cells secrete factors that stimulate proliferation and m igration of endothelial cells in an attempt to restore oxygen hom eostasis (for review see Hanahan et al, 1996, Cell, 86 :353-364).
  • Ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels.
  • solid tum ours typically have a disorganised blood supply, leading to hypoxic regions.
  • O ther disease conditions involving hypoxia include stroke, atherosclerosis, retinopathy, acute renal failure, myocardial infarction, stroke and hair loss. Therefore, apoptosis and angiogenesis as induced by the ischaemic condition are also considered to be involved in these disease states. It is generally considered that understanding the mechanism by w hich cells respond to these diseases m ay be the key to the disease pathology and thus relevant to disease treatment.
  • angiogenesis is necessary for tum our grow th and that retardation of this process provide a useful tool in controlling m alignancy and retinopathies.
  • neoangiogenesis is seen in m any forms of retinopathy and in tum our growth.
  • tumourigenic cells to undergo apoptosis is an extrem ely desirable goal; particularly in the cancer field, it has been observed that apoptosis and angiogenesis-related genes provide potent therapeutic . targets.
  • hypoxia plays a critical role in the selection of mutations that contribute to m ore severe tum ourigenic phenotypes (Graeber et al, 1996 Nature, 379(6560):88-91 ).
  • HIF-l alpha a transcription factor that is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia.
  • This protein is considered a m aster regulator of oxygen homeostasis (see, for example, Semenza, (1998) Curr. Op. Genetics and Dev. 8 :588-594).
  • HIF1 alpha is genetically knocked out, the hypoxia-inducible transcription of virtually all glycolytic enzymes has been shown to be inhibited. Glycolysis is an essential process which goes on in all m amm alian cells.
  • the m ethods of the present invention therefore extend and add to previous w ork perform ed in this field, in that the discoveries made now allow the design of agents that target the hypoxic response in specific tissues.
  • tissue For example, it is known that brain and heart tissues die very rapidly after ischaem ic insult. B y using the m ethod of the invention, it is quite possible that these tissues will be found to share com m on features in their response to hypoxia, that is different from other cell types. This might allow , for example, the design of a combination cardioprotective and neuroprotective agent effective against this subset of body tissues. Alternatively, the hypoxic response in these tissues m ight be found to be quite different, This information w ould then be taken into account when designing therapeutic countermeasures, in that an agent would be designed for the unique neurological or cardiological tissue concerned.
  • the m ethod of the invention involves the comparison of the transcriptomes or proteomes of at least tw o specialised cell types under tw o different physiological or genetic conditions.
  • B y "transcriptome” is meant the exact set of transcripts that are expressed in a cell. The transcriptome thus has a qualitative elem ent (the identity of individual gene transcripts) and a quantitative element (the proportion of each unique transcript in the total number of individual transcripts present in the cell at a particular m om ent).
  • B y "proteome” is meant the exact set of protein m olecules that are expressed in a cell.
  • specialised cell type is m eant a cell type that has a restricted biochemical capacity and that can be unambiguously identified as possessing a unique set of biochemical and physiological functions
  • the specialised cells are prim ary cells, and not cell lines or whole body tissues
  • Primary cells are cells that cannot proliferate indefinitely in culture
  • Prim ary cells can be derived from adult tissue, or from embryo tissue that is differentiated in culture to an adult cell or to a precursor of an adult cell that displays specialised characteristics.
  • Examples of preferred specialised cell types include cardiom yocytes, endothelial cells, sensory neurons, motor neurons, CNS neurons (all types), astrocytes, glial cells, schwann cells, m ast cells, eosinophils, smooth muscle cells, skeletal muscle cells, pericytes, lymphocytes, tum or cells, m onocytes, m acrophages, foamy m acrophages, granulocytes, synovial cells / synovial fibroblasts, epithelial cells (varieties from all tissues/ organs).
  • Suitable specialised cell types include vascular endothelial cells, smooth muscle cells (aortic, bronchial, coronary artery, pulmonary artery, etc), skeletal muscle cells, cardiom yocyte cells, fibroblasts (m any types, such as synovial), keratinocytes, hepatocytes, dendritic cells, astrocytes, neurone cells (including mesencephalic, hippocampal, striatal, thalamic, hypothalamic, olfactory bulb, substantia nigra, locus coeruleus, cortex, dorsal root ganglia, superior cervical ganglia, sensory, m otor, cerebellar cells), neutrophils, eosinophils, basophils, m ast cells, m onocytes, m acrophage cells, erythrocytes, megakaryocytes, hem atopoietic progenitor cells, hematopoietic pluri
  • the transcriptom es of the specialised cell types are compared under different experimental conditions.
  • experim ental conditions is used broadly in this context and is intended to embrace any physiological or genetic conditions to w hich a cell type m ay be exposed.
  • the intention of the method is to compare the transcriptomes or proteom es of the cell types under different experimental conditions that have a physiological relevance. Accordingly, the state of the transcriptome or proteome under one set of experim ental conditions will generally act as a control against which the transcriptome or proteom e m ay be compared under a second set of experimental conditions. Any distinct physiologically-relevant conditions may therefore be of interest.
  • physiological experim ental conditions include conditions under w hich the cell is subm itted to a physiological, mechanical, temperature, chem ical, toxic or pharmaceutical stress.
  • hypoxia defined herein as a physiological state in which oxygen dem and by the cell exceeds its supply to the cell.
  • the transcriptome or proteome under this set of experimental conditions may be compared to the transcriptome or proteome under conditions of normoxia, w hen oxygen supply is in concordance with the dem and by the cell.
  • the transcriptomes or proteomes may also be compared under different genetic conditions.
  • B y "genetic conditions" is meant that the genotype of the compared cell populations contains a different genetic component.
  • This m ay be the presence of one or m ore different, non-endogenous nucleic acid m olecules in the cell, herein referred to collectively as "genetic elem ents" .
  • Such genetic elem ent(s) m ay potentially be incorporated into the genome of the cell, or alternatively may exist as a separate genetic entity, for example, as an extra-chrom osom al elem ent such as a plasm id or episome.
  • the genome m ay have been perturbed by external intervention, for example, to increase or decrease the expression of a particular gene or genes.
  • a num ber of variations on this theme are possible, including the overexpression of a genetic elem ent via the adm inistration of the functional gene, the overexpression of a genetic element via the administration of a regulator of the functional gene (such as, for example, a transcription factor [either natural or artificially constructed via the fusion of a DN A binding dom ain with an activator dom ain]), the inhibition of the expression of a functional gene (for example, using antisense RNA or ribozym es), the inhibition of the expression of a functional gene (for example, using a transdominant protein) and the inhibition of the expression of a functional gene (for example, using a repressor protein that is either natural or artificially constructed from a DNA binding protein fused to a repressor dom ain).
  • a regulator of the functional gene
  • a particular example of a genetic perturbation as envisaged herein, that form s one preferred embodim ent of the m ethod of the present invention, is the so-called "Sm artomics" technology that form s the basis for co-pending, co-owned International patent application PCT/GB O 1 /00758 ,
  • a heterologous nucleic acid is introduced into a prim ary cell to augment a specific natural physiological response, "Sm artom ics" m ay be applied to the current invention by m easuring and comparing cellular responses to a heterologous gene in two or m ore distinct cell types, both with and without the natural physiological stim ulus.
  • Lentivirus technology is used to introduce the heterologous nucleic acid m olecule in such a w ay that there is negligible perturbation of endogenous gene expression, For this reason, this technology exhibits significant benefits over conventional technology of a similar nature, since the prior art m ethods are generally invasive, having downstream effects other than the simple introduction of the heterologous nucleic acid m olecule.
  • the Sm artomics technology allows much m ore precise m easurem ents to be taken of the effect of introducing the heterologous nucleic acid.
  • the method of the invention allows the identification of genes that are implicated in a specific disease or physiological condition.
  • the genes identified in this way are candidate targets for antagonists or agonists that m odulate disease states pertinent to that specialised cell type. This allows the development of selective agonists and antagonists, rather than broad spectrum agonists and antagonists. This approach thus adds value in the selective treatm ent of disease. Furtherm ore the identified genes are associated with regulatory elements that provide alternative and additional candidate targets for exploitation for the delivery of gene products to that cell in a cell-specific fashion.
  • genes and regulatory elements identified according to the method of the invention can be used directly in therapeutic applications via gene therapy, via recombinant protein m ethods or via chemical mimetics or as targets for the development of agonists and antagonists such as antibodies, small chemical m olecules, peptides, regulatory nucleic acids.
  • the step of comparison of the transcriptom es or proteomes of the first and second specialised cell types under first and second experimental conditions may be effected using any approach that allows the quantitative comparison of gene or protein expression, and a number of such means will be known to those of skill in the art.
  • experim ents have only becom e possible in recent years, due to certain advances in technology that have allowed the large scale, high throughput analysis of gene expression.
  • a m ethod that allow s the comparison of the transcriptome of a specific cell type with a second or subsequent transcriptom e involves the generation of a set of clones that represent all the transcripts expressed in a cell under the conditions in which the cell is m aintained. This m ay be done by constructing a cDNA library, in which copies of all mRNA transcripts expressed in the cell are cloned into a suitable vector for subsequent analysis.
  • Such libraries m ay be normalised cDNA libraries, in which the distribution of genes in the library has been biased to reduce the num ber of clones that represent genes with large num bers of transcripts (such as, for exam ple, beta-actin) and thus reduce the repetitive nature of the library.
  • Norm alisation thus acts to reduce the frequency of genes expressed at high levels and to enhance the frequency of genes expressed at low levels (see de Fatim a B onaldo et al, Genome Research 6: 791 -806 (1996)).
  • the comm ercially-available PCR Select kit (Clontech, Inc) is an example of a system useful to generate such libraries.
  • cDNA clones generated as reflective of the transcriptome of a specific cell type may then be amplified, and processed to evaluate the identity of the nucleic acid clones. For example, m ultiple clones m ay be picked and used as template for PCR amplification.
  • the PCR products may then be arrayed onto mem branes or glass slides to create nucleic acid arrays, For expression profiling, these arrays are then hybridised to complex nucleic acid probes in order to quantitate the abundance of individual genes contained in the probes.
  • a recent summ ary of nucleic acid array technology that is useful in the analysis of the transcriptom e of a cell population is provided in Nature Genetics, (1999) (21 suppl; 1 -61 ).
  • array technology There are various types of array technology currently used, including “microarrays”, or “chips”, which are high density cDNA arrays produced on glass slides, often produced using photolithography .
  • a second type of array is the "macroarray", w hich is an array with sub-m illimetre spot-spot distances produced on a nylon m em brane,
  • This type of array are the nylon-based m icroarrays sold comm ercially by Research Genetics Inc.
  • the transcriptom e of one specialised cell type under first experimental conditions is subtracted against the transcriptom e under second experimental conditions. This reveals the differences in expression under the two experimental conditions tested.
  • the differential regulation of gene expression under the two experim ental conditions is revealed.
  • the step of comparison is through the detection of genes that are differentially regulated in the two specialised cell types examined under the first and second experimental conditions.
  • a hum an cardiom yoblast (cell type A) and a human m acrophage (cell type B ) m ay be placed at the sam e temperature and at a high oxygen tension (first experimental conditions [1 ]), Cells from the same cell types are also incubated at this temperature, yet under conditions of low oxygen tension (second experim ental conditions [2]).
  • the m echanism of transcriptome comparison in the above example may be as follows. Subtracted cDNA libraries are separately prepared for hypoxic m acrophages and cardiom yoblasts; for both cell types, their cDNA under normoxic conditions is subtracted against their cDNA under hypoxic conditions. This might be effected by harvesting RNA from cells both in normoxia and hypoxia, and preparing cDNA . Subtractive hybridization, optionally including suppression PCR , may then be performed to rem ove genes from the hypoxic cell cDN A which are also present in cDNA from norm oxic cells. Insert DNA from these subtracted libraries can then be amplified and arrayed onto duplicate membranes.
  • Quantitative hybridization with pre-library cDNA m aterial then allows the comparison of differentially-expressed clones in the tw o cell types.
  • the clones representing hypoxia-inducible genes m ay be then be identified, for example, by sequencing.
  • M ethods such as these have been applied widely to study mechanism s of biological response.
  • m icroarrays have been used widely to com pare gene expression levels betw een norm al and diseased tissue.
  • comparisons are perform ed to detect changes in gene expression that are associated with specific aspects of disease progression or pathology. For instance, a study of prostate cancer would examine changes associated w ith the step-wise progression to full m alignancy or the dependence on androgens for growth.
  • Transcriptome analysis is complemented by the analysis of the complete protein make-up of a cell, referred to as proteom ics.
  • proteom ics The use of tw o dim ensional SD S-PA GE gels in combination with amino acid sequencing by m ass spectrometry is currently the m ost w idely-used technique in this field (see “Proteomics to study genes and genomes” Aviclesh Pandey and M atthias M ann, (2000), Nature 405 : 837- 846). Additionally, the recent developments in the field of protein and antibody arrays now allow the simultaneous detection of a large number of proteins.
  • low -density protein arrays on filter membranes such as the universal protein array system (Ge H, (2000) Nucleic Acids Res. 28(2), e3) allow im aging of arrayed antigens using standard ELISA techniques and a scanning charge-coupled device (CCD) detector.
  • Im muno-sensor arrays have also been developed that enable the simultaneous detection of clinical analytes. It is now possible using protein arrays, to profile protein expression in bodily fluids, such as in sera of healthy or diseased subjects, as well as in patients pre- and post-drug treatm ent.
  • Antibody arrays also facilitate the extensive parallel analysis of numerous proteins that are hypothetically implicated in a disease or particular physiological state. A number of methods for the preparation of antibody arrays have recently been reported (see Cahill, Trends in B iotechnology, 2000 7 :47-51 ). It is not the intention here to review studies that have been conducted in this area previously. However, one example of a physiological condition that has already received considerable attention is the response to hypoxia.
  • the present invention extends this work, and, indeed, defines a significant advance over sim ilar work that has been performed on the genetic mechanism s that act in response to other physiological or genetic stimuli.
  • the present inventors using the novel m ethods disclosed herein, have discovered that far from being generic, the cellular response to m any physiological conditions differs m arkedly betw een different cell types.
  • the cellular response that has been studied in order to illustrate this finding is the response to hypoxia. From these results, it has been inferred herein, quite reasonably, that far from being generic, cellular response mechanism s differ widely, depending on cell type,
  • an agent that is effective to prevent the drastic effects of hypoxia in a neurone (the effects of w hich include stroke) m ight be totally ineffective in countering the same effects in a cardiom yocyte (chronic ischemic heart disease).
  • a cardiom yocyte chronic ischemic heart disease
  • this w ould allow the design of a combined m edicament, for example, a com bined cardioprotective and neuroprotective agent. There thus rem ains a great need for the identification of proteins implicated in the physiological mechanism of hypoxia.
  • genes and proteins that are identified using a method according to any one of the above-described aspects of the invention.
  • Certain proteins whose sequences are identified herein as SEQ ID Nos: 1 , 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21 , 23, 25, 27, 29, 31 , 33 , 35, 37, 39, 41 , 43, 45, 47, 49, 51 , 53, 55 , 57, 59, 63, 67, 69, 73, 75, 77, 85 , 87, 89, 91 , 93 , 95, 99, 103 , 113 , 1 15, 1 19, 121 , 129, 131 , 133 , 137, 139, 141 , 145, 151 , 153, 157 , 159, 163 , 169, 181 , 187 , 201 , 205 , 207 and 209, are functionally annotated for the first time.
  • all of these sequences are functionally annotated for the first time.
  • the invention also includes proteins whose amino acid sequences are encoded by a nucleic acid sequence recited in various cDNAs and ESTs deposited in the public databases, or encoded by a gene identified from such an EST.
  • These cDNAs and ESTs are presented herein as SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186,
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67,
  • ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96
  • each of these sequences is generally labelled in the databases as a "hypothetical protein".
  • the methods of the present invention, described above, have now elucidated a biological function for these polypeptides, in that they have been found to be differentially regulated under physiological conditions of hypoxia.
  • polypeptides whose sequences are listed in SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 has been found to be hypoxia-regulated.
  • hypoxia hypoxia
  • other polypeptides have been found to be repressed.
  • hypoxia hypoxia
  • hypoxia-induced is meant that the polypeptide is expressed at a higher level when a cell is exposed to hypoxic conditions as compared to its expression level under normoxic conditions.
  • hypooxia-repressed is meant that the polypeptide is expressed at a lower level when a cell is exposed to hypoxic conditions as compared to its expression level under normoxic conditions.
  • polypeptides have been found to be hypoxia-induced: those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139 and 141; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118,
  • polypeptides have been found to be hypoxia-repressed: those polypeptides whose amino acid sequence is recited in SEQ ID Nos.: 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 1 88, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208,
  • hypoxic tissue should be taken to mean an environment of oxygen tension such that the oxygen content is betw een about 5 % and 0.1 % (v/v). In m ost cases, hypoxic tissue will have an oxygen content that is less than or equal to about 2% .
  • the term "normoxia” should be taken to mean conditions comprising a norm al level of oxygen for the environm ent concerned.
  • Norm oxic tissue typically has an oxygen content above about 5 %
  • sequences in this group fall into a num ber of different categories.
  • the first of these are cDNA clones, for which a protein sequence has not been predicted by the depositor.
  • a second category is expressed sequence tag (EST) sequences that are represented in the UniGene database (http://ww w .ncbi.nlm .nih.gov/UniGene/), which contain m odest or w eak hom ology to known proteins when translated.
  • ESTs are single-pass sequence files of the 5' region of an organism 's expressed genome as accessed via a force cloned cDNA library. EST sequences tend to be short and as a general rule are error-prone.
  • UniGene (see http://ww w .ncbi.nlm .nih.gov/W eb/New sltr/aug96.html for review) is an experimental system for autom atically partitioning these EST sequences into a non-redundant set of gene- oriented clusters.
  • Each UniGene cluster contains sequences that represent a unique gene, as well as related inform ation such as the tissue types in which the gene has been expressed and m ap location.
  • a third category of hits identified by the methods described herein is EST sequences that are contained in Unigene clusters, but w hich are not annotated and exhibit no hom ologies to proteins contained in the public databases.
  • the fourth and final category encompasses singleton EST sequence entries that are not incorporated as entries in the Unigene database and that only appear as single entries in the public databases.
  • the m ethods of the present invention, described above, have now elucidated a biological function for polypeptides that are encoded by genes incorporating cDNA and EST sequences that fall into the four categories set out above, in that these sequences have been found to be differentially regulated under physiological conditions of hypoxia.
  • Such polypeptides m ay have an am ino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 , 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 112, 1 14, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138 , 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198 , 200, 202, 204, 206, 208 , 210
  • this aspect of the invention also includes polypeptides that are encoded by a gene identified from an EST recited in any one of SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 , 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 18
  • Polypeptides of this aspect of the invention are intended to include fragm ents of polypeptides according to i) or ii) as defined above, provided that the fragment retains a biological activity that is possessed by the full length polypeptide of i) or ii), or has an antigenic determ inant in com m on with the polypeptide of i) or ii).
  • fragment refers to a polypeptide having an amino acid sequence that is the same as part, but not all, of an amino acid sequence as recited in any one of SEQ ID Nos: 1 , 3 , 5, 7, 9, 1 1 , 13 , 15 , 17, 19, 21 , 23, 25 , 27, 29, 31 , 33, 35, 37, 39, 41 , 43, 45, 47, 49, 51 , 53, 55, 57, 59, 63, 67, 69, 73 , 75, 77, 85, 87, 89, 91 , 93 , 95, 99, 103 , 1 13 , 1 15 , 1 19, 121 , 129, 131 , 133 , 137, 139, 141 , 145, 151 , 153, 157, 159, 163, 169, 181 , 187, 201 , 205, 207 and 209, an am ino acid sequence that is encoded by a nucleic
  • the fragm ents should comprise at least n consecutive amino acids from the sequence and, depending on the particular sequence, n preferably is 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more). Sm all fragm ents may form an antigenic determ inant.
  • Such fragm ents m ay be isolated fragments, that are not part of or fused to other amino acids or polypeptides, or they m ay be comprised within a larger polypeptide, of which they form a part or region.
  • W hen comprised within a larger polypeptide a fragment of the invention m ost preferably form s a single continuous region.
  • certain preferred embodiments relate to a fragm ent having a pre - and/or pro- polypeptide region fused to the am ino term inus of the fragment and/or an additional region fused to the carboxyl term inus of the fragment.
  • several fragm ents m ay be comprised within a single larger polypeptide.
  • polypeptides of the present invention or their immunogenic fragments can be used to generate ligands, such as polyclonal or m onoclonal antibodies, that are im munospecific for the polypeptides.
  • ligands such as polyclonal or m onoclonal antibodies
  • Such antibodies m ay be employed to isolate or to identify clones that express a polypeptide according to the invention or, for example, to purify the polypeptide by affinity chromatography.
  • Such antibodies m ay also be employed as diagnostic or therapeutic aids, am ongst other applications, as will be apparent to the skilled reader.
  • immunospecific m e ans that an antibody has substantially greater affinity for a polypeptide according to the invention than their affinity for related polypeptides.
  • antibody is intended to include intact m olecules as well as fragments thereof, such as Fab, F(ab') 2 and scFv, which are capable of binding to the antigenic determinant in question,
  • the invention also includes functional equivalents of a polypeptide of i), ii) or (iii) as recited above,
  • a functionally-equivalent polypeptide according to this aspect of the invention m ay be a polypeptides that is hom ologous to a polypeptide w hose sequence is explicitly recited herein.
  • Two polypeptides are said to be "hom ologous” if the sequence of one of the polypeptides has a high enough degree of identity or sim ilarity to the sequence of the other polypeptide for the skilled person to determ ine that they are similar in origin and function.
  • homology is used to refer to sequence identity.
  • the B LAST algorithm is described in detail at http://ww w .ncbi.nih.gov/B LAST/blast_help.html, which is incorporated herein by reference.
  • the search parameters are defined as follows, and are advantageously set to the defined default param eters.
  • substantially homology w hen assessed by B LAST equates to sequences which match w ith an EXPECT value of at least about 7, preferably at least about 9 and most preferably 10 or more.
  • the default threshold for EXPECT in B LAST searching is usually 10.
  • BLAST B asic Local Alignment Search Tool
  • blastp, blastn, blastx, tblastn, and tblastx these programs ascribe significance to their findings using the statistical methods of Karlin and Altschul (see http://www.ncbi.nih.gov/BLAST/blast_help.html) with a few enhancements.
  • BLAST programs were tailored for sequence similarity searching, for example to identify homologues to a query sequence.
  • the programs are not generally useful for motif-style searching.
  • blastp compares an amino acid query sequence against a protein sequence database
  • blastn compares a nucleotide query sequence against a nucleotide sequence database
  • blastx compares the six-frame conceptual translation products of a nucleotide query sequence (both strands) against a protein sequence database
  • tblastn compares a protein query sequence against a nucleotide sequence database dynamically translated in all six reading frames (both strands).
  • tblastx compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database.
  • BLAST uses the following search parameters:
  • HISTOGRAM Display a histogram of scores for each search; default is yes. (See parameter H in the BLAST M tract). DESCRIPTIONS Restricts the number of short descriptions of matching sequences reported to the number specified; default limit is 100 descriptions. (See parameter V in the manual page). See also EXPECT and CUTOFF.
  • ALIGNMENTS Restricts database sequences to the number specified for which high-scoring segment pairs (HSPs) are reported; the default limit is 50. If more database sequences than this happen to satisfy the statistical significance threshold for reporting (see EXPECT and CUTOFF below), only the matches ascribed the greatest statistical significance are reported. (See parameter B in the BLAST M tract).
  • EXPECT The statistical significance threshold for reporting matches against database sequences; the default value is 10, such that 10 m atches are expected to be found merely by chance, according to the stochastic model of Karlin and Altschul (1990). If the statistical significance ascribed to a match is greater than the EXPECT threshold, the match will not be reported. Lower EXPECT thresholds are more stringent, leading to fewer chance matches being reported. Fractional values are acceptable. (See parameter E in the BLAST Manual).
  • CUTOFF Cutoff score for reporting high-scoring segment pairs.
  • the default value is calculated from the EXPECT value (see above).
  • HSPs are reported for a database sequence only if the statistical significance ascribed to them is at least as high as would be ascribed to a lone HSP having a score equal to the CUTOFF value. Higher CUTOFF values are more stringent, leading to fewer chance matches being reported. (See parameter S in the BLAST Manual). Typically, significance thresholds can be more intuitively managed using EXPECT.
  • MATRIX Specify an alternate scoring matrix for BLASTP, BLASTX, TBLASTN and TBLASTX.
  • the default matrix is BLOSUM 62 (Henikoff & Henikoff, 1992).
  • the valid alternative choices include: PAM40, PAM 120, PAM250 and IDENTITY.
  • No alternate scoring matrices are available for BLASTN; specifying the M ATRIX directive in BLASTN requests returns an error response.
  • STRAND Restrict a TBLASTN search to just the top or bottom strand of the database sequences; or restrict a BLASTN, BLASTX or TBLASTX search to just reading frames on the top or bottom strand of the query sequence.
  • FILTER M ask off segm ents of the query sequence that have low compositional complexity, as determined by the SEG program of Wootton & Federhen (1993) Computers and Chemistry 17:149-163, or segments consisting of short-periodicity internal repeats, as determined by the XNU program of Claverie & States (1993) Computers and Chemistry 17:191 -201 , or, for BLASTN, by the DUST program of Tatusov and Lipman (see http://www.ncbi.nlm.nih.gov). Filtering can eliminate statistically significant but biologically uninteresting reports from the blast output (e.g., hits against common acidic-, basic- or proline-rich regions), leaving the more biologically interesting regions of the query sequence available for specific matching against database sequences.
  • Filtering can eliminate statistically significant but biologically uninteresting reports from the blast output (e.g., hits against common acidic-, basic- or proline-rich regions), leaving the more biologically interesting regions of the query sequence
  • Filtering is only applied to the query sequence (or its translation products), not to database sequences. Default filtering is DUST for BLASTN, SEG for other programs.
  • NCB I-gi causes NCB I gi identifiers to be shown in the output, in addition to the accession and/or locus name.
  • sequence comparisons are conducted using the sim ple B LAST search algorithm provided at http://w w w .ncbi.nlm ,nih,gov/B LAST.
  • sequence hom ology m ay be determined by algorithm s such as FastA , available at http://biology.ncsa.uiuc.edu/B W 30/B W .cgi.
  • FastA is considered to be superior to B LA ST for alignment of short sequences
  • the FastA algorithm is employed using default param eters at http://biology.ncsa.uiuc,edu/B W 30/BW ,cgi.
  • polypeptide sequence specifically identified herein, or with a fragment thereof, of greater than 50% .
  • M ore preferred polypeptides have degrees of identity of greater than 60% , 70% , 80% , 90% , 95% , 98 % or 99% , respectively.
  • Functionally-equivalent polypeptides according to the invention are therefore intended to include natural biological variants (for example, allelic variants or geographical variations within the species from w hich the polypeptides are derived) and mutants (such as mutants containing amino acid substitutions, insertions or deletions) of the polypeptides whose sequences are explicitly recited herein.
  • mutants m ay include polypeptides in which one or m ore of the amino acid residues are substituted with a conserved or non- conserved am ino acid residue (preferably a conserved amino acid residue) and such substituted am ino acid residue may or m ay not be one encoded by the genetic code.
  • Typical such substitutions are among Ala, Val, Leu and He; am ong Ser and Thr; am ong the acidic residues Asp and Glu; among A sn and Gin; among the basic residues Lys and Arg; or am ong the arom atic residues Phe and Tyr.
  • Particularly preferred are variants in which several, i.e. between 5 and 10, 1 and 5, 1 and 3, 1 and 2 or just 1 amino acids are substituted, deleted or added in any combination.
  • silent substitutions, additions and deletions which do not alter the properties and activities of the protein. Also especially preferred in this regard are conservative substitutions.
  • "M utant" polypeptides also include polypeptides in which one or more of the amino acid residues include a substituent group.
  • m ost surprisingly that the response to hypoxia differs between different specialised cell types or between different physiological states of the same cell type. For example, it has been found that in m acrophage cells, different polypeptides are induced/repressed during different physiological states. Furtherm ore, it has been found that a subset of this group of polypeptides are regulated only in activated m acrophage cells. M acrophages possess various biological activities, including cytotoxic effects towards tum our cells and phagocytosis of bacteria or cellular debris.
  • nucleic acid m olecule that encodes a polypeptide according to any one of the aspects of the invention discussed above.
  • nucleic acid m olecule m ay consist of the nucleic acid sequence as recited in any one of SEQ ID Nos.
  • an expression vector that contains a purified and isolated nucleic acid m olecule according to the aspects of the invention described above,
  • the invention also incorporates a delivery vehicle, such as a liposome, comprising a nucleic acid according to the above-described aspects of the invention,
  • the invention provides a host cell transformed with a vector of the above-described aspect of the invention.
  • the invention provides a ligand that binds specifically to a polypeptide according to the above-described aspects of the invention.
  • the ligand may be an antagonist ligand that inhibits the biological activity of the polypeptide, or may be an agonist ligand that activates the hypoxia-induced activity of the polypeptide to augment or potentiate a hypoxia-induced activity.
  • a ligand which binds specifically to, and which preferably inhibits the hypoxia-induced activity of, a polypeptide according to any one of the above- described aspects of the invention.
  • a ligand may, for example, be an antibody that is immunospecific for the polypeptide in question.
  • the invention provides a polypeptide, a nucleic acid molecule, vector or ligand as described above, for use in therapy or diagnosis of a disease or abnormal physiological condition.
  • the disease or abnormal physiological condition that is affected by hypoxia; examples of such diseases include cancer, ischaemic conditions (such as stroke, coronary arterial disease, peripheral arterial disease), reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions (including rheumatoid arthritis), hair loss and wound healing.
  • the undesired celluar process involved in said diseases might include, but is not restricted to; tumorigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
  • the undesired biochemical processes involved in said cellular processes might include, but is not restricted to, glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport or nitric oxide synthesis.
  • proteins have also been implicated in the biological response to hypoxia.
  • the functions of these proteins are known, meaning that these functions have been annotated in the public databases.
  • the sequences of these proteins are presented in SEQ ID Nos.: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 63
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9,
  • iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii); for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
  • the invention also provides a purified and isolated nucleic acid molecule that encodes a polypeptide according to this aspect of the invention, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
  • sequences of these molecules are provided in SEQ ID Nos.: 218, 220, 222, 224, 226, 228, 230, 232 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400 402, 404, 406, 408, 410, 412, 4
  • this aspect of the invention includes redundant equivalents and fragm ents of the sequences explicitly recited in SEQ ID Nos.: 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384
  • This aspect of the invention also includes ligands which bind specifically to, and which preferably inhibit the hypoxia-induced activity of, a polypeptide listed in SEQ ID Nos.: 217, 219, 221 , 223, 225, 227, 229, 231 , 233 , 235, 237, 239, 241 , 243 , 245 , 247, 249, 251 , 253, 255 , 257, 259, 261 , 263 , 265, 267, 269, 271 , 273, 275, 277, 279, 281 , 283 , 285 , 287, 289, 291 , 293 , 295, 297, 299, 301 , 303 , 305, 307, 309, 31 1 , 313 , 315, 317, 319, 321 , 323 , 325 , 327, 329, 331 , 333 , 335 , 337, 339, 341
  • the invention also provides a pharm aceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a a polypeptide, a nucleic acid m olecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable carrier.
  • the invention also provides a vaccine composition comprising a polypeptide, or a nucleic acid molecule as described above.
  • the invention also provides a method of treating a disease in a patient in need of such treatment by adm inistering to a patient a therapeutically effective amount of a polypeptide, a nucleic acid m olecule, vector, ligand or pharmaceutical composition as described above.
  • a polypeptide a nucleic acid m olecule, vector, ligand or pharmaceutical composition as described above.
  • the polypeptide, nucleic acid molecule, ligand, compound or composition administered to the patient should be an agonist.
  • the polypeptide, nucleic acid m olecule, vector, ligand, compound or composition adm inistered to the patient is an antagonist.
  • the term "agonist" is meant herein, any polypeptide, peptide, synthetic m olecule or organic m olecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzym atic activity.
  • the term "antagonist" is m eant herein, any polypeptide, peptide, synthetic molecule or organic m olecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharm acological receptor.
  • the invention also provides for the use of a polypeptide, nucleic acid molecule, vector, ligand or pharm aceutical composition according to any one of the above-described aspects of the invention in modifying the response of a cell to conditions of hypoxia.
  • the invention also provides a polypeptide, nucleic acid m olecule, vector, ligand or pharm aceutical composition according to any one of the above-described aspects of the invention, for use in the m anufacture of a medicament for the treatm ent of a hypoxia-regulated condition.
  • the invention also provides a m ethod of monitoring the therapeutic treatment of disease or physiological condition in a patient, comprising m onitoring over a period of time the level of expression or activity of polypeptide, nucleic acid m olecule, vector or ligand in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease or physiological condition.
  • the invention also provides a method of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by adm inistering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or m ore of the nucleic acid molecules as described above.
  • the invention also provides a method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of the aspects of the invention described above in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition.
  • Such a method of diagnosis may be carried out in vitro.
  • a suitable method comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
  • a further example of a suitable method m ay comprises the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid m olecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 , 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98 , 100, 102, 104
  • a still further example of a suitable method may comprise the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid prim er under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid m olecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 , 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144
  • a still further example of a suitable method m ay comprised the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of the above-described aspects of the invention from said tissue sample; and c) diagnosing the patient for the hypoxia-related condition by detecting the presence of a m utation which is associated w ith the hypoxia-related condition in the nucleic acid m olecule as an indication of the hypoxia-related condition.
  • This method may comprise the additional step of amplifying the nucleic acid m olecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
  • hypoxia-related conditions that may be diagnosed in this fashion include cancer, ischaemia, reperfusion, retinopathy, neonatal stress, preeclapm sia, atherosclerosis, rheum atoid arthritis, undesired hair loss, cardiac arrest or stroke, for example, caused by a disorder of the cerebral, coronary or peripheral circulation.
  • the invention provides a m ethod for the identification of a compound that is effective in the treatment and/or diagnosis of a hypoxia-regulated condition, comprising contacting a polypeptide, nucleic acid m olecule, or ligand according to any one of the above-described aspects of the invention with one or more compounds suspected of possessing binding affinity for said polypeptide, nucleic acid molecule or ligand, and selecting a compound that binds specifically to said nucleic acid m olecule, polypeptide or ligand.
  • a kit useful for diagnosing a hypoxia-regulated condition comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of the aspects of the invention described above; a second container containing primers useful for amplifying said nucleic acid m olecule; and instructions for using the probe and primers for facilitating the diagnosis of the hypoxia-regulated condition.
  • the kit may additionally comprise a third container holding an agent for digesting unhybridised RNA ,
  • the invention provides an array of at least tw o nucleic acid m olecules, wherein each of said nucleic acid m olecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of the aspects of the invention described above.
  • Such an array may contain nucleic acid m olecules that either correspond to the sequence of, are complem entary to the sequence of, or hybridise specifically to at least 2, 3 , 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 92a, 93, 94, 95,96,97,98,99, 100, 101,102
  • the nucleic acid molecules on the array may consist of oligonucleotides of between twelve and fifty nucleotides, more preferably, between forty and fifty nucleotides.
  • the nucleic acid molecules on the array may consist of PCR-amplified cDNA inserts where the nucleic acid molecule is between 300-2000 nucleotides.
  • the invention provides an array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia-regulated condition as described above.
  • the invention also provides an array of polypeptides, comprising at least two polypeptide species as recited above, wherein each polypeptide species is implicated in a hypoxia-regulated condition, or is a functional equivalent variant or fragment thereof.
  • Kits useful in the diagnostic methods of the invention may comprise such nucleic acid, antibody and/or polypeptide arrays.
  • a kit may also comprise one or more antibodies that bind to a polypeptide as recited above, and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide.
  • a genetically-modified non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of the aspects of the invention described above,
  • said genetically-modified animal is a transgenic or knockout animal.
  • the invention also provides a method for screening for a compound effective to treat a hypoxia-regulated condition, by contacting a non-hum an genetically-m odified anim al as described above with a candidate compound and determ ining the effect of the compound on the physiological state of the animal.
  • ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels.
  • m yocardial ischaemia encompasses several chronic and acute cardiac pathologies that involve the deprivation of the m yocardium of its blood supply, usually through coronary artery occlusion.
  • a key component of ischaemia is hypoxia. Following transient ischaemia, the affected tissue m ay be subjected to reperfusion and re-oxygenation, and this is of significance in its own right.
  • Ischaemia/reperfusion is well known to induce cell death in m yocardial tissue by apoptosis, leading to impaired function of the myocardium and infarction.
  • M any of the specific m olecules required to execute the process of apoptosis are known, but not all of these m olecules have been characterised in detail.
  • Cell death may also proceed by a distinct process called necrosis, which unlike apoptosis, is not initiated and controlled by specific and dedicated cellular and biochemical mechanism s (see Nicotera et al, B iochem Soc Symp. 1999; 66 :69-73).
  • w hich are responsible for m ediating apoptosis, specifically in ischaem ic m yocardial cells.
  • One target w hich plays a comm on role in mediating apoptosis in m any cell types, namely p53 , is not involved in apoptosis resulting from m yocardial ischaemia (Bialik et al, J Clin Invest. 1997 ; 100(6): 1363-72).
  • A53770 (151) ⁇ GIWGDC ERWQLHYNGALRDGQLAGPMG ⁇ SERH RQDOITWIG ⁇ l ' BAB15101 (35) GEWGDC E QLHC pALRDGQIAGPRAGVSKRHLRGDQITWlGG ⁇
  • E ⁇ CE- IMST& ⁇ BAB15101 (85) EEGCEA1 SFLLSLIDR V YCGSRLG ⁇ CY YVEERSKAMVAGYPGHGTGYVR
  • A53770 (351) ALAKEJ BAB15101 (235) A TED
  • the high degree of amino acid similarity suggests that the hum an protein B AB 15101 has an equivalent biochemical function to the rat protein A53770 ("Growth factor responsive smooth m uscle protein" or "SM20").
  • SM20 functions to promote apoptosis in neurons (Lipscom b et al, J Neurochem 1999; 73(l ):429-32; Lipsco b et al, J Biol Chem 2000 Nov 1 ; [epub ahead of print]).
  • SM 20 has been shown to be expressed at high levels in the heart (W ax et al. J Biol Chem 1994; 269(17): 13041 -7).
  • This gene was identified using Research Genetics Hum an GeneFilters arrays, which contain an EST corresponding to the gene (accession number H56028).
  • a fragm ent of this gene has been cloned from a cDNA library derived from hypoxic hum an cardiom yoblasts, and it has been shown that the gene is increased in expression in response to hypoxia in this cell type (see Table 1 herein ; penultimate row).
  • the nucleotide sequence of this cDNA fragm ent is referred to herein as SEQ ID No 90a.
  • the therapeutic modulation of the activity of EGLN3 (B AB 15101 ), c l orfl 2 (AAG34568), CAB 81622, SM 20 and other equivalent proteins and encoding genes therefore provides a novel means for the treatm ent of m yocardial ischaem ia, through the alteration of the propensity of m yocardial cells to undergo apoptosis.
  • a suitable treatm ent may involve altering the susceptibility of ischaem ic myocardial tissue to subsequent reperfusion and re-oxygenation, or m ay involve m odulating the susceptibility of chronic ischaemic myocardial tissue (including forms of angina) to later m ore severe ischaem ia, w hich would result in m yocardial infarction. It is submitted that, by w ay of analogy, cerebral ischaem ia m ay be treated using the same principle.
  • proline hydroxylases For example, two genes encoding proline hydroxylases have been identified herein as being increased in expression in response to hypoxia (proline 4-hydroxylase, alpha polypeptide 1 ; SeqID : 231/232, proline 4-hydroxylase, alpha polypeptide II; SeqID : 349/ 350). This identified a functional significance of proline hydroxylation as a response to hypoxia, A preferred embodim ent of the invention thus includes methods for modulating the biological response to hypoxia by modulating the proline hydroxylase activity of the EGLN3 (B AB 15101 ), cl orfl 2 (AAG34568), CAB 81622 and SM 20 proteins.
  • any bacteria contain, w ithin their genom e, genes encoding proteins that share homology to the EGLN family of prolyl hydroxylases.
  • these bacterial genes m ay initiate a hypoxic like response at the site of infection thereby causing localised inflamm ation.
  • the resulting inflam m atory infiltrate could then cause the tissue to become hypoxic thereby continuing the cycle of hypoxia response.
  • fragments and functional equivalents of the EGLN 3 (BAB 15101 ), cl orfl 2 (AAG34568), CAB 81622, SM 20 and other equivalent proteins are included within the present invention, in addition to ligands that bind specifically to these proteins.
  • the invention also em braces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid m olecules and host cells transformed with these vectors.
  • sm all molecule inhibitors of the EGLN 3 (B AB 15101 ), c l orfl 2 (AAG34568), CAB 81622, SM 20 and equivalent proteins and encoding genes are envisaged for utility as pharmaceutical agents, particularly in m odulating the proline hydroxylase activity of the EGLN3 and cl orfl 2 proteins.
  • Truncated or chimeric inhibitory derivatives of the encoding genes, or distinct genes that encode regulators of the B AB 15101 , A AG34568 , CAB 81622 and SM 20 encoding genes, are also envisaged for utility for gene therapy.
  • A53770 AAG34568 (1) MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQD Consensus (1)
  • A53770 (41 GGRITLHYSCRSQSGTPFSSEFQATFPAFAAKVARGPWLPQWEPPAR— - AAG34568 (101 DNA'SGDAJAKGKV AKPPADPAAAASPCRAAAGGQGSAVAAEAEPGKE ⁇ PP
  • A53770 (138 bLHEVGFCYLDNFLGE ⁇ AGDCVLERy'KQLI ⁇ YNGALRCGQ AGPRAGVSKR AAG34568 (201 Cr ⁇ roi ⁇ dDFLGKETGQQIGpEpR jHDTGKFTl)GQIjVSQKS--DSSp
  • A53770 (188 HLRGDQilTWIGGNEEGCEAfrNFJLLSLIDRLVLYCGSR ⁇ GKYYVKEp.s'KAM AAG34568 (250 D ⁇ RGDK T IEGKEPGCETiGLtMSStoDLlRHCNGKLGSYKlNG ⁇ TKAM
  • A53770 (238 ACYPGHGTGi ⁇ HVDKPNGDGRClKIYYLNiaI
  • A53770 (338 SKEFR LTRKTESAJLAKD AAG34568 (400 OTYLTGEKGTOVE ⁇ NKPSDSVGKDVF
  • the invention also provides a substantially purified polypeptide comprising the consensus sequence: KAJWACYPGNGTGYVR ⁇ TVDNPNGDGRCITCIYYL NWDAKLHGGILRIFPEGKSFIADVEPIFDRLLFF SDRRNPHEVQPSYATRYAMTV YFDAEERAEAK , or a variant thereof, in the treatment or diagnosis of a hypoxia-related disease or condition.
  • variant is m eant a variation of the consensus sequence given above, that exhibits a degree of hom ology with the consensus sequence above a certain threshold level of identity or sim ilarity, Degrees of identity and similarity can be readily calculated according to methods known in the art (see, for example, Computational Molecular B iology, Lesk, A .M ., ed using Oxford University Press, New York, 1988; B iocomputing. Informatics and Genom e Projects, Smith, D .W ., ed., Academ ic Press, New York, 1993). Typically, greater than 50% identity between two sequences is considered to be an indication of functional equivalence.
  • a variant consensus according to this aspect of the invention exhibits a degree of sequence identity with the consensus sequence given above, of greater than 50% .
  • M ore preferred polypeptides have degrees of identity of greater than 60% , 70% , 80% , 90% , 95 % , 98 % or 99% , respectively.
  • fragm ents and functional equivalents of these proteins are included within the present invention, in addition to ligands that bind specifically to these proteins.
  • the invention also em braces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid m olecules and host cells transformed with these vectors.
  • the therapeutic and diagnostic applications discussed above are also equally relevant to this aspect of the invention.
  • the polypeptide referred to above as that encoded by SEQ ID No 91 is a specific protein that is termed "Sem aphorin 4b" .
  • the gene encoding this protein is regulated (activated) by conditions of hypoxia.
  • the Sem aphorin 4b protein is encoded by a gene identified from the EST recited in SEQ ID N o 92.
  • the unequivocal and accurate full length cDNA sequence is provided herein as SEQ ID No 92a.
  • the accurate presumptive amino acid sequence is provided herein as SEQ ID No 91 .
  • This protein, functionally- equivalent variants of this protein, the encoding nucleic acid m olecules and ligands that regulate the activity and/or expression of this gene and protein are claimed above in the context of their role in hypoxia and hypoxia-related disorders.
  • Sem aphorins are a large family of proteins, characterised by the 500 am ino acid sema dom ain (Puschel et al., 1995, Neuron, 14(5): 941 -8; Tam agnone and Com oglio, 2000, Trends Cell Biol., 10(9): 377-83). Early work showed a role in the guidance of axons during brain development, and the regulation of cell migration.
  • Sem aphorin 4b protein which is unpublished and until now has not been assigned a full and accurate amino acid sequence.
  • W e have m ade experim ental discoveries which link the expression of Sem aphorin 4b to factors (hypoxia, gamma IFN and superoxide radicals) that are associated w ith a variety of human ischaemic and inflammatory diseases.
  • a key response of cells to hypoxia is to stim ulate angiogenesis, and a key part of inflamm ation is the recruitment and trafficking of im m une cells.
  • Sem aphorin 4b is a regulator of these cellular functions, and thus provides a novel target for therapeutic intervention . This paves the way for the developm ent of therapeutic agents that either potentiate or antagonise functions of Semaphorin 4b. Such agents are likely to be highly valuable in the treatment of hum an disease.
  • polypeptide refers to a chain (may be branched or unbranched) of two or more amino acids linked to each other by means of a peptide bond or modified peptide bond (isosteres),
  • polypeptide encompasses but is not limited to oligopeptides, peptides and proteins.
  • the polypeptide of the invention may additionally be either in a mature protein form or in a pre-, pro- or prepro-protein form that requires subsequent cleavage for formation of the active mature protein.
  • the pre-, pro-, prepro- part of the protein is often a leader or secretory sequence but may also be an additional sequence added to aid protein purification (for example, a His tag) or to conform a higher stability to the protein.
  • a polypeptide according to the invention may also include modified amino acids, that is, amino acids other than those 20 that are gene-encoded. This modification may be a result of natural processes such as post-translational processing or by chemical modification.
  • modifications include acetylation, acylation, amidation, ADP-ribosylation, arginylation, attachment of a lipid derivative or phosphatidylinositol, ⁇ -carboxylation, covalent attachment of a flavin or haeme moiety, a nucleotide or nucleotide derivative, cyclisation, demethylation, disulphide bond formation, formation of covalent crosslinks, formylation, glycosylation, GPI anchor formation, hydroxylation, iodination, lipid attachment, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemisation, selenoylation, sulphation, and ubiquitination.
  • M odification of the polypeptide can occur anywhere within the molecule including the backbone, the amino acid side-chains or at the N- or C- terminals,
  • a polypeptide according to the invention may either be isolated from natural sources (for example, purified from cell culture), or be a recombinantly produced polypeptide, or a synthetically produced polypeptide or a combination of all the above.
  • a polypeptide according to the invention, its functional equivalents and/or any immunogenic fragments derived from the polypeptide may be used to generate ligands including immunospecific monoclonal or polyclonal antibodies, or antibody fragments. These antibodies can then be used to isolate or identify clones expressing the polypeptide of the invention or to purify the polypeptide by affinity chrom atography. Further uses of these immunospecific antibodies m ay include, but are not limited to, diagnostic, therapeutic or general assay applications. Examples of assay techniques that employ antibodies are im m unoassays, radioim munoassays (RIA) or enzym e linked imm unosorbent assay (ELISA). In these cases, the antibodies m ay be labelled with an analytically-detectable reagent including radioisotopes, a fluorescent m olecule or any reporter molecule.
  • RIA radioim munoassays
  • ELISA enzym e linked imm unosorbent assay
  • im munospecific refers to antibodies that have a substantially higher affinity for a polypeptide of this invention compared with other polypeptides.
  • antibody refers to a m olecule that is produced by anim als in response to an antigen and has the particular property of interacting specifically with the antigenic determinant that induced its form ation. Fragm ents of the aforem entioned m olecule such as Fab, F(ab') 2 and scFv, which are capable of binding the antigen determinant, are also included in the term “antibody” .
  • Antibodies may also be modified to make chimeric antibodies, where non-hum an variable regions are joined or fused to human constant regions (for example, Liu et al, PNAS, USA, 84, 3439 (1987)). Particularly, antibodies may be modified to make them less im m unogenic to an individual in a process such as hum anisation (see, for example, Jones et al, Nature, 321 , 522 (1986); Verhoeyen et al, Science, 239, 1534 (1988); Kabat et al, J.
  • hum anisation see, for example, Jones et al, Nature, 321 , 522 (1986); Verhoeyen et al, Science, 239, 1534 (1988); Kabat et al, J.
  • humanised antibody refers to antibody m olecules in which the am ino acids of the CDR (com plementarity-determining region) and selected other regions in the variable dom ains of the heavy and/or light chains of a non-hum an donor antibody have been substituted with the equivalent amino acids of a human antibody, The humanised antibody therefore closely resembles a hum an antibody, but has the binding ability of the donor antibody.
  • Antibodies may also have a "bispecific" nature, that is, the antibody has two different antigen binding domains, each dom ain being directed against a different epitope.
  • Com m on anim als used for the production of antibodies include the m ouse, rat, chicken, rabbit, goat and horse.
  • the polypeptide used to immuno-challenge the animal may be derived by recombinant DNA technology or may be chem ically-synthesised.
  • the polypeptide may be conjugated to a carrier protein.
  • Com m only used carriers to which the polypeptides may be conjugated include, but are not lim ited to B SA (bovine serum albumin), thyroglobulin and keyhole limpet haem ocyanin. Serum from the im muno-challenged anim al is collected and treated according to known procedures, for example, by immunoaffinity chrom atography.
  • Specific monoclonal antibodies can generally be made by methods known to one skilled in the art (see for example, Kohler, G . and M ilstein, C, Nature 256, 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, 77 -96 in M onoclonal Antibodies and Cancer Therapy, Alan R . Liss, Inc. (1985) and Roitt, I. et al, Im munology, 25.10, M osby-Year B ook Europe Limited (1993)), Panels of m onoclonal antibodies produced against the polypeptides of the invention can be screened for various properties, i.e., for isotype, epitope, affinity, etc. against which they are directed. Alternatively, genes encoding the m onoclonal antibodies of interest m ay be isolated from hybridom as, for instance using PCR techniques known in the art, and cloned and expressed in appropriate vectors.
  • the polypeptides of the invention m ay also be used to search for interacting ligands.
  • M ethods for doing this include the screening of a library of compounds (see Coligan et al, Current Protocols in Immunology 1 (2); Chapter 5 (1991 ), isolating the ligands from cells, isolating the ligands from a cell-free preparation or natural product mixtures.
  • Ligands to the polypeptide may activate (agonise) or inhibit (antagonise) its activity.
  • compounds m ay affect the levels of the polypeptide present in the cell, including affecting gene expression, mRNA stability and the degree of post-translational modification of the encoded protein.
  • the invention thus em braces m ethods for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a polypeptide, a nucleic acid molecule or host cell according to any one of the embodiments of the invention described herein with one or m ore compounds suspected of possessing binding affinity for said polypeptide or nucleic acid m olecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide, or that affects the level of gene expression, mRNA stability or the degree of post-translational modification of the encoded protein.
  • Ligands to the polypeptide form a further aspect of the invention, as discussed in more detail above.
  • Preferred "antagonist” ligands include those that bind to the polypeptide of this invention and strongly inhibit any activity of the polypeptide.
  • Preferred "agonist” ligands include those that bind to the polypeptide and strongly induce activity of the polypeptide of this invention or increases substantially the level of the polypeptide in the cell.
  • the term "agonist” is meant to include any polypeptide, peptide, synthetic m olecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity .
  • antagonist is m eant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharmacological receptor.
  • Ligands to a polypeptide according to the invention may come in various forms, including natural or modified substrates, enzymes, receptors, small organic molecules such as small natural or synthetic organic molecules of up to 2000Da, preferably 800Da or less, peptidomimetics, inorganic molecules, peptides, polypeptides, antibodies, structural or functional mimetics of the aforementioned.
  • Preferred nucleic acid molecules of the invention are those which encode the polypeptide sequences recited in any one of SEQ ID Nos.1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43,45,47,49,51,53,55,57,59,63,67,69,73,75,77,85,87,89,91,93,95,99,103,113,115,119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209.
  • nucleic acid molecules examples include those listed in SEQ ID Nos.2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196,
  • a nucleic acid molecule according to this aspect of the invention may be in the form of RNA, such as mRNA, DNA, such as cDNA, synthetic DNA or genomic DNA.
  • the nucleic acid molecule may be double-stranded or single-stranded.
  • the single-stranded form may be the coding (sense) strand or the non- coding (antisense) strand.
  • a nucleic acid molecule may also comprise an analogue of DNA or RNA, including, but not limited to modifications made to the backbone of the molecule, such as, for example, a peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • PNA refers to an antisense molecule that comprises an oligonucleotide of at least five nucleotides in length linked to a peptide backbone of amino acid residues, preferably ending in lysine. The terminal lysine confers solubility to the composition. PNAs may be pegylated to extend their lifespan in a cell, where they preferentially bind complementary single- stranded DNA and RNA and stop transcript elongation (Nielsen, P.E, et al. (1993) Anticancer Drug Des. 8:53-63).
  • a nucleic acid m olecule according to this aspect of the invention can be isolated by cloning, purification or separation of the molecule directly from a particular organism , or from a library, such as a genomic or cDNA library.
  • the m olecule m ay also be synthesised, for example, using chemical synthetic techniques such as solid phase phosphoramidite chem ical synthesis.
  • RNA m ay be synthesized in vitro or in vivo by transcription of the relevant DNA molecule,
  • nucleic acid molecules included in this aspect of the invention include any m olecule comprising a variant of the sequence explicitly recited.
  • variants m include variant nucleic acid m olecules that code for the same polypeptide (or mature polypeptide) as that explicitly identified, that code for a fragment of the polypeptide, that code for a functional equivalent of the polypeptide or that code for a fragment of the functional equivalent of the polypeptide.
  • variant nucleic acid molecules that are derived from nucleotide substitutions, deletions, rearrangem ents or insertions or multiple combinations of the aforem entioned.
  • Such m olecules m ay be naturally occurring variants, such as allelic variants, non-naturally occurring variants such as those created by chemical mutagenesis, or variants isolated from a species, cell or organism type other than the type from w hich the sequence explicitly identified originated.
  • Variant nucleic acid m olecules may differ from the nucleic acid molecule explicitly recited in a coding region, non-coding region or both these regions.
  • Nucleic acid m olecules m ay also include additional nucleic acid sequence to that explicitly recited, for example, at the 5' or 3 ' end of the molecule.
  • Such additional nucleic acids may encode for a polypeptide w ith added functionality compared with the original polypeptide whose sequence is explicitly identified herein.
  • An example of this would be an addition of a sequence that is heterologous to the original nucleic acid sequence, to encode a fusion protein.
  • Such a fusion protein may be of use in aiding purification procedures or enabling techniques to be carried out where fusion proteins are required (such as in the yeast two hybrid system ).
  • a dditional sequences m ay also include leader or secretory sequences such as those coding for pro-, pre- or prepro- polypeptide sequences. These additional sequences may also include non-coding sequences that are transcribed but not translated including ribosome binding sites and termination signals.
  • a nucleic acid m olecule of the invention m ay include m olecules that are at least 70% identical over their entire length to a nucleic acid molecule as explicitly identified herein in SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 , 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166,
  • a nucleic acid molecule according to this aspect of the invention comprises a region that is at least 80% identical over its entire length to a nucleic acid m olecule as explicitly identified herein in these SEQ ID Nos., preferably at least 90% , m ore preferably at least 95 % and m ost preferably at least 98 % or 99% identical.
  • Further preferred embodiments include nucleic acid m olecules that encode polypeptides that retain substantially the same biological function or activity as the polypeptide explicitly identified herein.
  • the term s "hom ology" and "identity" should be given the meanings described in detail above with respect to polypeptide analysis.
  • nucleotide homology and identity are assessed using the blastn program available at http://www .ncbi.nlm .nih, gov.
  • the nucleic acid m olecules of the invention can also be engineered using m ethods generally known in the art. These methods include but are not lim ited to DNA shuffling; random or non-random fragm entation (by restriction enzym es or shearing methods) and reassem bly of fragments; insertions, deletions, substitutions and rearrangements of sequences by site-directed mutagenesis (for example, by PCR).
  • alterations m ay be for a num ber of reasons including for ease of cloning (such as introduction of new restriction sites), altering of glycosylation patterns, changing of codon preferences, splice variants changing the processing, and/or expression of the gene product (the polypeptide) in general or creating fusion proteins (see above).
  • Nucleic acid m olecules of the invention m ay also include antisense m olecules that are partially complementary to a nucleic acid m olecule as explicitly identified herein in SEQ ID Nos.: 2, 4, 6, 8, 10 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156 158, 160, 162, 164, 166,
  • antisense m olecules can be designed to recognise, specifically bind to and prevent transcription of a target nucleic acid encoding a polypeptide of the invention, as will be known by those of ordinary skill in the art (see Cohen, J.S ., Trends in Pharm . Sci., 10, 435 (1989), Okano, J. Neurochem . 56, 560 (1991 ); O 'Connor, J. Neurochem 56, 560 (1991 ); Lee et al, Nucleic Acids Res 6, 3073 (1979); Cooney et al, Science 241 , 456 (1988); Dervan et al, Science 251 , 1360 (1991 ).
  • hybridisation refers to any process by which a strand of nucleic acid binds with a complementary strand of nucleic acid by hydrogen bonding, typically forming W atson-Crick base pairs.
  • one of the nucleic acid populations is usually immobilised to a surface, whilst the other population is free. The two molecule types are then placed together under conditions conducive to binding.
  • stringency of hybridisation refers to the percentage of complementarity that is needed for duplex formation. "Stringency” thus refers to the conditions in a hybridization reaction that favour the association of very similar molecules over association of molecules that differ. Conditions can therefore exist that allow not only nucleic acid strands with 99-100% complementarity to hybridise, but sequences with lower complementarity (for example, 50%) to also hybridise.
  • High stringency hybridisation conditions are defined herein as overnight incubation at 42°C in a solution comprising 50% formamide, 5XSSC (150mM NaCl, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5x Denhardts solution, 10% dextran sulphate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1 X SSC at approximately 65°C, Low stringency conditions involve the hybridisation reaction being carried out at 35°C (see Sambrook et al [supra]). Preferably, the conditions used for hybridization are those of high stringency.
  • Some trans- and cis-acting factors that may affect the binding of two complementary strands include strand length, base composition (GC pairs have an extra hydrogen bond and are thus require more energy to separate than AT pairs) and the chemical environment.
  • monovalent cations such as Na +
  • chemical denaturants such as formamide and urea destabilise the duplex by disruption of the hydrogen bonds.
  • Use of compounds such as polyethylene glycol (PEG) can increase reassociation speeds by increasing overall DNA concentration in aqueous solution by abstracting water molecules.
  • Denhardt's reagent or BLOTTO are chemical agents often added to block non-specific attachment of the liquid phase to the solid support. Increasing the temperature will also increase the stringency of hybridisation, as will increasing the stringency of the washing conditions following hybridisation (Sambrook et al. [supra]).
  • Labelling methods include, but are not limited to radiolabelling, fluorescence labelling, chemiluminescent or chromogenic labelling or chemically coupling a modified reporter molecule to a nucleotide precursor such as the biotin-streptavidin system . This can be done by oligolabelling, nick-translation, end-labelling or PCR amplification using a labelled polynucleotide. Labelling of RNA m olecules can be achieved by cloning the sequences encoding the polypeptide of the invention into a vector specifically for this purpose. Such vectors are known in the art and m ay be used to synthesise RNA probes in vitro by the addition of an appropriate RNA polym erase such as T7, T3 or SP6 and labelled nucleotides.
  • Hybridisation assays include, but are not lim ited to dot-blots, Southern blotting, Northern blotting, chrom osome in situ hybridisation (for example, FISH [fluorescence in situ hybridisation]), tissue in situ hybridisation, colony blots, plaque lifts, gridded clone hybridisation assays, DNA microarrays and oligonucleotide microarrays.
  • FISH fluorescence in situ hybridisation
  • tissue in situ hybridisation colony blots
  • plaque lifts gridded clone hybridisation assays
  • DNA microarrays and oligonucleotide microarrays may be used by a skilled artisan to isolate copies of genomic DNA , cDN A , or RN A encoding homologous or orthologous proteins from other species.
  • the invention therefore also embodies a process for detecting a nucleic acid m olecule according to the invention, comprising the steps of: (a) contacting a nucleic probe with a biological sample under hybridising conditions to form duplexes: and (b) detecting any such duplexes that are form ed.
  • probe refers to a nucleic acid m olecule in a hybridisation reaction whose m olecular identity is known and is designed specifically to identify nucleic acids encoding homologous genes in other species.
  • the probe population is the labelled population, but this is not alw ays the case, as for example, in a reverse hybridisation assay.
  • a use of a probe is to find nucleic acid molecules with an equivalent function to those that are explicitly identified herein, or to identify additional fam ily members in the same or other species. This can be done by probing libraries, such as genomic or cDNA libraries, derived from a source of interest, such as a human, a non-human anim al, other eukaryote species, a plant, a prokaryotic species or a virus.
  • the probe m ay be natural or artificially designed using methods recognised in the art (for example, Ausubel et al, [supra]).
  • a nucleic acid probe w ill preferably possess greater than 15, m ore preferably greater than 30 and m ost preferably greater than 50 contiguous bases complementary to a nucleic acid molecule explicitly identified herein.
  • m ethod which may be used is "capture PCR” , which involves PCR amplification of DNA fragm ents adjacent to a know n sequence in hum an and yeast artificial chrom osome DNA (Lagerstrom , M . et al, (1991 ) PCR M ethods Applic, 1 :1 1 1 -1 19).
  • capture PCR involves PCR amplification of DNA fragm ents adjacent to a know n sequence in hum an and yeast artificial chrom osome DNA (Lagerstrom , M . et al, (1991 ) PCR M ethods Applic, 1 :1 1 1 1 -1 19).
  • Another m ethod which m ay be used to retrieve unknown sequences is that of Parker, J.D , et al, (1991 ); Nucleic Acids Res. 19:3055-3060).
  • PCR nested primers
  • libraries such as the PromoterFinderTM library (Clontech, Palo Alto, CA) to walk genomic DNA .
  • This latter process avoids the need to screen libraries and is useful in finding intron/exon junctions.
  • W hen screening for full-length cDNAs it is preferable to use libraries that have been size-selected to include larger cDNAs.
  • random -primed libraries are preferable, in that they will contain more sequences that contain the 5' regions of genes. Use of a randomly prim ed library m ay be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA .
  • Genomic libraries m ay be useful for extension of sequence into 5' non-transcribed regulatory regions.
  • a nucleic acid m olecule according to the invention m ay be used for chrom osom e localisation.
  • a nucleic acid molecule is specifically targeted to, and can hybridise with, a particular location on an individual hum an chrom osome,
  • the m apping of relevant sequences to chromosomes is an important step in the confirm atory correlation of those sequences with the gene-associated disease, Once a sequence has been m apped to a precise chromosom al location, the physical position of the sequence on the chromosom e can be correlated with genetic map data.
  • the nucleic acid m olecule may also be used to detect differences in the chromosom al location due to translocation, inversion, etc. am ong norm al, carrier, or affected individuals. Nucleic acid m olecules of the present invention are also valuable for tissue localisation. Such techniques facilitate the determ ination of expression patterns of the polypeptide in tissues by detection of the mRNAs that encode them . These techniques include in situ hybridisation techniques and nucleotide amplification techniques, such as PCR. Results from these studies provide an indication of the normal functions of the polypeptide in the organism, as well as highlighting the involvement of a particular gene in a disease state or abnormal physiological condition.
  • the nucleic acid molecules of the present invention may be incorporated into vectors for cloning (for example, pBluescript made by Stratagene) or expression purposes.
  • Vectors containing a nucleic acid molecule explicitly identified herein (or a variant thereof) form another aspect of this invention.
  • the nucleic acid molecule may be inserted into an appropriate vector by any variety of well known techniques such as those described in Sambrook et al [supra].
  • the encoding gene can be placed under the control of a control element such as a promoter, ribosome binding site or operator, so that the DNA sequence encoding the desired polypeptide is transcribed into RNA in the transformed host cell.
  • Vectors may be derived from various sources including, but not limited to bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses for example, baculoviruses and SV40 (simian virus), vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses, lentiviruses and retroviruses, or combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, including cosmids and phagemids.
  • Human, bacterial and yeast artificial chromosomes may also be employed to deliver larger fragments of DNA than can be contained and expressed in a plasmid.
  • retroviruses include but are not limited to: murine leukaemia virus (MLV), hum an immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukaemia virus (Mo-MLV), FBR murine osteosarcoma virus (FBR M SV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukaemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29), and Avian erythroblastosis virus (AEV).
  • a detailed list of retroviruses may be found in Coffin et al (“Retroviruses” 1997 Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763).
  • Lentiviruses can be divided into primate and non-primate groups.
  • primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto-immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV).
  • the non- primate lentiviral group includes the prototype "slow virus” visna/maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV) and the more recently described feline immunodeficiency virus (FIV) and bovine immunodeficiency virus (BIV).
  • lentivirus family and other types of retroviruses are that lentiviruses have the capability to infect both dividing and non-dividing cells (Lewis et al 1992 EM B O . J 1 1 : 3053 -3058 ; Lewis and Em erm an 1994 J. Virol. 68 : 510-516).
  • retroviruses - such as M LV - are unable to infect non-dividing cells such as those that m ake up, for example, m uscle, brain, lung and liver tissue.
  • a vector m ay be configured as a split-intron vector.
  • a split intron vector is described in PCT patent applications W O 99/15683 and W O 99/15684.
  • adenoviruses can be used to transduce target cells to become transient retroviral producer cells that could stably infect neighbouring cells.
  • retroviral producer cells engineered to express an antigen of the present invention can be implanted in organism s such as anim als or humans for use in the treatment of angiogenesis and/or cancer.
  • Poxvirus vectors are also suitable for use in accordance with the present invention.
  • Pox viruses are engineered for recom binant gene expression and for the use as recombinant live vaccines. This entails the use of recombinant techniques to introduce nucleic acids encoding foreign antigens into the genome of the pox virus.
  • the nucleic acid is integrated at a site in the viral DNA which is non-essential for the life cycle of the virus, it is possible for the new ly produced recombinant pox virus to be infectious, that is to say to infect foreign cells and thus to express the integrated DNA sequence,
  • the recombinant pox virus prepared in this w ay can be used as live vaccines for the prophylaxis and/or treatment of pathologic and infectious disease.
  • preferred vectors are vaccinia virus vectors such as M VA or NYVAC .
  • M ost preferred is the vaccinia strain modified virus ankara (M VA) or a strain derived therefrom .
  • Alternatives to vaccinia vectors include avipox vectors such as fowlpox or canarypox known as ALVAC and strains derived therefrom which can infect and express recombinant proteins in hum an cells but are unable to replicate.
  • B acterial vectors may be also used, such as salmonella, listeria and mycobacteria.
  • M ethods include calcium phosphate transfection, cationic lipid-mediated transfection, DEAE-dextran mediated transfection, electroporation, microinjection, scrape loading, transduction, and ballistic introduction or infection.
  • host cells are . often dependent on the vector type used as a carrier for the nucleic acid molecule of the present invention.
  • Bacteria and other microorganisms are particularly suitable hosts for plasmids, cosmids and expression vectors generally (for example, vectors derived from the pBR322 plasmid), yeast are suitable hosts for yeast expression vectors, insect cell systems are suitable host for virus expression vectors (for example, baculovirus) and plant cells are suitable hosts for vectors such as the cauliflower mosaic virus (CaMV) and tobacco mosaic virus (TM V).
  • Other expression systems include using animal cells (for example, with the LentiVectorsTM, Oxford BioMedica) as a host cell or even using cell-free translating systems.
  • shuttle vectors may be maintained in a variety of host cells.
  • An example of such a vector would be pEG 202 and other yeast two-hybrid vectors which can be maintained in both yeast and bacterial cells (see Ausubel et al, [supra] and Gyuris, J., Cell, 75, 791 - 803).
  • suitable bacterial hosts include Streptococci, Staphylococci, Escherichia coli, Streptomyces and Bacillus subtilis cells.
  • Yeast and fungal hosts include Saccharomyces cerevisiae and Aspergillus cells.
  • M ammalian cell hosts include many immortalised cell lines available from the American Type Culture Collection (ATCC) such as CHO (Chinese Hamster Ovary) cells, HeLa cells, BHK (baby hamster kidney) cells, monkey kidney cells, C 127, 3T3, BHK, HEK 293, Bowes melanoma and human hepatocellular carcinoma (for example, Hep G2) cells.
  • ATCC American Type Culture Collection
  • Insect host cells that are used for baculovirus expression include Drosophila S2 and Spodoptera Sf9 cells. Plant host cells include most plants from which protoplasts be isolated and cultured to give whole regenerated plants. Practically, all plants can be regenerated from cultured cells or tissues, including but not limited to all major species of sugar cane, sugar beet, cotton, fruit and other trees, legumes and vegetables.
  • expression vectors that comprise a nucleic acid molecule as described above.
  • Expression vectors and host cells are preferably chosen to give long term , high yield production and stable expression of the recombinant polypeptide and its variants.
  • Expression of a polypeptide can be effected by cloning an encoding nucleic acid molecule into a suitable expression vector and inserting this vector into a suitable host cell.
  • the positioning and orientation of the nucleic acid molecule insert with respect to the regulatory sequences of the vector is important to ensure that the coding sequence is properly transcribed and translated.
  • control and other regulatory sequences may be ligated onto the nucleic acid molecule of this invention prior to its insertion into the expression vector.
  • the sequence of the nucleic acid molecule may have to be adjusted in order to effect correct transcription and translation (for example, addition of nucleotides may be necessary to obtain the correct reading frame for translation of the polypeptide from its encoding nucleic acid molecule).
  • a nucleic acid m olecule of the invention may comprise control sequences that encode signal peptides or leader sequences. These sequences may be useful in directing the translated polypeptide to a variety of locations within or outside the host cell, such as to the lumen of the endoplasmic reticulum, to the nucleus, to the periplasmic space, or into the extracellular environment. Such signals may be endogenous to the nucleic acid molecules of the invention, or may be a heterologous sequence. These leader or control sequences may be removed by the host during post-translational processing.
  • a nucleic acid molecule of the present invention m ay also comprise one or more regulatory sequences that allow for regulation of the expression of polypeptide relative to the growth of the host cell.
  • these regulatory signals may be due to a heterologous sequence from the vector.
  • Stimuli that these sequences respond to include those of a physical or chemical nature such as the presence or absence of regulatory compounds, changing temperatures or metabolic conditions.
  • Regulatory sequences as described herein, are non-translated regions of sequence such as enhancers, promoters and the 5' and 3' untranslated regions of genes. Regulatory sequences interact with host cellular proteins that carry out translation and transcription. These regulatory sequences may vary in strength and specificity. Examples of regulatory sequences include those of constitutive and inducible promoters.
  • an inducible promoter is the hybrid lacZ promoter of the Bluescript phagemid (Stratagene, LaJolla, CA) or pSportlTM plasmid (Gibco BRL).
  • the baculovirus polyhedrin promoter m ay be used in insect cells.
  • An example of a preferred expression system is the lentivirus expression system , for example, as described in International patent application W 098/17815.
  • Vectors frequently have marker genes that can be easily assayed. Thus, vector uptake by a host cell can be readily detected by testing for the relevant phenotype. Markers include, but are not limited to those coding for antibiotic resistance, herbicide resistance or nutritional requirements.
  • Markers include, but are not limited to those coding for antibiotic resistance, herbicide resistance or nutritional requirements.
  • DHFR dihydrofolate reductase
  • M arkers only indicate that a vector has been taken up by a host cell but does not distinguish between vectors that contain the desired nucleic acid molecule and those that do not.
  • One method of detecting for the said nucleic acid m olecule is to insert the relevant sequence at a position that will disrupt the transcription and translation of a m arker gene. These cells can then be identified by the absence of a m arker gene phenotype.
  • a m arker gene can be placed in tandem with a sequence encoding a polypeptide of the invention under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
  • M ore direct and definitive methods to detect the presence of the nucleic acid molecule of the present invention include DNA -DNA or DNA -RNA hybridisation with a probe comprising the relevant antisense molecule, as described above.
  • M ore direct methods to detect polypeptide expression include protein bioassays for example, fluorescence activated cell sorting (FAC S), immunoassay techniques such as ELISA or radioim m unoassays.
  • FAC S fluorescence activated cell sorting
  • immunoassay techniques such as ELISA or radioim m unoassays.
  • a nucleic acid m olecule according to the invention may be used to create a transgenic anim al, most commonly a rodent,
  • the m odification of the animal' s genome m ay either be done locally, by m odification of som atic cells or by germ line therapy to incorporate inheritable modifications.
  • Such transgenic animals may be particularly useful in the generation of animal models for drug molecules effective as modulators of the polypeptides of the present invention.
  • a polypeptide according to the invention m ay be recovered and purified from recombinant cell cultures by methods including, but not limited to cell lysis techniques, ammonium sulphate precipitation, ethanol precipitation, acid extraction, anion or cation chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chrom atography, high perform ance liquid chrom atography (HPLC) or fast perform ance liquid chrom atography (FPLC).
  • HPLC ance liquid chrom atography
  • FPLC fast perform ance liquid chrom atography
  • the polypeptide may need refolding after purification or isolation and many well known techniques are available that will help regenerate an active polypeptide conform ation.
  • any expression vectors are com m ercially available that aid purification of the relevant polypeptide. These include vectors that join the sequence encoding the polypeptide to another expressed sequence creating a fused protein that is easier to purify. W ays in which these fused parts can facilitate purification of the polypeptide of this invention include fusions that can increase the solubility of the polypeptide, joining of metal chelating peptides (for example, histidine-tryptophan modules) that allow for purification with imm obilised metals, joining of protein A dom ains w hich allow for purification with immobilised immunoglobulins and the joining of the dom ain that is utilised in the FLAGS extension/affinity purification system (Immunex Corp., Seattle, W A).
  • metal chelating peptides for example, histidine-tryptophan modules
  • Fusion of the polypeptide of this present invention with a secretion signal polypeptide m ay also aid purification. This is because the medium into which the fused polypeptide has been secreted can subsequently be used to recover and purify the expressed polypeptide, If necessary, these extraneous polypeptides often comprise a cleavable linker sequence which allow s the polypeptide to be isolated from the fusion.
  • Cleavable linker sequences between the purification dom ain and the polypeptide of the invention include those specific for Factor Xa or for enterokinase (Invitrogen, San Diego, CA).
  • One such expression vector provides for expression of a fusion protein containing the polypeptide of the invention fused to several histidine residues preceding a thioredoxin or an enterokinase cleavage site.
  • the histidine residues facilitate purification by IM A C (immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp. Purif. 3 : 263-281 ), while the thioredoxin or enterokinase cleavage site provides a means for purifying the polypeptide from the fusion protein.
  • IM A C immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp. Purif. 3 : 263-281
  • the thioredoxin or enterokinase cleavage site provides a means for purifying the polypeptide from the fusion protein.
  • Another aspect of this invention includes assays that m ay be carried out using a polypeptide or nucleic acid molecule according to the invention.
  • Such assays m ay be for m any uses including the development of drug candidates, for diagnostic purposes or for the gathering of inform ation for therapeutics.
  • the polypeptide is to be expressed for use in screening assays, generally it is preferred that it be produced at the surface of the host cell in which it is expressed. In this event, the host cells m ay be harvested prior to use in the screening assay, for example using techniques such as fluorescence activated cell sorting (FA CS) or im munoaffinity techniques. If the polypeptide is secreted into the medium , the m edium can be recovered in order to recover and purify the expressed polypeptide. If polypeptide is produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
  • FFA CS fluorescence activated cell sorting
  • the polypeptide of the invention can be used to screen libraries of compounds in any of a variety of drug screening techniques. Such compounds m ay activate (agonise) or inhibit (antagonise) the level of expression of the gene or the activity of the polypeptide of the invention and form a further aspect of the present invention.
  • suitable com pounds are those w hich are effective to alter the expression of a natural gene which encodes a polypeptide of the invention or to regulate the activity of a polypeptide of the invention.
  • Agonist or antagonist compounds m ay be isolated from , for example, cells, cell-free preparations, chemical libraries or natural product mixtures. These agonists or antagonists may be natural or modified substrates, ligands, enzymes, receptors or structural or functional mim etics. For a suitable review of such screening techniques, see Coligan et al., Current Protocols in Immunology l (2):Chapter 5 (1991 ).
  • Potential agonists or antagonists include small organic m olecules, peptides, polypeptides and antibodies that bind to the polypeptide of the invention and thereby m odulate its activity. In this fashion, binding of the polypeptide to normal cellular binding molecules may be potentiated or inhibited, such that the norm al biological activity of the polypeptide is enhanced or prevented.
  • the polypeptide of the invention that is employed in such a screening technique m ay be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly.
  • screening procedures m ay involve using appropriate cells or cell membranes that express the polypeptide that are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response.
  • the functional response of the cells contacted with the test compound is then compared with control cells that were not contacted with the test compound.
  • Such an assay may assess whether the test compound results in a signal generated by activation of the polypeptide, using an appropriate detection system .
  • Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist in the presence of the test compound is observed.
  • simple binding assays m ay be used, in which the adherence of a test compound to a surface bearing the polypeptide is detected by means of a label directly or indirectly associated w ith the test compound or in an assay involving competition with a labelled competitor.
  • competitive drug screening assays m ay be used, in which neutralising antibodies that are capable of binding the polypeptide specifically compete with a test compound for binding, In this m anner, the antibodies can be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide.
  • Assays may also be designed to detect the effect of added test compounds on the production of mRNA encoding the polypeptide in cells, For example, an ELISA m ay be constructed that measures secreted or cell-associated levels of polypeptide using monoclonal or polyclonal antibodies by standard methods known in the art, and this can be used to search for compounds that may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues. The formation of binding complexes between the polypeptide and the compound being tested may then be measured.
  • Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the polypeptide of interest (see International patent application W O 84/03564).
  • This method large numbers of different small test compounds are synthesised on a solid substrate, which may then be reacted with the polypeptide of the invention and washed.
  • One way of immobilising the polypeptide is to use non-neutralising antibodies. Bound polypeptide m ay then be detected using methods that are well known in the art. Purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques.
  • a polypeptide according to the invention may be used to identify membrane-bound or soluble receptors, through standard receptor binding techniques that are known in the art, such as ligand binding and crosslinking assays in which the polypeptide is labelled with a radioactive isotope, is chemically modified, or is fused to a peptide sequence that facilitates its detection or purification, and incubated with a source of the putative receptor (for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids), The efficacy of binding may be measured using biophysical techniques such as surface plasmon resonance and spectroscopy.
  • Binding assays may be used for the purification and cloning of the receptor, but may also identify agonists and antagonists of the polypeptide, that compete with the binding of the polypeptide to its receptor. Standard methods for conducting screening assays are well understood in the art.
  • a typical polypeptide-based assay might involve contacting the appropriate cell(s) or cell membrane(s) expressing the polypeptide with a test compound.
  • a polypeptide according to the invention may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. Any response to the test compound, for example a binding response, a stimulation or inhibition of a functional response may then be compared with a control where the cell(s) or cell membrane(s) was/were not contacted with the test compound.
  • a binding response could be measured by testing for the adherence of a test compound to a surface bearing a polypeptide according to the invention.
  • the test compound may aid polypeptide detection by being labelled, either directly or indirectly.
  • the polypeptide itself may be labelled, for example, with a radioisotope, by chemical modification or as a fusion with a peptide or polypeptide sequence that will facilitate polypeptide detection.
  • a binding response may be measured, for example, by performing a competition assay with a labelled competitor or vice versa.
  • a competition assay is a competitive drug screening assay, where neutralising antibodies that are capable of specifically binding to the polypeptide compete with a test compound for binding. In this manner, the antibodies may be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide.
  • Alternative binding assay methods are well known in the art and include, but are not limited to, cross-linking assays and filter binding assays. The efficacy of binding may be measured using biophysical techniques including surface plasmon resonance and spectroscopy.
  • High throughput screening is a type of assay which enables a large number of compounds to be searched for any significant binding activity to the polypeptide of interest (see patent application WO84/03564). This is particularly useful in drug screening.
  • many different small test compounds are synthesised on to a solid substrate.
  • the polypeptide is then introduced to this substrate and the whole apparatus washed.
  • the polypeptide is then immobilised by, for example, using non-neutralising antibodies.
  • Bound polypeptide may then be detected using methods that are well known in the art.
  • Purified polypeptide may also be coated directly onto plates for use in the aforementioned drug screening techniques.
  • Assay methods that are also included within the term s of the present invention are those that involve the use of the genes and polypeptides of the invention in overexpression or ablation assays. Such assays involve the manipulation of levels of these genes/polypeptides in cells and assessment of the impact of this manipulation event on the physiology of the manipulated cells. For example, such experiments reveal details of signaling and metabolic pathways in which the particular genes/polypeptides are implicated, generate information regarding the identities of polypeptides with which the studied polypeptides interact and provide clues as to methods by which related genes and proteins are regulated.
  • Another aspect of this invention provides for any screening kits that are based or developed from any of the aforementioned assays.
  • a further aspect of the invention provides a pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharm ceutically-acceptable carrier.
  • a composition containing a polypeptide, nucleic acid molecule, ligand or any other compound of this present invention (herein known as X) is considered to be "substantially free of impurities" (herein known as Y) when X makes up more than 85% mass per mass of the total [X+Y] mass.
  • X comprises at least 90% of the total X+Y m ass. More preferably X comprises at least 95% , 98% and m ost preferably 99% of the total X+Y m ass.
  • Carrier m olecules m ay be genes, polypeptides, antibodies, liposom es or indeed any other agent provided that the carrier does not itself induce toxicity effects or cause the production of antibodies that are harm ful to the individual receiving the pharm aceutical composition.
  • Further examples of known carriers include polysaccharides, polylactic acids, polyglycolic acids and inactive virus particles.
  • Carriers m ay also include pharmaceutically acceptable salts such as m ineral acid salts (for example, hydrochlorides, hydrobromides, phosphates, sulphates) or the salts of organic acids (for example, acetates, propionates, malonates, benzoates).
  • Pharm aceutically acceptable carriers may additionally contain liquids such as water, saline, glycerol, ethanol or auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like.
  • Carriers m ay enable the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions to aid intake by the patient.
  • Carriers m ay enable the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions to aid intake by the patient.
  • a thorough discussion of pharm aceutically acceptable carriers is available in Rem ington's Pharmaceutical Sciences (M ack Pub. Co., N J. 1991 ).
  • the am ount of component X in the composition should also be in therapeutically effective am ounts.
  • the phrase "therapeutically effective am ounts" used herein refers to the am ount of agent needed to treat, ameliorate, or prevent (for example, when used as a vaccine) a targeted disease or condition.
  • An effective initial method to determ ine a "therapeutically effective amount" m ay be by carrying out cell culture assays (for example, using neoplastic cells) or using anim al models (for example, mice, rabbits, dogs or pigs).
  • animal models may also yield other relevant information such as preferable routes of administration that w ill give maximum effectiveness. Such information may be useful as a basis for patient administration.
  • a "patient” as used in herein refers to the subject who is receiving treatment by adm inistration of X. Preferably, the patient is human, but the term may also include animals.
  • the therapeutically-effective dosage will generally be dependent on the patient' s status at the time of adminstration, Factors that may be taken into consideration w hen determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug com binations, reaction sensitivities and the patient' s tolerance or response to the therapy. The precise amount can be determined by routine experimentation but m ay ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 m g/kg (m ass of drug compared to mass of patient) to 50 m g/kg, preferably 0.05 mg/kg to 10 m g/kg. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • Uptake of a pharmaceutical composition of the invention by a patient may be initiated by a variety of methods including, but not limited to enteral, intra-arterial, intrathecal, intramedullary, intramuscular, intranasal, intraperitoneal, intravaginal, intravenous, intraventricular, oral, rectal (for example, in the form of suppositories), subcutaneous, sublingual, transcutaneous applications (for example, see W O98/20734) or transdermal means.
  • compositions of the invention may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • Direct delivery of the compositions can generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue,
  • the compositions can also be administered into a lesion, Dosage treatment may be a single dose schedule or a multiple dose schedule.
  • One approach comprises administering to a patient an inhibitor compound (antagonist) along with a pharmaceutically acceptable carrier in an amount effective to inhibit the function of the polypeptide, such as by blocking the binding of a ligand, substrate, enzyme, receptor, or by inhibiting a second signal, and thereby alleviating the abnormal condition.
  • an antagonist molecule may, for example, be an antibody.
  • antibodies are chimeric and/or humanised to minimise their immunogenicity, as previously described.
  • soluble form s of the polypeptide that retain binding affinity for the ligand, substrate, enzyme, receptor, in question may be administered to the patient to compete with the biological activity of the endogenous polypeptide, Typically, the polypeptide may be administered in the form of a fragment that retains a portion that is relevant for the desired biological activity.
  • expression of the gene encoding the polypeptide can be inhibited using expression blocking techniques, such as by using antisense nucleic acid molecules (as described above), either internally generated or separately administered.
  • M odifications of gene expression may be effected by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5' or regulatory regions (signal sequence, promoters, enhancers and introns) of the gene encoding the polypeptide.
  • inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules.
  • the complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.
  • Such oligonucleotides may be administered or may be generated in situ from expression in vivo, Gene silencing approaches may also be undertaken to down-regulate endogenous expression of a gene.
  • RNA interference (Elbashir, SM et al., Nature 2001 , 411 , 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed, Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA, reducing or ablating target protein expression.
  • expression of a polypeptide according to the invention may be prevented by using a ribozyme specific to the encoding mRNA sequence for the polypeptide.
  • Ribozymes are catalytically active RNAs that can be natural or synthetic (see for example Usman, N, et al, Curr. Opin. Struct. B iol (1996) 6(4), 527-33). Synthetic ribozymes can be designed to specifically cleave mRNAs at selected positions thereby preventing translation of the mRNAs into functional polypeptide. Ribozymes may be synthesised with a natural ribose phosphate backbone and natural bases, as normally found in RNA molecules. Alternatively the ribozymes may be synthesised with non-natural backbones, for example, 2'-0-methyl RNA, to provide protection from ribonuclease degradation and may contain modified bases.
  • Efficacy of the gene silencing approaches assessed above may be assessed through the measurement of polypeptide expression (for example, by Western blotting), and at the RNA level using TaqMan-based methodologies.
  • RNA molecules may be modified to increase their intracellular stability and half-life, Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule.
  • This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of non-traditional bases such as inosine, queosine and butosine, as well as acetyl-, methyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine and uridine that are not as easily recognised by endogenous endonucleases.
  • Activation of a polypeptide activity include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than
  • m ethods m ay be used.
  • An example of such a m ethod includes administering a therapeutically effective am ount of compound that can activate (i.e. an agonist) or cause increased expression of the polypeptide concerned.
  • a dm inistration of such a compound m ay be via any of the methods described previously.
  • Gene therapy m ay be used to affect the endogenous production of the polypeptide of the present invention by relevant cells in a patient.
  • gene therapy can be used perm anently to treat the inappropriate production of a polypeptide by replacing a defective gene with the corrected therapeutic gene.
  • Ex vivo gene therapy generally involves the isolation and purification of the patient' s cells, introduction of the therapeutic gene into the cells and finally, the introduction of the genetically-altered cells back into the patient,
  • In vivo gene therapy does not require the isolation and purification of patient cells prior to the introduction of the therapeutic gene into the patient. Instead, the therapeutic gene can be packaged for delivery into the host.
  • Gene delivery vehicles for in vivo gene therapy include, but are not lim ited to, non-viral vehicles such as liposom es, replication-competent and replication-deficient viruses (for example, adenovirus as described by Berkner, K.L., in Curr. Top. M icrobiol.
  • naked DNA may be directly injected into the bloodstream or muscle tissue as a form of in vivo gene therapy.
  • a nucleic acid molecule encoding a polypeptide of the invention is engineered for expression in a replication-defective or replication-competent vector, such as a retroviral vector.
  • This expression construct m ay then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding the polypeptide, such that the packaging cell now produces infectious viral particles containing the gene of interest.
  • These producer cells may be administered to a patient for engineering cells in vivo and expression of the polypeptide in vivo (see Chapter 20, Gene Therapy and other M olecular Genetic-based Therapeutic Approaches, (and references cited therein) in Hum an M olecular Genetics (1996), T Strachan and A P Read, B IOS Scientific Publishers Ltd). Genetic delivery of antibodies that bind to polypeptides according to the invention may also be effected, for example, as described in International patent application WO98/55607.
  • a further embodiment of the present invention provides that the polypeptides or nucleic acid molecules identified may be used in the development of vaccines.
  • vaccine development can involve the raising of antibodies against such agents.
  • vaccine development can involve the raising of antibodies or T cells against such agents (as described in W O00/29428).
  • Vaccines according to the invention may either be prophylactic (i.e. prevents infection) or therapeutic (i.e. treats disease after infection).
  • Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid, usually in combination with pharmaceutically-acceptable carriers as described above. Additionally, these carriers may function as immunostimulating agents ("adjuvants"). Furthermore, the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H, pylori, and other pathogens.
  • Vaccination processes may involve the use of heterologous vectors eg: prime with MVA and boost with DNA,
  • vaccines comprising polypeptides are preferably administered parenterally (for instance, subcutaneous, intramuscular, intravenous, or intradermal injection).
  • parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents.
  • the vaccine formulations of the invention may be presented in unit-dose or multi-dose containers.
  • sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use.
  • the dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.
  • polypeptides can be delivered by viral or non-viral techniques.
  • Non-viral delivery systems include but are not limited to DNA transfection methods.
  • transfection includes a process using a non-viral vector to deliver a antigen gene to a target mammalian cell.
  • Typical transfection methods include electroporation, nucleic acid biolistics, lipid-mediated transfection, compacted nucleic acid-m ediated transfection, liposom es, immunoliposomes, lipofectin, cationic agent-m ediated, cationic facial amphiphiles (CFA s) (Nature B iotechnology 1996 14; 556), multivalent cations such as sperm ine, cationic lipids or polylysine, 1 , 2,-bis (oleoyloxy)-3- (trim ethylam m onio) propane (DOTAP)-cholesterol complexes (W olff and Trubetskoy 1998 Nature B iotechnology 16: 421 ) and combinations thereof.
  • CFA s cationic facial amphiphiles
  • Viral delivery systems include but are not limited to adenovirus vectors, adeno-associated viral (AAV) vectors, herpes viral vectors, influenza, retroviral vectors, lentiviral vectors or baculoviral vectors, Venezuelan equine encephalitis virus (VEE), poxviruses such as: canarypox virus (Taylor et al 1995 Vaccine 13 :539-549), entom opox virus (Li Y et al 1998 XHth International Poxvirus Symposium pl 44. Abstract), penguine pox (Standard et al. J Gen Virol. 1998 79: 1637-46) alphavirus, and alphavirus based DNA vectors.
  • AAV adeno-associated viral
  • herpes viral vectors influenza
  • retroviral vectors lentiviral vectors
  • baculoviral vectors Venezuelan equine encephalitis virus (VEE)
  • poxviruses such as
  • this aspect of the invention includes the use of genetically-based vaccines, for example, those vaccines that are effective through eliciting the expression of a particular gene (either endogenous or exogenously derived) in a cell, so targeting this cell for destruction by the im mune system of the host organism .
  • Another aspect of the present invention provides for the use of a nucleic acid m olecule identified herein as a diagnostic reagent.
  • a nucleic acid molecule may be detected or isolated from a patient' s tissue and used for diagnostic purposes.
  • tissue refers to blood, urine, any matter obtained from a tissue biopsy or any matter obtained from an autopsy, Genomic DNA from the tissue sample may be used directly for detection of a hypoxia-related condition.
  • the DNA may be amplified using methods such as polymerase chain reaction (PCR), the ligase chain reaction (LCR), strand displacem ent amplification (SDA), or other amplification techniques (see Saiki et al, Nature, 324, 163-166 (1986); B ej, et al, Crit. Rev. B iochem . Molec.
  • a method of diagnosis of disease using a polynucleotide m comprise assessing the level of expression of the natural gene and comparing the level of encoded polypeptide to a control level measured in a norm al subject that does not suffer from the disease or physiological condition that is being tested.
  • the diagnosis m ay comprise the following steps: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid molecule of the invention and the probe; b) contacting a control sample with said probe under the sam e conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of differing levels of the hybrid complex in the patient sample compared to levels of the hybrid complex in the control sam ple is indicative of the dysfunction.
  • a further aspect of the invention comprises a diagnostic method comprising the steps of: a) obtaining a tissue sample from a patient being tested for disease; b) isolating a nucleic acid m olecule according to the invention from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation in the nucleic acid molecule which is associated w ith disease.
  • an amplification step such as PCR , m ay be included.
  • An example of this includes detection of deletions or insertions indicative of the dysfunction by a change in the size of the amplified product in comparison to the norm al genotype.
  • Point mutations can be identified by hybridising amplified DNA to labelled RNA of the invention or alternatively, labelled antisense DNA sequences of the invention, Perfectly m atched sequences can be distinguished from mismatched duplexes by RNase digestion or by assessing differences in m elting temperatures.
  • the presence or absence of the mutation in the patient m may be detected by contacting DNA with a nucleic acid probe that hybridises to the DNA under stringent conditions to form a hybrid double- stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion corresponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation in the corresponding portion of the DNA strand.
  • Point mutations and other sequence differences between the reference gene and "mutant" genes can be identified by other well-known techniques, such as direct DNA sequencing or single-strand conform ational polym orphism , (see Orita et al, Genomics, 5, 874-879 (1989)).
  • a sequencing primer may be used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR.
  • the sequence determination is performed by conventional procedures with radiolabelled nucleotides or by automatic sequencing procedures with fluorescent-tags.
  • Cloned DNA segm ents m ay also be used as probes to detect specific DNA segments. The sensitivity of this m ethod is greatly enhanced when combined with PCR .
  • point mutations and other sequence variations can be detected as described above, for example, through the use of allele-specific oligonucleotides for PCR amplification of sequences that differ by single nucleotides.
  • DNA sequence differences m ay also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (for example, M yers et al, Science (1985) 230:1242). Sequence changes at specific locations m ay also be revealed by nuclease protection assays, such as RNase and S I protection or the chemical cleavage method (see Cotton et al, PNA S .
  • mutations such as microdeletions, aneuploidies, translocations, inversions, can also be detected by in situ analysis (see, for example, Keller et al, DNA Probes, 2nd Ed using Stockton Press, New York, N .Y ., USA (1993)), that is, DNA or RNA sequences in cells can be analysed for mutations without need for their isolation and/or imm obilisation onto a membrane.
  • FISH Fluorescence In situ hybridization
  • an array of oligonucleotide probes comprising a nucleic acid molecule according to the invention can be constructed to conduct efficient screening of genetic variants, mutations and polym orphism s.
  • Array technology m ethods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability (see for example: M .Chee et al, Science (1996), Vol 274, pp 610-613).
  • the array is prepared and used according to the methods described in W 095/1 1995 (Chee et al); Lockhart, D . J. et al (1996) Nat. Biotech. 14: 1675-1680); and Schena, M . et al (1996) PNAS 93 : 10614-10619).
  • Oligonucleotide pairs m ay range from two to over one million.
  • the oligomers are synthesized at designated areas on a substrate using a light-directed chemical process.
  • the substrate may be paper, nylon or other type of m embrane, filter, chip, glass slide or any other suitable solid support.
  • an oligonucleotide m ay be synthesized on the surface of the substrate by using a chem ical coupling procedure and an ink jet application apparatus, as described in PCT application W 095/251 1 16 (B aldeschweiler et al).
  • a "gridded" array analogous to a dot (or slot) blot m ay be used to arrange and link cDNA fragm ents or oligonucleotides to the surface of a substrate using a vacuum system , therm al, UV, mechanical or chemical bonding procedures.
  • An array such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), m aterials (any suitable solid support), and machines (including robotic instrum ents), and may contain 8, 24, 96, 384, 1536 or 6144 oligonucleotides, or any other number between two and over one million which lends itself to the efficient use of commercially-available instrumentation .
  • diseases m ay be diagnosed by methods comprising determ ining, from a sam ple derived from a subject, an abnormally decreased or increased level of polypeptide or mRNA .
  • Decreased or increased expression can be measured at the RNA level using any of the methods w ell known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR , RT-PCR, RN ase protection, Northern blotting and other hybridization methods.
  • Assay techniques that can be used to determ ine levels of a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art and are discussed in some detail above (including radioimmunoassays, competitive-binding assays, W estern Blot analysis and ELISA assays).
  • a diagnostic method which comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the form ation of a ligand-polypeptide complex; and (b) detecting said complex.
  • Protocols such as ELISA , RIA , and FAC S for measuring polypeptide levels m ay additionally provide a basis for diagnosing altered or abnorm al levels of polypeptide expression.
  • Norm al or standard values for polypeptide expression are established by combining body fluids or cell extracts taken from norm al m amm alian subjects, preferably humans, with antibody to the polypeptide under conditions suitable for complex form ation
  • the am ount of standard complex form ation m ay be quantified by various methods, such as by photom etric means.
  • Antibodies which specifically bind to a polypeptide of the invention m ay be used for the diagnosis of conditions or diseases characterised by expression of the polypeptide, or in assays to m onitor patients being treated with the polypeptides, nucleic acid molecules, ligands and other compounds of the invention.
  • Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for the polypeptide include methods that utilise the antibody and a label to detect the polypeptide in hum an body fluids or extracts of cells or tissues.
  • the antibodies may be used w ith or without modification, and may be labelled by joining them , either covalently or non-covalently, with a reporter m olecule.
  • reporter m olecules known in the art m ay be used, several of which are described above.
  • Diagnostic assays m ay be used to distinguish between absence, presence, and excess expression of polypeptide and to m onitor regulation of polypeptide levels during therapeutic intervention. Such assays m ay also be used to evaluate the efficacy of a particular therapeutic treatment regimen in anim al_studies, in clinical trials or in m onitoring the treatment of an individual patient.
  • a diagnostic kit of the present invention m ay comprise:
  • a diagnostic kit m ay comprise a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to the invention; a second container containing primers useful for amplifying the nucleic acid m olecule; and instructions for using the probe and primers for facilitating the diagnosis of disease.
  • the kit m ay further comprise a third container holding an agent for digesting unhybridised RNA .
  • a diagnostic kit m comprise an array of nucleic acid molecules, an array of antibody m olecules, and/or an array of polypeptide molecules, as discussed in m ore detail above.
  • kits will be of use in diagnosing a disease or susceptibility to disease, particularly inflamm ation, oncology, or cardiovascular disease.
  • Figure 1 show s a scatter plot, showing normalised signal intensities in hypoxia versus norm oxia, with each dot representing a single gene.
  • Figure 2 Hypoxia responses am plified by HIFl alpha overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1 ). Error bars represent standard error of the mean.
  • Figure 3 Hypoxia responses amplified by EPAS l overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1 ). Error bars represent standard error of the mean.
  • Figure 4 Hypoxia responses amplified by HIFlalpha / EPAS l overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1). Error bars represent standard error of the mean.
  • Figure 5 shows genes that are induced by hypoxia to a greater degree in resting macrophages, as compared to activated macrophages.
  • Error bars show the standard deviation from both repeat experiments and multiple exposures from single experiments. These data are not shown in table form. All bars are ratios of mRNA expression in hypoxia/ normoxia. These are calculated separately for resting (light bars) and activated (dark bars) macrophages, and do not illustrate differences resulting from activation in normoxia,
  • Figure 6 shows genes which are induced by hypoxia to a greater degree in activated m acrophages, compared to resting macrophages
  • Figure 7 shows genes that are repressed by hypoxia to a greater degree in activated macrophages
  • mRNA levels determined from a custom gene array, of particular genes are shown on the Y-axis, expressed as a value as compared to the median expression level of this gene throughout all samples. Eleven primary human cell types as shown on the x-axis were cultured in normoxia (black), or exposed to hyopxia for 6hr (grey) or 18hr (white).
  • Figure 8 Ecotropic viral integration site 2A (Seq ID :475/476).
  • Figure 9a Novel PI-3-kinase adapter (Seq ID:79/80); Image clone accession R62339.
  • Figure 9b TaqM an Real-time Q-RT-PCR data for Novel PI-3-kinase adapter (Seq ID :79/80); Image clone accession R62339.
  • Figure 9c IMAGE clone ace R59598 (Syk).
  • Figure 10 Regulator of G-protein signalling 1 (Seq ID :375/376)
  • Figure 1 1 GM2 ganglioside activator protein (Seq ID:389/390)
  • CYP1 cytochro e P450, subfamily XXVIIB (Seq ID:339/340)
  • Figure 14 Alpha-2-macroglobulin (Seq ID :405/406)
  • Figure 15 Interleukin 1 receptor antagonist (Seq ID :357/358)
  • Figure 16 SCYA3L (Seq ID:469/470)
  • Figure 29 Hypothetical protein FLJ22690 (SeqID :205/206)
  • Figure 30 cDNA DKFZp586E1624 (SeqID: 65/66)
  • Figure 32a EGL nine (C.elegans) homolog 3 (SeqID :85/86)
  • Figure 32b Gene expression profiles in macrophages with and without activation, mRNA levels, determined from a custom gene array, of clorf 12 are shown on the Y-axis, expressed as a value compared to the mean value of a set of control genes on each array (per-chip normalisation). All cells were human macrophages, cultured either without cytokines or with IL-10 or with the combination of IFND andLPS in normoxia and hypoxia,
  • Figure 32c Gene expression profiles in macrophages with and without activation. mRNA levels, determined from a custom gene array, of EGLN3 are shown on the Y-axis, expressed as a value compared to the mean value of a set of control genes on each array (per-chip normalisation). All cells were human macrophages, cultured either without cytokines or with IL-10 or with the combination of IFNQ andLPS in normoxia and hypoxia.
  • Figure 32d Clorfl2 (SeqID: 89.90)
  • Figure 32e The effect of EPAS/ HIF overexpression on expression of the gene C 1 orf 12 EGLN genes using a custom gene array. mRNA expression levels of the gene cl0RF12 as determined by the custom array, in response to hypoxia and adenoviral over-expression of HIF or EPAS are shown.
  • Experimental conditions are as follows: #1 no adeno / normoxia; #2 empty adeno (low dose)/ normoxia; #3 empty adeno (high dose)/ normoxia; #4 empty adeno (low dose)/ hypoxia; #5 empty adeno (high dose)/ hypoxia; #6 HIF-1 adeno (low dose)/ hypoxia; #7 HIF-1 adeno (high dose)/ hypoxia; #8 EPAS adeno (low dose)/ hypoxia; #9 EPAS adeno (high dose)/ hypoxia. Error bars are the standard error of the mean.
  • Figure 32f The effect of EPAS/ HIF overexpression on expression of the gene EGLN3 gene using a custom gene array. mRNA expression levels of the gene EGLN3 as determined by the custom array, in response to hypoxia and adenoviral over-expression of HIF or EPAS are shown.
  • Experimental conditions are as follows: #1 no adeno / normoxia; #2 empty adeno (low dose)/ normoxia; #3 empty adeno (high dose)/ normoxia; #4 empty adeno (low dose)/ hypoxia; #5 empty adeno (high dose)/ hypoxia; #6 HIF-1 adeno (low dose)/ hypoxia; #7 HIF-1 adeno (high dose)/ hypoxia; #8 EPAS adeno (low dose)/ hypoxia; #9 EPAS adeno (high dose)/ hypoxia.
  • Figure 32h The effect of EPAS/ HIF overexpression on expression of the clorf 12 gene using AffyMetrix Hu95 ver2 GeneChips, mRNA expression levels of the gene in response to hypoxia and adenoviral over- expression of HIF or EPAS are shown. Graphs show the mean of two replicate arrays, with error bars as standard deviation. Above each graph, data values are shown, including the normalised values and raw values (the AffyMetrix average difference parameter) and Present/ Absent flags.
  • Figure 32i Flag immunocytochemistry in HEK293T cells
  • Figure 32j Human Cardiomyocyte Caspase Activity after 72 hours transduction with EIAV-ELG9- Homolog 3
  • Figure 34 Hypothetical protein hqp0376 (SeqID:337/338)
  • Figure 35 Metallothionein 2A (SeqID :265/266)
  • Figure 49 Decidual protein induced by progesterone (SeqID :387/388)
  • Figure 50 Integrin, alpha 5 (SeqID :379/380)
  • Figure 51 Tissue factor (SeqID :225/226)
  • Figure 52 COX-2 (SeqID :237/238)
  • Figure 53 Genes up-regulated by macrophage activation. Normalised mRNA levels in the 6 experimental conditions (#1 no cytokines/ normoxia, #2 no cytokines/ hypoxia, #3 IL-10/ normoxia, #4 IL-10/ hypoxia, #5 LPS/IFN/ normoxia, #6 LPS/IFN/ hypoxia) are shown as values referenced to the median value of that gene throughout all 6 experimental conditions. Error bars show the standard error of the mean.
  • Figure 54 Genes downregulated by macrophage activation (I)
  • FIG. 55 Genes downregulated by macrophage activation (II)
  • Figure 57 shows an RNase protection assay for the gene encoding Semaphorin 4b.
  • Figure 58 shows a Northern blot showing the size of the mRNA and tissue distribution for the Semaphorin 4b gene. Examples
  • Subtracted cDNA libraries were separately prepared for hypoxic m acrophages and cardiom yoblasts. This involved harvesting RNA from cells both in norm oxia and hypoxia, and preparing cDNA . Subtractive hybridization / suppression PCR w as then perform ed to rem ove genes from the hypoxic cell cDNA , which are also present in cDNA from norm oxic cells. Insert DNA from the libraries was PCR amplified and arrayed onto duplicate membranes. Quantitative hybridizations with pre-library cDNA material (norm oxia and hypoxia) were done to identify clones in the libraries that actually contain hypoxia inducible genes. The insert DNA was then sequenced. This procedure was done independently for macrophage and cardiom yoblast. The hypoxia inducible genes identified from these different cell types differed widely, with only a m inority of these. genes being identified from both cell types.
  • Example la Comparison of the hypoxic-response between human macrophages and cardiomyoblasts by a subtraction cloning / array screening approach M ethods / Results
  • monocytes were derived from peripheral blood of healthy hum an donors. 100ml bags of buffy coat from the B ristol B lood Transfusion Centre were mixed with an equal volume of RPM I1640 m edium (Sigm a). This was layered on top of 10ml ficol-paque (Pharm acia) in 50ml centrifuge tubes and centrifuged for 25 min at 800 x g. The interphase layer w as removed, w ashed in M ACS buffer (phosphate buffered saline pH 7.2, 0.5 % bovine serum albumin, 2mM EDTA) and resuspended at 80 microliter per 10n7 cells.
  • M ACS buffer phosphate buffered saline pH 7.2, 0.5 % bovine serum albumin, 2mM EDTA
  • the cells are then washed and resuspended in culture medium at 5 x 105 cell/m l and plated out in Primeria 10 cm tissue culture petri dishes (Falcon Becton Dickinson) at 5 x 10n6 cells per dish. Culture is continued for 16-24hr to allow cell adherence, prior to experimentation involving hypoxia.
  • cardiom yoblast cultures were established.
  • Cells derived from the ventricular tissue of newborn or foetal hearts were purchased from BioWhittaker (CC-2582). Growth conditions were used to allow m aximum expansion of the cells in vitro, by using a m edium rich in grow th factors. Under such conditions cardiom yoblast-like cells predom inate (the developmental precursor of cardiom yocytes). This has been previously described by Goldm an and W urzel (In Vitro Cell. Dev. Biol. 28A : 109-1 19 (1992)) and Goldman et al, (1996, Exp.Cell.Res. 228(2): 237-245).
  • cells were seeded at l xlO 6 per T150 flask in human smooth muscle growth m edium (TCS CellWorks ZHM -3935) and were expanded in the same medium up to a maximum number of 4 passages.
  • the grow th medium is purchased pre-prepared, and includes in the form ula, 5% fetal bovine serum , insulin, epiderm al grow th factor and fibroblast grow th factor. Prior to experimentation involving hypoxia, cells were plated onto 10 cm tissue culture petri dishes and allowed to reach confluency.
  • hypoxia period of 6 hr was previously determined to be sufficient to allow the induction of known hypoxia-regulated genes, as determined by RNase protection assays.
  • RNase protection assays m acrophages, cardiomyoblasts and an additional control cell type, Jurkat T-cells, showed different patterns of gene induction in response to hypoxia:
  • Macrophage Myoblast T-cell phosphoglycerate kinase-1 none none high
  • VEGF solute carrier family 2, member 1 high low high
  • the final subtracted cDNA samples were evaluated by performing RT-PCR using the following primers for human beta actin: sense: TCACCCACACTGTGCCCATCTACGA antisense: CAGCGGAACCGCTCATTGCCAAATGG
  • the three subtracted cDNA populations were ligated into a plasmid vector (pCRII, Invitrogen) to generate libraries, which were transformed into E.coli (INV ⁇ F', Invitrogen) and plated out onto agar, supplemented with ampicillin and X-Gal, according to standard methods.
  • Colonies that are white indicate the presence of a recombinant plasmid, and these were picked into individual wells of 96-well plates containing 100 microliters LB -Ampicillin, and given 3-8 hr growth at 37 degrees. In this way, for each library, up to 15 x 96-well plates of clones were generated.
  • replicate arrays of plasmid insert DNA were generated on nylon m embranes: Firstly, PCR was performed using nested PCR primers 2R and 1 , which flank the cDNA insert of each clone (sequence described in the PCR Select kit).
  • the reaction mix also contains 200 uM d(A ,T,C,G)TP, Advantage2 polym erase mix (Clontech Laboratories) and supplied l Ox buffer, 40 ul reactions were set up in 96-well PCR reaction plates and inoculated with 0.5 ul bacteria from the library plates. 23 cycles of PCR were performed (95 degrees 10 sec; 68 degrees 2 m in), and a selection of wells were checked on an agarose gel. In this m anner a 96-well plate of insert DNA was generated for each 96-well plate of bacterial clones.
  • Arrays of insert DNA were generated by transferring 4ul of each well to 384-w ell plates (Genetix), and denaturing the DNA by adding 4ul 0.4M NaOH and incubating at 37 degrees for 15 minutes. Brom ophenol blue w as added to the wells to allow visualisation of arraying.
  • a 384-pin replicator (Genetix) was used to spot sm all volum es of denatured insert DNA onto dry nylon membranes (Hybond N+, AmershamPharmacia).
  • M atched pairs of m embranes were hybridised w ith subtracted cDNA samples; from hypoxic and norm oxic cells, to determine the abundance of the genes corresponding to each spotted clone in the cDNA samples. Because the cDNA probes were subtracted, large differences in the hybridisation signal for individual spots were apparent, which can be identified by eye. Prior to probe labelling, subtracted cDNA samples were digested with Rsal and run through Qiagen Qiaquick PCR purification columns to remove adapter sequences added during the PCR Select procedure.
  • Hybridisation, hybridisation and washes were performed essentially according to the Research Genetics GeneFilters protocol, but supplem enting the hybridisation mixture with 10 ug of a cocktail of oligonucleotides complementary to the Clontech PCR Select nested PCR primers (equimolar mix of prim ers 1 and 2R and their reverse complements).
  • Hybridized arrays were exposed to X-ray film or were exposed to a phosphorim ager (M olecular D ynamics, Storm) and clones showing gross differences in the hybridization signals with hypoxic compared to norm oxic cDNA probes were identified. This procedure was used to process all clones originally picked from the primary libraries and PCR amplified.
  • the selected clones were grouped together onto a single array (referred to here as a secondary array), and vtere re-screened with cDNA probes which had not been subtracted, to allow a m ore quantitative though less sensitive, evaluation of the relative abundance of the genes in hypoxia vs. norm oxia.
  • probes were ds cDNA generated from the Clontech SM ART cDNA synthesis kit (labelled using the Prom ega Prime-a-gene kit) or w ere total RNA (labelled according to the Research Genetics GeneFilters protocol), and hybridisations were done according to the Research Genetics GeneFilters protocol.
  • H ybridization signals were measured using a phosphorim ager and were processed with ArrayVision (Im aging Research Inc) softw are using m ultiple beta-actin spots to norm alise the quantitation and individual spot background correction.
  • ArrayVision Im aging Research Inc
  • the identity of the genes were determ ined using B LAST at the NCB I (NLM , NIH) against the non- redundant data base collection. W here significant m atches to human genes were not m ade, the hum an EST database was used, For both EST and non-EST hits, identifier numbers w ere also obtained from the UniGene database. The above strategy was used independently for libraries derived from macrophages and from cardiomyoblasts. B y screening a relatively large num ber of clones (several thousand per library), single genes were identified from m ultiple clones from any individual library. M ultiple clones covered either the same or different regions of the genes.
  • hypoxia-inducible genes were identified from clones only derived from the cardiom yoblast library. These genes are listed in Table 1. Certain hypoxia-inducible genes were identified from clones only derived from the macrophage libraries. These genes are listed in Table 2. Certain hypoxia-inducible genes were identified from clones derived from both m acrophage and m yoblast libraries, These genes are listed in Table 3.
  • Table 3 contains m any less genes than either Tables 1 and 2; demonstrating that these cell types have large differences in the genes induced by hypoxia.
  • the subtracted libraries for m acrophage and cardiom yoblast were constructed in parallel. Therefore, m ajor differences in the spectrum of genes isolated from these libraries are likely to be due to differences in the starting m aterial, rather than due to technical differences in the production of the libraries.
  • the genes contained in these tables were confirmed to be hypoxia-regulated in the relevant cell type(s) by the described two- stage array hybridisation screening process.
  • cardiom yoblast cDNA isolated from normoxic and hypoxic cells was hybridised to an array of macrophage-derived clones. These data are presented as a scatter plot, showing norm alised signal intensities in hypoxia versus norm oxia, with each dot representing a single gene on the array, This plot is presented in Figure 1 .
  • IM AGE clones were obtained from the UK M RC HGM P Resource Centre (Hinxton, Cam bridge CB 10 1 SB , UK) and were re-isolated as individual colonies and sequenced to verify the correct identity of the clone. In the m ajority of cases, the same IM AGE clone identified from the Research Genetics Hum an GeneFilters was selected, but in some instances these clones were not available and alternatives were selected, corresponding to the same gene.
  • the custom gene array is a single colour type array, and contains a selection of additional IM AGE clones corresponding to genes which w ere empirically determined not to be affected by hypoxia and which are highly expressed in a wide range of hum an tissues and cell types.
  • spot intensities were divided by the mean of all the reference genes shown below , each of which was present in quadruplicate on each array.
  • a GE clone plasm id miniprep DNA was prepared and PCR amplified with flanking vector primers of the sequences GTTTTCCCAGTCACGA CGTTG and TGAGCGGATAACAATTTCACACAG. This was then purified and concentrated by ethanol precipitation, and the presence of a single band and DNA concentration were determined by agarose gel electrophoresis and by digital imaging methods,
  • IMAGE and non-IMAGE Purified PCR product corresponding to all the clones (IMAGE and non-IMAGE) were normalised to 0,5 mg/ ml by dilution, Arrays were fabricated onto Hybond N+ (Amersham) membranes using a BioRobotics TAS arrayer (Biorobotics, Cambridge CB37LW , UK) with a 500 micron pin tool, Using 384-well source plates and a 2x2 arraying format this array was relatively low density, thereby eliminating problems of spot-to-spot signal bleed. Also the large pin size and high source plate DNA concentration improves the sensitivity of detection. Post-arraying denaturation/ neutralisation was essentially as described by Bertucci F et al, 1999 (Oncogene 18: 3905-3912).
  • the cDNA was then denatured by heating and added to the pre-hybridisation, which was continued for 18- 20hr. Washing steps were done as follows: 2xSSC/ 1 % SDS 2x20min at 50 degrees and 0.5xSSC/ 1 % SDS lOmin at 55 degrees. Arrays were exposed to Amersham Low Energy phosphor screens for 24hr and scanned using a phosphorimager at 50 micron resolution. Image analysis was done using ArrayVision software (Imaging Research Inc). Tab delimited data files were exported and a full analysis performed using GeneSpring software (Silicon Genetics).
  • Example lc Hypoxia regulation of gene expression in macrophages by exposing cells to hypoxia +/- additional signal amplification.
  • HIF- l ⁇ The transcription factor HIF- l ⁇ , is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia. This protein is considered a master regulator of oxygen hom eostasis (see, for example, Semenza, (1998) Curr. Op, Genetics and Dev. 8:588-594).
  • HIF- la is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPASl) or HIF-2a, which shares 48% sequence identity with HIF-la (Tian H, et al. Genes Dev. 1997 11 :72-82.).
  • adenoviral vectors were used to overexpress HIF-l a and EPAS l in primary human macrophages prior to exposure to hypoxia, in order to amplify the response. Because the role of these transcription factors as mediators of the hypoxia response is very well established, any further increases in the inducibility of specific genes resulting from this approach represents credible supporting evidence that those genes are responsive to hypoxia.
  • a commercially available system was used herein to produce adenoviral particles involving the adenoviral transfer vector AdApt, the adenoviral genome plasmid AdEasy and the packaging cell line Per-c6 (Crucell, Leiden, The Netherlands).
  • AdApt ires-GFP Three derivatives of the AdApt transfer vector have been prepared, named AdApt ires-GFP, AdApt HIF- la-ires-GFP and AdApt EPAS l -ires-GFP.
  • AdApt was modified such that inserted genes (i.e. HIF-l a or EPAS l) expressed from the powerful cytomegalovirus (CMV) promoter were linked to the green fluorescent protein (gfp) marker, by virtue of an internal ribosome entry site (ires). Therefore presence of green fluorescence provides a convenient indicator of viral expression of HIF-l a or EPAS l in transduced mammalian cells.
  • CMV cytomegalovirus
  • the control vector AdApt ires-GFP was used to allow discrimination between effects of the inserted genes (i.e. HIF-la or EPASl) to that of potential non-specific effects of adenoviral transduction or GFP expression.
  • Standard subcloning methods we e used to construct the adenoviral constructs as described in detail elsewhere (see co-pending, co- owned International patent application PCT/GB01/00758; Example 2).
  • adenoviral transfer vectors AdApt HIF-la-ires-GFP and AdApt EPAS l -ires-GFP were verified prior to production of adenoviral particles, for their ability to drive expression of functionally active HIF-la or EPASl protein from the CMV promoter in mammalian cells. This was achieved by transient transfection luciferase-reporter assays as described (Boast K et al Hum Gene Ther. 1999 Sep 1 ;10:2197-208).
  • adenoviral preparations were quantitated by spectrophotometry, yielding values of viral particles (VP) per milliliter.
  • RNA samples from the experimental conditions shown above were each hybridised to individual copies of the Custom gene array and processed as described earlier. To ensure reproducible data, this was repeated so each RNA sample was hybridised to 4 separate arrays. Therefore a total of 36 arrays were used for this experiment. Data analysis was done taking the mean signal of each spot from the four array replicates of each RNA sample. W hen displayed graphically, standard error of the mean is displayed as the error bar. Expression values were calculated so that they represent the fold-change ratio as compared to condition#l , i.e. untreated cells.
  • Example 2 Differences in the hypoxia responses of resting and activated macrophages.
  • Macrophages accumulate at hypoxic areas in various disease states, including cancer, rheumatoid arthritis, atherosclerosis and wound healing, At these sites macrophages activation is liable to occur, such as in response to T-cell derived gamma interferon. For instance, in atherosclerotic plaques there is an accumulation of both T-cells and macrophages, and these are known to interact with one another (reviewed in Lusis AJ, Atherosclerosis, Nature, 2000 Sep 14;407(6801):233-41).
  • RNA can be labelled to make cDNA probes, in a single step reaction, and probes are labelled with the same chemical group (33P), so there are no errors introduced as a result of using different dyes, which may differ in stability etc.
  • Phosphorimager allows detection over a wide range of intensities (over 4 logs).
  • Table 8 shows genes that are induced by hypoxia to a greater degree in resting m acrophages, as compared to activated macrophages. These data are presented illustratively in Figure 5.
  • Table 9 shows genes which are induced by hypoxia to a greater degree in activated macrophages, compared to resting m acrophages.
  • genes respond to hypoxia by decreasing mRNA expression (repression), and these genes therefore have hypoxia/normoxia ratios of ⁇ 1.0. This phenomenon is known in the field of hypoxia, although the mechanism is obscure. Data is presented in tables 7-9, which unexpectedly shows that this hypoxia- induced repression for specific genes is not a generic process, but is dependent on the cellular context.
  • Table 10/ Figure 7 genes are presented that are hypoxia-repressed to a greater degree in activated (column 7) compared with resting (column 8) macrophages. Prior to any hypoxic challenge, these gene are induced to varying degrees, in response to macrophage activation (column 9), suggesting a shared mechanism for these separate responses. From Table 10, genes in rows 1-6 show that macrophage activation is necessary to obtain any response to hypoxia. In resting m acrophages, these genes are not responsive to hypoxia at all.
  • Table 10/ Figure 7 shows that seven separate genes encoding chemokine proteins (Monocyte chemotactic protein 1 , Macrophage inflammatory protein lb, Monocyte chemotactic protein 3 and Small inducible cytokine A3, Monocyte chemotactic protein 2, Macrophage inflammatory protein 2a and Macrophage inflammatory protein 2 precursor) are more strongly repressed in activated macrophages as compared to resting macrophages. These genes are also among the most inducible in response to activation alone, in normoxia (column 9). These findings are of potential utility in view of the great significance of chemokines to inflammatory disease.
  • macrophage chemotactic factor 1 (Table 10, row 19) is key to the pathological role of the macrophage in atherosclerosis ("Chemokines and atherosclerosis” Reape TJ and Groot PHE, Atherosclerosis 147: 213-225, 1999).
  • Example 3 Tissue-specific hypoxia regulation of gene expression by an analysis of a series of prim ary human cell cultures.
  • RNA from hepatocytes at the 16hr timepoint of hypoxia was not available for this work.
  • RNA samples which were induced or repressed preferentially in particular cell ty ⁇ e(s) were identified by hybridisation of the RNA samples to the custom gene array, as described in Examples lb and lc.
  • Each RNA sample was hybridised to duplicate or triplicate arrays, to ensure reproducible data, and was analysed using GeneSpring software. Data from replicate arrays were merged during analysis to generate mean values. Data normalisation was achieved per-array using the aforementioned list of control genes, such that differences in RNA labelling or hybridisation due to experimental variation were corrected by referencing each gene to the mean value of the reference genes on the same array. Also, for each gene, expression values were obtained which represent the value in each experimental condition (e.g.
  • Table 12 shows the full dataset of this analysis. From this it can be seen that certain genes respond to hypoxia differently, depending on the particular cell type. This information is valuable in identifying biological targets for the development of therapeutic and diagnostic products. Not only does it indicate a particularly significant role for these genes in the specific cell type implicated in a disease, but it also identifies that any therapeutic product is less likely to produce problematic toxicological effects. Data shown in Table 12 and the derived figures, are reproducible, and are an accurate determination of mRNA expression levels. This m ay be confirmed by independent means, such as quantitative real time RT-PCR.
  • monocytes and macrophages are similar cell types, the latter derived from the former, they will be analysed together,
  • Ecotropic viral integration site 2A (Seq ID :475/476) is induced in hypoxic monocytes to a level over 25 times higher than the median expression level of this gene throughout the other cell types.
  • This gene of unknown function, is located on Chromosome 17ql 1.2 close to genes with immune functions.
  • expression of Ecotropic viral integration site 2A is downregulated in response to the inflammatory cytokine interferon gamm a.
  • Novel PI-3-kinase adapter Seq ID:79/80 Clone plE9 (EST accession R62339).
  • Seq ID :79/80 (EST accession R62339). It is seen that in hypoxic macrophages, this gene is expressed at 6-fold higher levels than the median expression level of this gene throughout the other cell types. Therefore, the levels of the encoded protein in hypoxic monocytes/ macrophages, as found at various disease sites, are likely to be higher than in other cell types not involved in the disease process or present at the site of disease. This illuminates a novel utility of this gene as a target for the development of therapeutic products for diseases involving monocytes/ macrophages and hypoxia,
  • RNA samples were examined by real time quantitative RT- PCR .
  • the advantages of this m ethod are that it is m ore sensitive and because two gene-specific primers are used, the data will be more specific to the gene in question.
  • RNA from the above samples (except for the hepatocyte RNA w hich w as unavailable) was Dnase I- treated prior to reverse transcription to rem ove possible contaminating genomic DNA and w as reverse transcribed using an oligo dT ( ⁇ 5) primer and Superscript II reverse transcriptase. These samples were used as template for PCR reactions using primers specific to EST accession R62339 or to beta-actin. Primer sequences were as follows:
  • Novel PlX-kinase adapter Seq ID:79/80 Clone pIE9 (EST accession R62339). Forward Primer 5' GCC CTT A GT TTT TCA CTT CTT CGT 3 ' Reverse Primer 5' CCT TAA GAT CCA TTC TCA TTG CTG AT 3 ' Beta Actin
  • RT-PCR reactions were performed using an AB I Prism 7700 Sequence Detector system .
  • a m aster mix w as prepared with 2x SYBR Green I m aster mix (Applied B iosystem s) and primers at 5 ⁇ M .
  • the thermal cycling conditions comprised 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles at 95°C for 15 seconds, and 60°C for 1 minute.
  • PCR reactions were set up in 96 well form at with duplicate amplifications for each data point including 8 serial cDNA dilutions (0.2, 0.1 , 0.05, 0.025, 0.01 , 0,005, 0,001 and 0.0001) of macrophage treated with 18 hours hypoxia to compose a standard curve, a no template control, no amplification control lacking reverse transcriptase, and each cDNA sample at a dilution value of 0.1.
  • the experiment for the novel PI3K adapter was carried out in triplicate for reproducibility which were later determined by linear regression analysis. Data was analysed with necessary adjustm ent of the default baseline and threshold line using ABI Prism 7700 software.
  • the C value, an important raw data for each sample, was calculated as the cycle number at which the ⁇ Rn crosses the baseline.
  • Data for the Novel PI-3-kinase adapter was normalized to that of beta-actin to correct for potential differences in efficiency of cDNA synthesis betw een the RNA samples.
  • adipocyte norm oxia 0.050 adipocyte hypoxia 6hr 0.007 adipocyte hypoxia 18hr 0.015 cardiom yocyte normoxia 0.163 cardiom yocyte hypoxia 6hr 0.037 cardiomyocyte hypoxia 18hr 0.222 endothelial norm oxia 3.093 endothelial hypoxia 6hr 0.059 fibroblast normoxia 0.527 fibroblast hypoxia 6hr 0.043 fibroblast hypoxia 18hr 0.037 m acrophage norm oxia 404.593 macrophage hypoxia 6hr 503.026 m acrophage hypoxia 18hr 1 162.056 m am mary epithelial norm oxia 0.026 mammary epithelial hypoxia 6hr 0.068 m ammary epithelial hypoxia 18hr 0.112 m onocyte normoxia 565.471 m onocyte hypoxia 6hr 657.
  • the array method is m ore likely to suffer from cross-hybridisation between similar genes.
  • the TaqM an data illustrates dramatically the concept that the hypoxia response is not just a generic response found in all cell types, relating to generic cell processes such as m etabolism ,
  • IM A GE clone acc:R62339 Database searches for gene sequences showing identity with IM AGE clone acc:R62339 reveal that there are no m atching hum an sequences of any type other than ESTs. This includes full length cD NAs, truncated cDNAs, gene sequences from chrom osom al data or hypothetical protein gene sequences. Therefore the hum an gene represented by IM A GE clone acc:R62339 is a novel human gene.
  • PI3-kinases are key to many cellular processes relevant to human disease, including proliferation, apoptosis and inflam mation.
  • the data presented for the gene encoded by Seq ID :79/80 provides evidence that the encoded protein is a novel drug target in hum ans, specifically targeting m onocyte/ macrophages at hypoxic disease sites.
  • the protein is identified as an adapter molecule connecting the non-receptor protein tyrosine kinase Syk to the p85 subunit of PI3-kinase, and therefore to the pivotal signalling pathw ays centred around PI3-kinase (Okada T et al "B CAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation.” Immunity. 2000 13:817-27).
  • Syk is acting as the intracellular signalling component of the B cell antigen receptor, which is present exclusively on B -cells
  • Syk has been shown to initiate intracellular signalling from other cell surface receptors which are expressed on macrophages, including the Fc gamm a receptor, the chemokine receptor CCR5 and m acrophage-expressed CD 8 (Darby C et al "Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein" .
  • fragments and functional equivalents of the PI-3-kinase adapter protein represented in Seq ID :79/80 and other equivalent proteins are included within the present invention, in addition to ligands that bind specifically to these proteins.
  • the invention also embraces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid molecules and host cells transformed with these vectors.
  • FIG. 10 Another intracellular signalling protein, Regulator of G-protein signalling 1 (RGS 1 ; Seq ID:375/376), in shown in Figure 10.
  • RGS 1 Regulator of G-protein signalling 1
  • the expression levels in the hypoxic monocyte is 30-fold higher than the median expression level of this gene throughout the other cell types.
  • the function of this protein is to negatively regulate G protein signalling pathways, and inhibit chemokine-induced cell migration of immune cells (M oratz C et al J Immunol 2000 164:1829-38 and Denecke B et al J Biol Chem. 1999 274:26860-8.).
  • Figure 10 shows that Regulator of G-protein signalling 1 is upregulated during differentiation of monocytes to macrophages, with significance to changes in cell motility,
  • inhibitors of RGS 1 have utility in increasing the motility of macrophages that are used for cell-based therapies.
  • one embodiment of this aspect of the invention provides for the use of an inhibitor of RGS 1 in therapy, by increasing the motility of macrophage cells.
  • GM2 ganglioside activator protein was originally characterised as a lysosomal co-factor required for degradation of gangliosides. It has been proposed to have alternative roles as a secreted protein, and can bind and inhibit the actions of the inflammatory mediator, platelet activating factor (Rigat B et al Biochem Biophys Res Commun. 1999 258:256-9.).
  • the gene interleukin 1 receptor antagonist (Seq ID :357/358) is seen to be down-regulated by hypoxia in the macrophage. Since the function of the encoded protein is anti-inflammatory, then down- regulation of this gene would be expected to have a pro-inflammatory effect. Therefore, corrective expression of the gene, would be expected to produce therapeutic effects in inflammatory disorders involving macrophages and hypoxia, such as Rheumatoid Arthritis (Hollander AP et al, Arthritis Rheum. 2001 44:1540-4). This correlates with effects seen from the application the drug Anakrina / KineretTM developed by Amgen. This supports the applicability of the genes disclosed herein as novel targets for therapeutic products.
  • gene interleukin 1 receptor antagonist also provides good exemplification of the concept that different cell types respond to hypoxia differently.
  • this gene is -/ ⁇ wfl-regulated by hypoxia in macrophages, but up- regulated by hypoxia in several other cell types, such as renal epithelial cells (see Figure 15), Such findings are not documented in the art.
  • SeqID 205/206 Hypothetical protein FLJ22690 SeqID :65/66 cDNA DKFZp586E1624 SeqID:197/198 EST
  • the dataset of Table 12 also contains genes which are induced preferentially in hepatocytes, in response to hypoxia. These genes are presented in Figures 32a and 33-38. It is noted that most of these genes, including hqp0376, encode proteins of the metallotheionein family, Furthermore, close inspection of these data reveals that the fold induction in hypoxia compared to normoxia for monocyte/ macrophages are very high, though the absolute levels of expression are below that of hepatocytes.
  • SeqID :337/338 Hypothetical protein hqp0376 (a metallotheionein) SeqID :265/266 M etallothionein 2A
  • EGL nine (C.elegans) homolog 3 As described above, it has been discovered that a polypeptide encoded by a gene identified from the EST recited in SEQ ID No 86, having the Protein accession number BAB 15101 (encoded by Homo sapiens cDNA: FLJ21620 fis, clone COL07838 Nucleotide accession AK025273) is regulated by hypoxia. Other public domain sequences corresponding to this gene include Homo sapiens cDNA: FLJ23265 fis, clone COL06456 Nucleotide accession AK026918.
  • SM20 Rascomb et al, J Neurochem 1999; 73(l):429-32; Lipscomb et al, J Biol Chem 2000 Nov 1; [epub ahead of print]).
  • SM20 has been shown to be expressed at high levels in the heart (Wax et al, J Biol Chem 1994; 269(17): 13041-7).
  • a fragm ent of this gene has been cloned from a cDNA library derived from hypoxic hum an cardiom yoblasts, and it has been shown that the gene is increased in expression in response to hypoxia in this cell type (see Table 1 herein; penultim ate row ).
  • the nucleotide sequence of this cDNA fragment is referred to herein as SEQ ID No 90a.
  • a suitable treatment may involve altering the susceptibility of ischaemic myocardial tissue to subsequent reperfusion and re-oxygenation, or m ay involve modulating the susceptibility of chronic ischaem ic m yocardial tissue (including form s of angina) to later m ore severe ischaem ia, which would result in m yocardial infarction. It is submitted that, by way of analogy, cerebral ischaem ia may be treated using the same principle.
  • SM 20 and related genes such as EGLN3 (B AB 15101 ), c l orfl 2 (AAG34568), and CAB 81622, namely, apoptosis and angiogenesis might be explained as follows.
  • the apoptotic effect of N GF withdraw al may be mediated by induction of the hypoxia pathway, but m ay be an aspect of the supposed involvement of the HIF protein in the stress response.
  • FHFl ⁇ is induced by reactive oxygen species (see Richard et al. J Biol Chem 2000 Sep 1 ;275 (35):26765-71 ).
  • m odulation of SM 20 and the related genes EGLN3 (BAB 15101 ), cl orfl 2 (AAG34568), and CAB 81622 m ay have applications in the treatment of diseases resulting from disturbances in proteosome function, such as prion diseases and other neuro-degenerative diseases.
  • proline hydroxylases For example, two genes encoding proline hydroxylases have been identified herein as being increased in expression in response to hypoxia (proline 4-hydroxylase, alpha polypeptide 1 ; SeqID : 231/232, proline 4-hydroxylase, alpha polypeptide II; SeqID : 349/ 350). This identified a functional significance of proline hydroxylation as a response to hypoxia,
  • Proline hydroxylase leads to degradation of HIFl ⁇ in normoxia (HDF regulates its own degradation - feedback). Hydroxylated HEFl ⁇ + VHL leads to ubquitination and consequent degradation of HFl ⁇ by proteosome.
  • the activity of the prolyl hydroxylase is 0 2 -dependent, so under conditions of hypoxia, HIFl ⁇ is not hydroxylated efficiently and is stabilised. HIFl ⁇ protein thus accumulates to a high level.
  • the hypoxia-induction of the prolyl hydroxylase ensures that when O 2 concentration returns to normal, there is sufficient enzyme available to target this high level of HDFl ⁇ efficiently for rapid degradation.
  • SM20 and the related genes EGLN3 (BAB 15101), cl orfl2 (AAG34568), and CAB 81622 may act as tetramers
  • Known prolyl hydroxylases such as prolyl 4-hydroxylase (P4H) are known to act as tetramers of two alpha subunits and two beta subunits.
  • P4H prolyl 4-hydroxylase
  • SM20 and the related genes exhibits high similarity to the alpha subunit of P4H and it therefore seems likely that SM20 and the related genes are likely to have a binding partner that is equivalent to the beta subunit of P4H.
  • SM20 has been shown to bind to the transcription factor HIFl ⁇ , and shares a low level homology with a p53 binding protein.
  • P53 is a transcription factor that is known to be involved in apoptosis. Accordingly, it is proposed that in addition to binding to HIF1A, SM 20 and the related genes EGLN3 (BAB 15101 ), clorfl2 (AAG34568), and CAB 81622 may also bind and modify other transcription factors that are involved in the hypoxic response such as EPAS and HIF3A, or other transcription factors such as p53 and thereby influencing apoptosis.
  • This aspect of the invention thus provides dimer and tetrameric forms of the EGLN3 (BAB 15101), cl orfl2 (AAG34568), and CAB81622 proteins, preferably complexed with a protein selected from the group consisting of HIFl ⁇ , p53 and a protein binding partner that is equivalent to the beta subunit of P4H.
  • a protein selected from the group consisting of HIFl ⁇ , p53 and a protein binding partner that is equivalent to the beta subunit of P4H Preferably, such dimers and tetramers are heterodimers/heterotetramers.
  • both genes are inducible in response to hypoxia in m acrophages whether activated by gamm a interferon and lipopolysaccharide or if de-activated by treatment with interleukin-10.
  • the absolute expression level of C l orf 12 appears to be higher than EGLN3.
  • EGLN and clorf 12 are 0.015 and 0.0074 respectively, i.e. EGLN being the dom inant gene.
  • the normalised expression values of EGLN and c l orfl 2 after 6hr hypoxia are 0.0012 and 0.108 respectively, i.e. cl orf 12 being the dominant gene by a large margin.
  • therapeutic products may be developed based on this data, with the goal of modulating proline hydroxylation of target proteins (such as HIFl alpha) in specific tissues, based on the differing expression profile of cl ORF12 and EGLN 3 in those tissues.
  • target proteins such as HIFl alpha
  • Example l b genes were identified from a custom array, which give a greater induction in macrophages (by a factor of at least 1.5) when hypoxia is augmented by over-expression of HIFl alpha or EPAS from an adenovirus.
  • the data from the HIF/ EPAS over-expression w ork is presented herein in Example l c, but specifically relating to c l ORF12 and EGLN3 is summ arised in Figures 32e and 32f.
  • RNA samples for experimental conditions 1 ,3,5,7,9 were also measured using a different array-based m ethodology- the AffyMetrix GeneChip. The results of this experiment are presented in Figures 32g and 32h.
  • EGLN3 has been cloned into pONY ⁇ .l and Smart2.
  • IRES GFP equine infectious anaemia virus (EIAV) vectors
  • AdCM V. TRACK GFP (AdenoQuest) adenoviral genome vectors (see co-owned co-pending
  • Human embryo kidney (HEK 293T) and dog osteosarcoma (D 17) cell lines have been used in transient plasmid transfection experiments to confirm EGLN3 expression from viral vector genomes.
  • Rat cardiomyocyte cell line (H9C2) and primary human neonatal cardiomyocytes (PHNC) BioWhittaker,
  • CC2582 have been used in viral transduction experiments to determine the biological activity of EGLN3.
  • Immunofluorescence and Western blotting employ an antibody specific for the FLAG epitope engineered into the 3' terminus of EGL nine (C.elegans) homolog 3 (Sigma, F3165).
  • TaqMan quantitative PCR utilises the SYBR Green method (Applied Biosystems).
  • TaqMan primers have been designed and optimised for the initial measurement of EGL nine (C.elegans) homolog 3 expression in EIAV or Adenovirus transduced H9C2 and PHNC (Forward: TCATCGACAGGCTGGTCCTC ; Reverse: GTTCCATTTCCCGGATAGAA). All findings at the RNA level are corroborated by immunofluorescence and Western blotting analyses at the protein level.
  • EIAV transduction of H9C2 and PHNC has been optimised with constructs containing green fluorescence protein (GFP) and LacZ reporter genes, using the VSVg envelope and a range of MOI between 10 and 100. GFP results were scored by fluorescence microscopy, while LacZ transductants were identified through the assay of ⁇ -galactosidase activity. An MOI of 50 transduced approximately 50% of the cell population.
  • GFP green fluorescence protein
  • EGLN3 is predicted to have pro-apoptotic activity in cardiomyocytes.
  • PS membrane phospholipid phosphatidylserine
  • Translocation of PS has been identified through use of ApoAlert kit (Clontech; K2025-1), which employs FITC-labelled antibodies to detect surface expression of the PS, Annexin V.
  • Caspase activity has been followed using the homogeneous fluorimetric caspase assay (Roche; 3005372) which allows the quantification of caspase activity through the cleavage of a fluorescent substrate.
  • DNA fragmentation has been estimated using the nuclear stain Hoescht 33345 (Sigma, B2261 ; and fluorescence microscopy to locate areas of chromatin condensation.
  • EGL nine (C.elegans) homolog 3 in transduced cells is confirmed by TaqMan, immunofluorescence and Western blotting. Similar experiments are performed to determine whether EGL nine (C.elegans) homolog 3 expression further sensitises H9C2 and PHNC to previously defined ischaemic insults. Staurosporine (Calbiochem ; 569397) and Smart2. IRES. GFP EIAV vectors containing the Bax gene will be applied as chemical and viral pro-apoptotic controls, respectively (Yue, T-L., et al., J. M ol. Cell, Cardiol. 1998, 30, 495-507; Reed, J.C. J Cell Biol, 1994, 124(1 -2):1 -6).
  • RNA interference (Elbashir, SM et al., Nature 2001 , 411 , 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed. Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA , reducing or ablating target protein expression.
  • a Hammerhead ribozyme library, contained in EIAV expression vectors, may also be ' applied. Efficacy of both gene silencing approaches m ay be assessed initially through the measurement of EGLN3 expression, at the RN A level by TaqM an and at the protein level by W estern blotting, Protection against previously described ischaemic insults provided by these methods of EGLN3 gene silencing may be assayed biologically as detailed above.
  • C aspase inhibitors caspase 3 inhibitor V, 2129002 and caspase inhibitor I, 627610, both Calbiochem
  • GFP EIA V vectors containing the B cl-2 gene may be applied as chemical and viral anti-apoptotic controls, respectively (Kroemer, G, Nat Med. 1997, 3(6):6 l4-20). Similar "gain-of-function" and gene silencing approaches will be applied to the related gene, encoded by SEQ ID 90, named cl ofl 2.
  • Table 12 also contains genes which are induced preferentially in renal epithelial cells, in response to hypoxia. These genes are presented in Figures 39-44. SeqID :1 17/1 18 EST
  • Sem aphorin 4b Sem aphorin 4b (SeqID :91/92/92a), the clone presented in Figure 43 is p l Pl4, corresponding to IMAGE clone ace B E910319, the sequence of w hich covers a large region of the gene including protein coding sequence, which may cross-hybridise to other members of the semaphorin family.
  • Table 12 also contains genes which are induced preferentially in m ammary epithelial cells, in response to hypoxia. These genes are presented in Figures 45-52. SeqID :447/448 Calgranulin A SeqID :67/68 ER01 (S, cerevisiae)-like
  • Cox-2 which encodes a key drug target
  • endothelial cells there is a clear induction in response to hypoxia.
  • endothelial cells there is a very significant time-dependent decrease in Cox-2 gene expression in response to hypoxia
  • Calgranulin A there is strong positive induction in hypoxic mammary epithelial cells, but in the macrophage, the response to hypoxia is negative.
  • Example 4 Additional disclosure of the effect of macrophage activation on hypoxia regulation of gene expression
  • Example 2 it is shown that activated and resting macrophages respond to hypoxia in different ways, showing that the hypoxia response is not a generic phenomenon.
  • experiments were performed with the custom array, using additional experimental conditions and with a more in-depth analysis.
  • the expression values used are not simple hypoxia/ normoxia ratios, done separately for macrophages of differing activation status, but rather the values used allow comparison of the relative expression levels throughout the entire set of experimental conditions.
  • all values throughout the entire set of experimental conditions are calculated by comparison to the median level of that gene throughout the dataset. This allows a clearer appreciation of the effects of hypoxia in the context of cell activation status.
  • LPS Lipopolysaccharide
  • IFN gamma Interferon
  • IL-10 Interleukin-10
  • the gene SCYA8 (plI21 ; SeqID : 479/480) is decreased in expression by hypoxia, changing from 0.54 to 0.18 between conditions #1 and #2.
  • condition #5 LPS+IFN normoxia
  • expression is dramatically increased to a value of 19.6.
  • LPS+IFN is combined with hypoxia, this increase is dampened-down to a value of 12.2.
  • hypoxia and cell activation have opposing effects on gene expression.
  • a similar expression profile is found for several other genes in Table 15,
  • the gene P8 protein-candidate of metastasis 1 (pl F17; SeqID: 329/330) is increased in expression by hypoxia, changing from 0.26 to 1.78 between conditions #1 and #2.
  • condition #5 LPS+IFN normoxia
  • condition #6 LPS+IFN normoxia
  • the expression is further increased to a value of 2.59. So for this example, hypoxia and cell activation have similar effects on expression (i.e. increases) and these are found to be synergistic.
  • a similar expression profile is found for several other genes in Table 15, including for Semaphorin 4b (plP14; SeqID :91/92/92a), which has been independently verified by RNase protection assay (see Figure 57). .
  • IMAGE clones were classed as novel and unannotated when the original patent filing was made (8 Dec 2000), but which can now be assigned to named genes. These are Uridine 5' monophosphate hydrolase 1 (clone pi 17 ; SeqID: 49/50) and Insulin induced protein 2 (clone pID IO; SeqID:75/76).
  • Table 17 show s genes responsive to IL-10 (increased or decreased) but not affected significantly by LPS+IFN . Various patterns of hypoxia regulation will be appreciated.
  • One of the utilities of the genes identified herein relates to the diagnosis and treatment of human tumors, on the basis that hypoxia is frequently found in tumors.
  • E 50 year old Caucasian female.
  • Diagnosis ovarian adenocarcinom a. Norm al ovarian tissue derived from an age-m atched separate individual.
  • F 60 year old female. Diagnosis: poorly differentiated adenocarcinoma. Norm al ovarian tissue derived from the same individual. G: 41 year old female. Diagnosis: moderately-differentiated adenocarcinoma. Normal ovarian tissue derived from the same individual.
  • H 40 year old female. Diagnosis: invasive ductal carcinoma. Normal breast tissue derived from the same individual. K: 58 year old female. Diagnosis: invasive ductal carcinoma. Normal breast tissue derived from the same individual.
  • Per-gene normalisation was done such that the expression values of each gene are relative to the median value of that gene throughout the series of samples, By comparing the expression values under normal (nor) and tumor (tum) for a single patient, differences in expression between the normal and malignant tissue of that patient can be inferred.
  • Table 18 are genes which are up-regulated at least 3-fold in at least one patient, comparing the tumor tissue to the adjacent normal tissue.
  • Table 19 are genes which are down-regulated at least 3-fold in at least one patient, comparing the tumor tissue to the adjacent normal tissue.
  • Example 6 Effects of inflammatory cytokines on hypoxia-regulated genes
  • Tumor necrosis factor alpha is a key pro-inflammatory cytokine both produced by and acting on the macrophage.
  • TNF ⁇ Tumor necrosis factor alpha
  • Gene expression levels were measured and compared using the custom gene array. In data analysis per- gene normalisation was set up such that expression values represent the fold-change compared with the expression in untreated normoxic cells. Genes which are increased in expression in response to TNF ⁇ by at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 20. Genes which are decreased in expression in response to TNF ⁇ by at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 21. Another inflammatory cytokine implicated in diseases where hypoxia is frequently found is In terleu kin - 17 (IL-17).
  • IL-17 terleu kin - 17
  • this cytokine has been shown to mediate inflammation and joint destruction in arthritis (Lubberts et al J.Immunol 2001 167:1004-1013).
  • IL-17 has also been shown to stimulate macrophages to release other key pro-inflammatory cytokines (Jovanovic et a 1 J Immunol 1998 160:3513-21). Therefore genes which respond to both hypoxia and IL-17 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
  • Genes which are increased in expression in response to IL-17 by at least 2- fold, in either normoxic or hypoxic cells are shown in Table 22.
  • Genes which are decreased in expression in response to IL-17 by at least 2-fold, in either normoxic or hypoxic cells are shown in Table 23.
  • the cytokine IL-15 is implicated in several disease in which macrophages and hypoxia both feature as elements of the inflammatory state, such as in atherosclerosis (Wuttge DM et al Am J Pathol. 2001 159:417-23) and rheumatoid arthritis (Mclnnes IB et al Immunol Today. 1998 19:75-9).
  • atherosclerosis Wangtge DM et al Am J Pathol. 2001 159:417-23
  • rheumatoid arthritis Mclnnes IB et al Immunol Today. 1998 19:75-9
  • T-cells effects have also been shown on monocytes (Badolato R et al Blood, 1997 90:2804-9). Therefore genes which respond to both hypoxia and IL-15 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
  • Primary rat foetal cardiomyocytes provide an attractive experimental model for studying the responses of cardiac cells to ischaemia.
  • Cells are obtained which are non-immortalised and which are seen to contract or beat in culture. It is of interest to examine how the responses of these cells to hypoxia (or related experimental conditions) compared and contrasts to other cell types. These other cell types might include those that are similarly sensitive to the effects of hypoxia (such as neurones) or might be cells that show a higher tolerance to hypoxia (such as macrophages).
  • Experiments are performed in parallel for cardiomyocytes and other cell type(s). The responses of these specific cell types is then determined by hybridising labelled mRNA to microarrays. Alternative methods will include the construction of subtracted cDNA libraries for the individual treated cell types and assessing which genes are contained therein by sequencing.
  • Cardiomyocytes are harvested from heart ventricles of embryos aged E18 days, using a cell isolation kit (Neonatal cardiomyocyte isolation system; Worthington Biochemical Corporation, Lakewood, New Jersey, 08701). They are seeded at 5xl0 6 cells/lOOcm diameter petri dish in DMEM/M 199, 10% horse serum , 5% FCS, 1 % penicillin, streptomycin, glutamine for 5 days at 37C . Media is changed during the 5 days.
  • cell types used for comparison with cardiomyocytes are cultured according to their optimum conditions and/ or the standard routine. These cell types may include cardiomyocytes in a different physiological setting, such as in an intact beating heart, or a different developmental state of the cardiomyocyte, such as cardiomyoblast.
  • Identical seeded petri dishes are placed either in a standard tissue culture incubator (95% air/ 5% C02) or in a hypoxia incubator (0.1 % oxygen / 5% C02 / 0.1 % oxygen for 6 hours. This is done separately for both cardiomyocytes and the other cell type(s) to be compared. Other experimental conditions might more closely approximate ishemia, by incorporating components additional to hypoxia.
  • RNA is extracted using RNazol B (Tel-Test, Inc; distributed by Biogenesis Ltd) following the manufacturers instructions. W here appropriate, polyadenylated mRNA is extracted from the total RNA using a commercial kit following the manufacturers instructions (Promega; PolyATract mRNA isolation System IV),
  • Example 8 Comparison of the hypoxic-responses between populations of rat primary cultured neurons by a subtraction cloning / array screening approach.
  • Such comparisons may be m ade by hybridizing labelled mRNA to microarrays or derivatives thereof, Alternatively subtracted libraries might be constructed individually for each treated neuron subtype, and clones which are confirmed to be changed in expression to be sequenced, The collection of genes arising from the different neuron subtypes will be compared.
  • Isolated neurons include but are not limited to those from ventral mesencephalon, striatum, hippocampus, cerebellum , cerebral cortex, dorsal root ganglia and superior cervical ganglia.
  • hypoxic stimulus either independent from or subsequent to hypoxia- preconditioning, cells are transferred to the hypoxic incubator for 2-6 hours as determined in time course experiments. Additionally, as appropriate, the medium in which the cells are grown is replaced with glucose-free media for establishment of experimental ischaemia (Ray AM , Owen DE, Evans ML, Davis JB Benham , 2000. Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA 1 death in rat organotypic hippocampal slices).
  • RNA is extracted using RNazol B (Tel-Test, Inc; distributed by Biogenesis Ltd) following the manufacturers instructions. W here appropriate, polyadenylated mRNA is extracted from the total RNA using a commercial kit following the manufacturers instructions (Promega; PolyATract mRNA isolation System IV).
  • Example 9 Semaphorin 4b W e have screened cDNA libraries derived from the human brain and leukocytes, to obtain an unequivocal and accurate full length cDNA sequence (SEQ ID No 92a) and the accurate presumptive amino acid sequence (SEQ ID No 91 ).
  • hypoxia is a feature of several inflamm atory conditions often accompanied by superoxide radicals and the immune regulator gam m a interferon.
  • hypoxia is a feature of several inflamm atory conditions often accompanied by superoxide radicals and the immune regulator gam m a interferon.
  • psd-95 is another m acrophage hypoxia-induced protein (see SEQ ID N o 299). This is based on the fact that psd-95 binds the cytoplasmic tail of Sem a4c (Inagaki et al., J B iol Chem . 2001 ; 276(12): 9174-81 ), w hich like Sema4b, contains proline rich sequence. Therefore, both Sem aphorin 4B , and a probable partner are co- ordinately regulated by hypoxia.
  • Hypothetical protein FLJ13611 The protein sequence encoded by Hypothetical protein FLJ13611 is represented in the public databases by the accession NP_079217 and is described in this patent by Seq ID 1.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_024941 and is described in this patent by Seq ID 2.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
  • the Oxford BioM edica clone p l F2 represents Hypothetical protein FLJ20037.
  • the protein sequence encoded by Hypothetical protein FLJ20037 is represented in the public databases by the accession CAB65981 and is described in this patent by Seq ID 3.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM, 017633 and is described in this patent by Seq ID 4.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found.
  • Hypothetical protein FLJ20037 is downregulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. W e expect increased activity of the gene product to have an anti-tum our effect.
  • the O xford BioMedica clone pl Fl O represents Hypothetical protein D KFZp434P0116.
  • the protein sequence encoded by Hypothetical protein DKFZp434P0116 is represented in the public databases by the accession T46364 and is described in this patent by Seq ID 5.
  • Hypothetical protein DKFZ ⁇ 434P0116 is predicted to be a kinase due to high structural similarity with other known kinases, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypothetical protein DKFZp434P01 16 is repressed in m acrophages activated by LPS and gamma interferon. W e expect it to have an anti-inflammatory role.
  • the Oxford BioM edica clone p 1 FI 9 represents Hypothetical protein KIAA0212.
  • the protein sequence encoded by Hypothetical protein KIAA0212 is represented in the public databases by the accession B AA 13203 and is described in this patent by Seq ID 7
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014674 and is described in this patent by Seq ID 8.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioMedica clone p lF8 represents Hypothetical protein KIAA0914.
  • the protein sequence encoded by Hypothetical protein KIAA0914 is represented in the public databases by the accession NP_055698 and is described in this patent by Seq ID 9.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014883 and is described in this patent by Seq ID 10.
  • Hypothetical protein KIAA0914 show s high structural similarity to Human Class I alpha 1 ,2- M annosidase and conservation of active site and binding site residues, therefore we predict that Hypothetical protein KIAA0914 will act as a mannosidase.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein KIAA0914 is repressed in m acrophages activated by LPS and gamma interferon. W e expect the gene product to have an anti-inflamm atory role.
  • Hypothetical protein FLJ20281 The protein sequence encoded by Hypothetical protein FLJ20281 is represented in the public databases by the accession XP_008736 and is described in this patent by Seq ID 11.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_017742 and is described in this patent by Seq ID 12.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • TNFalpha is an inflam m atory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatm ent of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Hypothetical protein FLJ20281 is induced in .m acrophages activated by TNFalpha.
  • the O xford B ioM edica clone plFl 8 represents Hypothetical protein KIAA0876.
  • the protein sequence encoded by Hypothetical protein KIAA0876 is represented in the public databases by the accession BAA74899 and is described in this patent by Seq ID 13.
  • the nucleotide sequence is represented in the public sequence databases by the accession XM_035625 and is described in this patent by Seq ID 14.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford BioMedica clone pl F7 represents Spectrin, beta, non-erythrocytic 1 .
  • the protein sequence encoded by Spectrin, beta, non-erythrocytic 1 is represented in the public databases by the accession NP_0031 19 and is described in this patent by Seq ID 15.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003128 and is described in this patent by Seq ID 16.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tum ours w here m acrophage infiltrates are also found.
  • Spectrin, beta, non-erythrocytic 1 is downregulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
  • W e expect increased activity of the gene product to have an anti-tum our effect,
  • Hematopoietic Zinc finger protein The Oxford BioM edica clone p l F21 represents Hem atopoietic Zinc finger protein.
  • the protein sequence encoded by Hem atopoietic Zinc finger protein is represented in the public databases by the accession AAL08625 and is described in this patent by Seq ID 17.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK024404 and is described in this patent by Seq ID 18.
  • Hematopoietic Zinc finger protein is a transcriptional regulator that contains a Cys2-His2 zinc finger motif. It is predicted to bind to metal response elements (MRE) and therefore activate the transcription of genes that contain a MRE sequence within their promoter region such as metallothioneins.
  • MRE metal response elements
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types.
  • Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD .
  • Hematopoietic Zinc finger protein is preferentially induced by hypoxia in monocytes or macrophages and a restricted number of other cell types. It is therefore a candidate for specific intervention for treatment or diagnosis of the above diseases.
  • the Oxford BioMedica clone plF9 represents Hypothetical protein KIAA0742.
  • the protein sequence encoded by Hypothetical protein KIAA0742 is represented in the public databases by the accession NP_060903 and is described in this patent by Seq ID 19.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB018285 and is described in this patent by Seq ID 20.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • hypothetical protein KIAA0742 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. Hypothetical protein KIAA0742 shows significant homolgy to the transcription factor hairless. W e therefore propose that Hypothetical protein KIAA0742 may play a crucial role in the regulation of hair growth.
  • this aspect of the invention includes the use of this protein, fragments and functional equivalents of this protein, encoding nucleic acid molecules, in addition to ligands that bind specifically to this protein, in the diagnosis and treatment of hair loss.
  • the Oxford BioMedica clone plEl 3 represents Hypothetical protein PRO0823.
  • the protein sequence encoded by Hypothetical protein PRO0823 is represented in the public databases by the accession AAF71073 and is described in this patent by Seq ID 21.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF116653 and is described in this patent by Seq ID 22.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein PRO0823 is repressed in m acrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role.
  • Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • Hypothetical protein PRO0823 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect increased activity of the gene product to have an anti-tumour effect.
  • Hypothetical protein FLJ10134 The Oxford BioMedica clones plD l and plD2 represent the Hypothetical protein FLJ10134.
  • the protein sequence encoded by Hypothetical protein FLJ10134 is represented in the public databases by the accession NP_060474 and is described in this patent by Seq ID 23.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018004 and is described in this patent by Seq ID 24.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFl alpha and EPAS l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • Hypothetical protein FLJ10134 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPASl .
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant,
  • Hypothetical protein FLJ10134 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role.
  • Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • Hypothetical protein FLJ10134 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plD4 represents Hypothetical protein FLJ20500.
  • the protein sequence encoded by Hypothetical protein FLJ20500 is represented in the public databases by the accession NP_061931 and is described in this patent by Seq ID 25.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_019058 and is described in this patent by Seq ID 26.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypothetical protein FLJ20500 is preferentially induced by hypoxia in mammary epithelial cells.
  • the Oxford BioMedica clone plD9 represents Hypothetical protein DKFZP564D 116.
  • the protein sequence encoded by Hypothetical protein DKFZP564D 116 is represented in the public databases by the accession T08708 and is described in this patent by Seq ID 27,
  • the nucleotide sequence is represented in the public sequence databases by the accession AL050022 and is described in this patent by Seq ID 28.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • hypothetical protein DKFZP564D 116 is repressed in macrophages activated by LPS and gamma interferon.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Hypothetical protein DKFZP564D 116 is induced in macrophages activated by TNFalpha.
  • the Oxford BioMedica clone plD 12 represents Hypothetical protein KIAA 1376.
  • the protein sequence encoded by Hypothetical protein KIAA 1376 is represented in the public databases by the accession BAA92614 and is described in this patent by Seq ID 29.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB037797 and is described in this patent by Seq ID 30,
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • TRIP-Br2 The protein sequence encoded by TRIP-Br2 is represented in the public databases by the accession NP_055570 and is described in this patent by Seq ID 31.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014755 and is described in this patent by Seq ID 32,.
  • TRIP-BR2 is a PHD zinc finger and bromodomain interacting protein transcriptional regulator and is involved in the regulation of cell cycle progression. Its hypoxia-regulation is likely to have important disease-relevant effects. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue.
  • TRIP-B r2 is preferentially induced by hypoxia in renal epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes.
  • hypothetical protein FLJ20308 The protein sequence encoded by Hypothetical protein FLJ20308 is represented in the public databases by the accession XP_039852 and is described in this patent by Seq ID 33.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK000315 and is described in this patent by Seq ID 34.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein FLJ20308 is repressed in macrophages activated by LPS and gamm a interferon. W e expect it to have an anti-inflamm atory role.
  • the Oxford B ioM edica clone p 1 J 13 represents Hypothetical nuclear factor SBB I22.
  • the protein sequence encoded by Hypothetical nuclear factor SB B I22 is represented in the public databases by the accession NP_065128 and is described in this patent by Seq ID 35.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_020395 and is described in this patent by Seq ID 36.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone pi 122 represents Hypothetical protein KIAA 1429.
  • the protein sequence encoded by Hypothetical protein KIAA 1429 is represented in the public databases by the accession B AA92667 and is described in this patent by Seq ID 37.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB 037850 and is described in this patent by Seq ID 38, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford BioM edica clone pl J6 represents Hypothetical protein FLJ10206.
  • Hypothetical protein FLJ10206 The protein sequence encoded by Hypothetical protein FLJ10206 is represented in the public databases by the accession AAH06108 and is described in this patent by Seq ID 39.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018025 and is described in this patent by Seq ID 40.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein FLJ10206 is repressed in macrophages activated by IL-17 and is also repressed in m acrophages activated by IL-15. These are pro-inflamm atory cytokines, and we expect the hypothetical protein FLJ10206 to have an anti-inflam matory role.
  • Hypothetical protein FLJ10815 The protein sequence encoded by Hypothetical protein FLJ10815 is represented in the public databases by the accession B AA91830 and is described in this patent by Seq ID 41. The nucleotide sequence is represented in the public sequence databases by the accession NM_018231 and is described in this patent by Seq ID 42, Hypothetical protein FLJ10815 is structurally sim ilar to an alpha / beta barrel structure. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein FLJ10815 is repressed in m acrophages activated by LPS and gamm a interferon. W e expect it to have an anti-inflammatory role.
  • the O xford B ioMedica clone p 1 II 3 represents Hypothetical protein FLJl l l OO.
  • Hypothetical protein FLJl l lOO is represented in the public databases by the accession NP_060701 and is described in this patent by Seq ID 43.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018321 and is described in this patent by Seq ID 44.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypothetical protein FLJ20644 The protein sequence encoded by Hypothetical protein FLJ20644 is represented in the public databases by the accession NP_060387 and is described in this patent by Seq ID 45. Hypothetical protein FLJ20644 is a putative Serine/threonine phosphotase. Region 250 - 450 show s high structural similarity to other Serine/threonine phosphotases.
  • nucleotide sequence is represented in the public sequence databases by the accession NM_017917 and is described in this patent by Seq ID 46, Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
  • Hypothetical protein CGI-1 17 The protein sequence encoded by Hypothetical protein CGI-1 17 is represented in the public databases by the accession Q9Y3C 1 and is described in this patent by Seq ID 47 .
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016391 and is described in this patent by Seq ID 48 .
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore im plicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFl alpha and EPA S l are transcription factors that m ediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • B y adenoviral over-expression of HIFl alpha or EPAS l we show augmentation of the hypoxic induction of certain genes, further confirm ing their status as responsive to hypoxia.
  • Hypothetical protein C GI-1 17 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of either HIF l alpha or EPA S l .
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein CGI-117 is repressed in m acrophages activated by LPS and gamma interferon. W e expect it to have an anti-inflammatory role.
  • the O xford BioMedica clone p 117 represents Uridine 5' monophosphate hydrolase 1.
  • the protein sequence encoded by Uridine 5' monophosphate hydrolase 1 is represented in the public databases by the accession NP_057573 and is described in this patent by Seq ID 49.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016489 and is described in this patent by Seq ID 50.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • cytokines which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Uridine 5' monophosphate hydrolase 1 is induced in m acrophages activated by LPS and gamma interferon and is also is induced in m acrophages activated by IL-15. W e expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflam m atory effect.
  • the protein sequence encoded by Hypothetical protein KIAA0014 is represented in the public databases by the accession NP_055480 and is described in this patent by Seq ID 51.
  • nucleotide sequence is represented in the public sequence databases by the accession NM_014665 and is described in this patent by Seq ID 52, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone p 114 represents Hypothetical protein HSPC 196.
  • the protein sequence encoded by Hypothetical protein HSPC 196 is represented in the public databases by the accession NP_057548 and is described in this patent by Seq ID 53.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016464 and is described in this patent by Seq ID 54.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hypothetical protein HSPC 196 is repressed in m acrophages activated by LPS and gam ma interferon. W e expect it to have an anti-inflamm atory role.
  • the O xford B ioMedica clone p l I8 represents Hypothetical protein FLJ1 1296.
  • the protein sequence encoded by Hypothetical protein FLJ1 1296 is represented in the public databases by the accession XP_004747 and is described in this patent by Seq ID 55.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018384 and is described in this patent by Seq ID 56.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone p 1 II 6 represents Hypothetical protein KIAA 1668.
  • Hypothetical protein KIAA 1668 is represented in the public databases by the accession B AB 33338 and is described in this patent by Seq ID 57.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB051455 and is described in this patent by Seq ID 58.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • SECIS binding protein 2 The Oxford B ioM edica clone pl ll l represents SECIS binding protein 2.
  • the protein sequence encoded by SECIS binding protein 2 is represented in the public databases by the accession AAK57518 and is described in this patent by Seq ID 59.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF380995 and is described in this patent by Seq ID 60.
  • SECIS binding protein 2 is a crucial component in the complex required for the translation of mammalian selenoprotein mRNAs. Selenoproteins are important responders to redox conditions and many selenoproteins are known to protect from cell death. Our demonstration of the hypoxia induction of SECIS binding protein 2 opens new avenues for diagnosis and therapeutic intervention.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SECIS binding protein 2 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect increased activity of the gene product to have an anti-tumour effect.
  • the Oxford BioMedica clone plE8 represents cDNA: FLJ22249 fis, clone HRC02674.
  • the sequence cDNA : FLJ22249 fis, clone HRC02674 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK025902 and is described in this patent by Seq ID 62. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Plexin C l The Oxford BioMedica clone p IE 18 represents Plexin C l .
  • the protein sequence encoded by Plexin C l is represented in the public databases by the accession NP_005752 and is described in this patent by Seq ID
  • Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates and play a significant role in signal transduction [Tamagnone et al 1999, Cell 99:71 -80].
  • Elsewhere in this patent we disclose hypoxic regulation of a new semaphorin 4b, and we propose co-regulation of these molecules by hypoxia and their relevance to inflammatory disease, its diagnosis and therapy. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Plexin C l is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford BioMedica clone plE16 represents cDNA DKFZp586E1624.
  • the sequence cDNA DKFZp586E1624 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AL1 10152 and is described in this patent by Seq ID 66.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFl alpha and EPAS l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • EPAS l By adenoviral over-expression of EPAS l we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Its preferential regulation by EPAS l provides a route to preferential intervention, to avoid toxicity to other tissues.
  • the cDNA DKFZp586El 624 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPAS l . Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheumatoid arthritis.
  • the cDNA DKFZp586E1624 is preferentially induced by hypoxia in endothelial cells. We expect this gene product to have a pro-angiogenic effect, and its inhibition to have an anti-angiogenic effect.
  • ERO l S . cerevisiae
  • the protein sequence encoded by ERO l (S . cerevisiae)-like is represented in the public databases by the accession NP_055399 and is described in this patent by Seq ID 67.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014584 and is described in this patent by Seq ID 68.
  • ERO l (S. cerevisiae)-like has been shown to be a flavin adenine dinucleotide (FAD) binding protein, Binding of FAD enables ERO l (S.
  • FAD flavin adenine dinucleotide
  • PDI oxidise protein disulfide isomerase
  • ERO l S. cerevisiae
  • EROl S. cerevisiae-like has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPAS l . Its preferential regulation by EPASl provides a route to preferential intervention, to avoid toxicity to other tissues. EROl (S. cerevisiae)-like is preferentially induced by hypoxia in mammary epithelial cells.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, ERO l (S, cerevisiae)-like is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, ERO l (S . cerevisiae)-like is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the O xford B ioM edica clone pl E12 represents Hypothetical protein DKFZP434E1723.
  • the protein sequence encoded by Hypothetical protein DKFZP434E1723 is represented in the public databases by the accession XP_05338 and is described in this patent by Seq ID 69.
  • the nucleotide sequence is represented in the public sequence databases by the accession B C010005 and is described in this patent by Seq ID 70.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clone pl El O represents cDNA FLJ1 1041 fis clone PLACE 1004405.
  • the sequence encoded by cDNA FLJ1 1041 fis, clone PLACE 1004405 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK001903 and is described in this patent by Seq ID 72.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the cDNA FLJ11041 fis clone PLACE 1004405 is induced in macrophages activated by LPS and gamma interferon. We expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflam m atory effect.
  • the Oxford B ioMedica clone p l C21 represents Tubulin, beta, 4.
  • the protein sequence encoded by Tubulin, beta, 4 is represented in the public databases by the accession NP_006077 and is described in this patent by Seq ID 73.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006086 and is described in this patent by Seq ID 74.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford BioMedica clone p i D 10 represents Insulin induced protein 2.
  • the protein sequence encoded by Insulin induced protein 2 is represented in the public databases by the accession AAD43048 and is described in this patent by Seq ID 75.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF125392 and is described in this patent by Seq ID 76.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Insulin induced protein 2 is induced in m acrophages activated by LPS and gam m a interferon. W e expect it to have a pro- inflamm atory role,-and its inhibition may have an anti-inflammatory effect.
  • the Oxford B ioM edica clones p lD 13 and p i A22 represent Adenylate kinase 3.
  • the protein sequence encoded by Adenylate kinase 3 is represented in the public databases by the accession NP_037542 and is described in this patent by Seq ID 77 and 263.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_013410 and is described in this patent by Seq ID 78 and 264.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Adenylate kinase 3 is induced in m acrophages activated by LPS and gam ma interferon.
  • TNFalpha is an inflamm atory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis, Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions.
  • Adenylate kinase 3 is induced in m acrophages activated by TNFalpha.
  • the Oxford BioM edica clone pl E9 represents a novel PI-3-kinase adapter.
  • the protein sequence encoded by the novel PI-3-kinase adapter is not represented in the public databases by a protein accession but is described in this patent by Seq ID 79.
  • the nucleotide sequence of an unannotated EST corresponding to the novel PI-3-kinase adapter is represented in the public sequence databases by the accession R62339 and is described in this patent by Seq ID 80.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types, M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD and peripheral arterial disease.
  • the novel PI-3-kinase adapter is preferentially induced by hypoxia in monocytes or macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving macrophages and hypoxia.
  • W e also show novel data regarding Syk, in that it is also induced in response to hypoxia in a tissue specific manner identical to that of the novel PI-3-kinase adapter. Therefore the biological relevance and utility of our discovery of hypoxic induction of the novel PI-3-kinase adapter gene is further highlighted.
  • the Oxford B ioMedica clone plFl represents an unannotated EST .
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession AA489477 and is described in this patent by Seq ID 82,
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
  • the Oxford B ioM edica clone p l E7 represents a novel M etallothionein.
  • the protein sequence encoded by Novel M etallothionein is not represented in the public databases by a protein accession but is described in this patent by Seq ID 83.
  • the nucleotide sequence is represented in the public sequence databases by the accession R06601 and is described in this patent by Seq ID 84.
  • M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFl alpha and EPA S l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia.
  • the novel Metallothionein represented by Seq ID 84 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFl alpha.
  • Hepatocytes are the m ain cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to developm ent of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis.
  • the novel Metallothionein represented by Seq ID 84 is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the novel Metallothionein represented by Seq ID 84 is induced in macrophages activated by LPS and gamma interferon.
  • the O xford B ioM edica clone pl E6 represents EGL nine (C .elegans) hom olog 3.
  • the protein sequence encoded by EGL nine (C.elegans) hom olog 3 is represented in the public databases by the accession NP_071356 and is described in this patent by Seq ID 85.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_022073 and is described in this patent by Seq ID 86.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFl alpha and EPA S l are transcription factors that m ediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • B y adenoviral over-expression of EPAS l we show augm entation of the hypoxic induction of certain genes, further confirm ing their status as responsive to hypoxia.
  • EGL nine (C .elegans) hom olog 3 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPA S l . Its preferential regulation by EPAS l provides a route to preferential intervention, to avoid toxicity to other tissues.
  • Hepatocytes are the m ain cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis.
  • EGL nine (C .elegans) hom olog 3 is preferentially induced by hypoxia in hepatocytes.
  • EGLN and cl orfl 2 are 0.015 and 0.0074 respectively, i.e. EGLN being the dominant gene.
  • the normalised expression values of EGLN and cl orfl 2 after 6hr hypoxia are 0.0012 and 0.108 respectively, i.e. cl orfl 2 being the dominant gene by a large m argin.
  • target proteins such as HIFl alpha
  • the Oxford BioM edica clone p l D 14 represents C l orf 12.
  • the protein sequence encoded by C l orfl 2 is represented in the public databases by the accession NP_071334 and is described in this patent by Seq ID 89.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_022051 and is described in this patent by Seq ID 90.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • W e find that C l orf 12 and a related hum an gene EGLN3 (seq ID 85/86) both of which are predicted to be proline hydroxylases, are expressed at differing absolute expression levels in different tissues.
  • EGLN3 an gene EGLN3 (seq ID 85/86) both of which are predicted to be proline hydroxylases, are expressed at differing absolute expression levels in different tissues.
  • the norm alised expression values of EGLN and cl orf 12 are 0.015 and 0.0074 respectively, i.e. EGLN being the dominant gene.
  • the normalised expression values of EGLN and c 1 o rf 12 after 6hr hypoxia are 0,0012 and 0.108 respectively, i.e. cl orfl 2 being the dominant gene by a large m argin.
  • the Oxford BioM edica clone p2B l represents PRAME.
  • the protein sequence encoded by PRAM E is represented in the public databases by the accession NP_006106 and is described in this patent by Seq ID 87.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_0061 15 and is described in this patent by Seq ID 88.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tum ours where macrophage infiltrates are also found.
  • PRAM E is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
  • PRAME is a w ell-known tumour-associated antigen.
  • Our surprising dem onstration of its hypoxia-regulation provides for an important diagnostic test to distinguish false-positive results.
  • the Oxford BioM edica clones p 1 D 17 and plP 14 represent Semaphorin 4b.
  • the protein sequence encoded by Semaphorin 4b is represented in the public databases by the accession BAB21836 and is described in this patent by Seq ID 91.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB 051532 and is described in this patent by Seq ID 92.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue.
  • Sem aphorin 4b is preferentially induced by hypoxia in renal epithelial cells.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Semaphorin 4b is induced in m acrophages activated by LPS and gamm a interferon.. Semaphorin 4b is also induced by the presence of reactive oxygen species. W e expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflammatory effect.
  • Semaphorin 4b is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. Semaphorin 4b is also induced in response to superoxide radicals, as found in various disease states, implying utility. Semaphorin 4b is predicted to function in modulating several cellular processes key to human disease, including angiogenesis, inflammation, immune cell migration and tissue remodelling. Other Semaphorins including Semaphorin E, which are induced in response to hypoxia will also be implicated in these disease processes and have utility as described for Semaphorin 4b.
  • the Oxford BioMedica clone plC24 represents SLC25A 19
  • the protein sequence encoded by SLC25A 19 is represented in the public databases by the accession NP_068380 and is described in this patent by Seq ID 93.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021734 and is described in this patent by Seq ID 94
  • SLC25A 19 transports deoxynucleotides into mitochondria and is therefore essential for mtDNA synthesis
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plD3 represents Serine carboxypeptidase 1.
  • the protein sequence encoded by Serine carboxypeptidase 1 is represented in the public databases by the accession NP_067639 and is described in this patent by Seq ID 95.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021626 and is described in this patent by Seq ID 96.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions, Serine carboxypeptidase 1 is induced in macrophages activated by TNFalpha.
  • the Oxford BioMedica clone plE14 represents an unknown mRNA (schizophrenia-linked).
  • the protein sequence encoded by the unknown mRNA (schizophrenia-linked) is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AY0101 12 and is described in this patent by Seq ID 98.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Unknown mRNA schizophrenia-linked
  • TNFalpha is induced in macrophages activated by TNFalpha. There are many enzymic activities that can give rise to neurological abnormalities, and their hypoxia regulation is pertinent to the diagnosis and treatment of such diseases, including schizophrenia.
  • the Oxford BioMedica clone plE20 represents Myo-inositol monophosphatase A3
  • the protein sequence encoded by M yo-inositol monophosphatase A3 is represented in the public databases by the accession AAK52336 and is described in this patent by Seq ID 99
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_017813 and is described in this patent by Seq ID 100
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • M yo-inositol monophosphatase A3 is repressed in macrophages activated by LPS and gamm a interferon.
  • the Oxford B ioMedica clone p2A24 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA521314 and is described in this patent by Seq ID 102.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypothetical protein FLJ31668 The protein sequence encoded by Hypothetical protein FLJ31668 is represented in the public databases by the accession B AB71 124 and is described in this patent by Seq ID 103.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK056230 and is described in this patent by Seq ID 104.
  • Hypoxia is an im portant feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioMedica clone p l E 19 represents an unannotated EST .
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession R51835 and is described in this patent by Seq ID 106.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 106 is up-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
  • the Oxford B ioM edica clone pl E 15 represents cDNA YI27F12.
  • the protein sequence encoded by cDNA YI27F12 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF075018 and is described in this patent by Seq ID 108.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the cDNA YI27F12 is induced in macrophages treated with the inhibitory cytokine IL-10.
  • the cDNA YI27F12 is repressed in macrophages activated by IL-17.
  • the Oxford BioMedica clone plE23 represents cDNA FLJ14041 fis, clone HEMBA1005780.
  • the protein sequence encoded by cDNA FLJ14041 fis, clone HEMBA1005780 is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession AK024103 and is described in this patent by Seq ID 112
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plE21 represents Glutamate-cysteine ligase, modifier subunit.
  • the protein sequence encoded by Glutamate-cysteine ligase, modifier subunit is represented in the public databases by the accession NP_002052 and is described in this patent by Seq ID 1 13.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002061 and is described in this patent by Seq ID 114.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Glutamate-cysteine ligase is the rate-limiting enzyme of glutathione synthesis, and this enzyme is relevant to cell survival under stress, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Glutamate-cysteine ligase, modifier subunit is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plD23 represents PTEN .
  • the protein sequence encoded by PTEN is represented in the public databases by the accession NP_000305 and is described in this patent by Seq ID 115.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000314 and is described in this patent by Seq ID 116.
  • PTEN is a member of the mixed function, serine/threonine/tyrosine phosphatase subfamily of protein phosphatases. Its physiological substrates, however, are primarily 3-phosphorylated inositol phospholipids, which are products of phosphoinositide 3-kinases [Downes et al 2001 , Biochem Soc Trans 29:846-51].
  • Hypoxia-regulation of this gene is a further element in the hypoxic regulation of this important second messenger system .
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plD24 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession T73780 and is described in this patent by Seq ID 118.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic-, prognostic and diagnostic products.
  • the response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue.
  • the EST represented by Seq ID 118 is preferentially induced by hypoxia in renal epithelial cells. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 118 is induced in macrophages activated by LPS and gamma interferon,
  • the Oxford BioMedica clones plD22 and plG5 represent MAX-interacting protein 1.
  • the protein sequence encoded by MAX-interacting protein 1 is represented in the public databases by the accession NP_005953 and is described in this patent by Seq ID 119 and 279.
  • the nucleotide sequence is . represented in the public sequence databases by the accession NM_005962 and is described in this patent by Seq ID 120 and 280.
  • M AX-interacting protein 1 is a negative regulator of myc oncoprotein with tumor suppressor properties. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes,
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, MAX-interacting protein 1 is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford BioMedica clone plE2 represents Mannosidase, alpha, class 1A, member 1.
  • the protein sequence encoded by Mannosidase, alpha, class 1 A, member 1 is represented in the public databases by the accession NP_005898 and is described in this patent by Seq ID 121.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005907 and is described in this patent by Seq ID 122.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • Mannosidase, alpha, class 1A, member 1 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plEl represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA446361 and is described in this patent by Seq ID 124.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 124 is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford BioMedica clone plE4 represents an unannotated EST,
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA931411 and is described in this patent by Seq ID 126.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in. the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 126 is repressed in macrophages activated by LPS and gamma interferon, We expect this gene product to have an anti-inflammatory role. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 126 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioM edica clone plD 18 represents cDNA FLJ13443 fis, clone PLACE1002853.
  • the protein sequence encoded by cDNA FLJ13443 fis, clone PLACE1002853 is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession AK023505 and is described in this patent by Seq ID 128.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • hypoxia and cytokines are especially relevant.
  • the cDNA FLJ13443 fis, clone PLACE1002853 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role.
  • the Oxford BioM edica clone pl D21 represents Hypothetical protein FLJ22622.
  • the protein sequence encoded by Hypothetical protein FLJ22622 is represented in the public databases by the accession B AB 15424 and is described in this patent by Seq ID 129.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue.
  • Hypothetical protein FLJ22622 is preferentially induced by hypoxia in renal epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes.
  • hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found.
  • Hypothetical protein FLJ22622 is up-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford B ioM edica clone p l C22 represents CD 84-H 1 .
  • the protein sequence encoded by CD84-H 1 is represented in the public databases by the accession AAK69052 and is described in this patent by Seq ID 131.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF275725 and is described in this patent by Seq ID 132. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone p l C23 represents Hypothetical protein FLJ12832
  • the protein sequence encoded by Hypothetical protein FLJ12832 is represented in the public databases by the accession XP_043394 and is described in this patent by Seq ID 133.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK022894 and is described in this patent by Seq ID 134.
  • Hypothetical protien FLJ12832 is a putative ubiquitin as it shows high structural similarity to ubiquitin C and contains a ubiquitin dom ain, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clone p l D l l represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA251748 and is described in this patent by Seq ID 136.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have, utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clones plE3 and plFl ⁇ represent CYPIB I.
  • the protein sequence encoded by CYP1B 1 is represented in the public databases by the accession NP_000095 and is described in this patent by Seq ID 137 and 325.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000104 and is described in this patent by Seq ID 138 and 326.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types.
  • M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD.
  • CYPIB I is preferentially induced by hypoxia in monocytes or macrophages and a restricted number of other cell types.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • CYPIB I is repressed in m acrophages activated by LPS and gamma interferon.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • CYPIB I is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, CYPl B l is up-regulated and also down regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plD20 represents Hypothetical protein KIAA 1125.
  • the protein sequence encoded by Hypothetical protein KIAA 1125 is represented in the public databases by the accession XP_012932 and is described in this patent by Seq ID 139.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB032951 and is described in this patent by Seq ID 140.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plE5 represents Hepcidin antimicrobial peptide.
  • the protein sequence encoded by Hepcidin antimicrobial peptide is represented in the public databases by the accession NP_066998 and is described in this patent by Seq ID 141.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021175 and is described in this patent by Seq ID 142.
  • Hypoxia is an important feature. of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hepatocytes are the main cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis.
  • Hepcidin antimicrobial peptide is preferentially induced by hypoxia in hepatocytes.
  • Hepcidin antimicrobial peptide is induced in macrophages treated with the inhibitory cytokine IL-10.
  • TNFalpha is an inflam m atory cytokine, w hich acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis.
  • the O xford B ioMedica clone plD 19 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession R68736 and is described in this patent by
  • Seq ID 144 Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown, to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 144 is induced in macrophages activated by LPS and gamma interferon and. is also induced in m acrophages activated by IL-15. W e expect the gene product relevant to the EST represented by Seq ID 144 to have a pro-inflam matory role, and its inhibition may have an anti-inflammatory effect.
  • the O xford B ioM edica clone p2A 15 represents Sialyltransferase.
  • the protein, sequence encoded by Sialyltransferase is represented in the public databases by the accession NP_006447 and is described in this patent by Seq ID 145.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clone pi II 4 represents cDNA DKFZp564D 016.
  • the protein sequence encoded by cDNA DKFZp564D016 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AL050021 and is described in this patent by Seq ID 148.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone p 112 represents cDNA FLJ11302 fis, clone PLACE1009971.
  • the protein sequence encoded by cDNA FLJ11302 fis, clone PLACE1009971 is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession AK002164 and is described in this patent by Seq ID 150.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease
  • clone PLACE1009971 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role.
  • the Oxford BioMedica clone p 1112 represents Hypothetical protein MGC4549, The protein sequence encoded by Hypothetical protein MGC4549 is represented in the public databases by the accession XP_032794 and is described in this patent by Seq ID 151. The nucleotide sequence is represented in the public sequence databases by the accession NM_032377 and is described in this patent by Seq ID 152.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypothetical protein M GC4549 is induced in macrophages treated with the inhibitory cytokine IL-10.
  • Hypothetical protein M GC4549 is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. We expect it to have an anti-inflammatory role.
  • the Oxford BioMedica clone p 113 represents ELM02.
  • the protein sequence encoded by ELM 02 is represented in the public databases by the accession AAL14467 and is described in this patent by Seq ID 153.
  • the nucleotide sequence is represented in the public sequence databases by the accession XM_012933 and is described in this patent by Seq ID 154.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • This gene has been shown recently to promote phagocytosis and cell shape changes [Gumienny et al 2001 , Cell 107:27-41]. These functions are typical of the macrophage, and are likely to play a role in macrophage-associated diseases.
  • the Oxford BioMedica clone pill 0 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA420992 and is described in this patent by Seq ID 156.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford B ioMedica clone p l H 18 represents Ubiquitin specific protease 7.
  • the protein sequence encoded by Ubiquitin specific protease 7 is represented in the public databases by the accession NP_003461 and is described in this patent by Seq ID 157.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003470 and is described in this patent by Seq ID 158.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found.
  • Ubiquitin specific protease 7 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford B ioMedica clone p l H24 represents Nucleolar phosphoprotein Nopp34.
  • the protein sequence encoded by Nucleolar phosphoprotein Nopp34 is represented in the public databases by the accession NP_1 15766 and is described in this patent by Seq ID 159.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_032390 and is described in this patent by Seq ID 160.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioMedica clone p l E22 represents cDNA FLJ13618 fis, clone PLACE 1010925.
  • the protein sequence encoded by cDNA FLJ13618 fis, clone PLACE1010925 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK023680 and is described in this patent by Seq ID 162.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the cDNA FLJ13618 fis, clone PLACE1010925 is induced in macrophages activated by LPS and gamma interferon.
  • the Oxford B ioM edica clone p l H21 represents Hypothetical protein FLJ1351 1.
  • the protein sequence encoded by Hypothetical protein FLJ13511 is represented in the public databases by the accession NP_149014 and is described in this patent by Seq ID 163.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_033025 and is described in this patent by Seq ID 164.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types.
  • M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD .
  • Hypothetical protein FLJ13511 is preferentially induced by hypoxia in m onocytes or macrophages and a restricted number of other cell types.
  • Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • Hypothetical protein FLJ13511 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioM edica clone pi ll represents Ribosomal RNA intergenic spacer.
  • the protein sequence encoded by Ribosom al RNA intergenic spacer is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession AA664228 and is described in this patent by Seq ID 166, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products
  • the O xford B ioM edica clone plH 14 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession R44397 and is described in this patent by Seq ID 168 . Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
  • the Oxford B ioMedica clone pl H l l represents Carboxypeptidase M .
  • the protein sequence encoded by Carboxypeptidase M is represented in the public databases by the accession NP_001865 and is described in this patent by Seq ID 169.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001874 and is described in this patent by Seq ID 170.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioMedica clone pl H 17 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession W 87747 and is described in this patent by Seq ID 172.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 172 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone pi H 12 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA973568 and is described in this patent by Seq ID 174.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
  • the Oxford BioMedica clone plH7 represents an unannotated EST
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession
  • the nucleotide sequence is represented in the public sequence databases by the accession T98529 and is described in this patent by Seq ID 176
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plH 15 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA022679 and is described in this patent by Seq ID 178.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 178 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plH20 represents an unannotated EST.
  • the protein sequence encoded by EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession H17921 and is described in this patent by Seq ID 180.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 180 is up-regulated in the malignant tissue as . compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plH8 represents ABL.
  • the protein sequence encoded by ABL is represented in the public databases by the accession NP_009297 and is described in this patent by Seq ID 181.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_007313 and is described in this patent by Seq ID 182.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • ABL is induced in macrophages treated with the inhibitory cytokine IL-10.
  • ABL is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. We expect it to have an anti-inflammatory role Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, ABL is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the O xford BioMedica clone p lH 16 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession W91958 and is described in this patent by Seq ID 184.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 184 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plH9 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession R63694 and is described in this patent by Seq ID 186.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone plH23 represents Hypothetical protein FLJ21094.
  • the protein sequence encoded by Hypothetical protein FLJ21094 is represented in the public databases by the accession AAH14003 and is described in this patent by Seq ID 187.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK024747 and is described in this patent by Seq ID 188. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford B ioM edica clone p i H 10 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA909912 and is described in this patent by Seq ID 190.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone plH6 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession T99032 and is described in this patent by Seq ID 192. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the EST represented by Seq ID 192 is induced in m acrophages treated with the inhibitory cytokine IL-10.
  • the EST represented by Seq ID 192 is repressed in m acrophages activated by IL-15. W e expect it to have an anti-inflammatory role.
  • the Oxford B ioMedica clone p l H 13 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession H52503 and is described in this patent by Seq ID 194.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 194 is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford B ioMedica clone p I H 19 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession A A 127017 and is described in this patent by Seq ID 196.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found.
  • the EST represented by the Seq ID 196 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plG22 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession R38647 and is described in this patent by Seq ID 198 .
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheum atoid arthritis.
  • the EST represented by Seq ID 198 is preferentially induced by hypoxia in endothelial cells. W e expect this gene product to have a pro- angiogenic effect, and its inhibition to have an anti-angiogenic effect.
  • the Oxford B ioM edica clone pi G21 represents an unannotated EST,
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession,
  • the nucleotide sequence is represented in the public sequence databases by the accession T87233 and is described in this patent by Seq ID 200.
  • Hypoxia is an important-feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clone pl H l represents Hypothetical protein FLJ10826.
  • the protein sequence encoded by Hypothetical protein FLJ10826 is represented in the public databases by the accession BAB 14226 and is described in this patent by Seq ID 201.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018233 and is described in this patent by Seq ID 202.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility, in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford B ioM edica clone p l G20 represents cDNA YO23H03.
  • the protein sequence encoded by cDNA YO 23H03 is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF075053 and is described in this patent by Seq ID 204.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the cDNA YO23H03 is repressed in macrophages activated by LPS and gamma interferon.
  • Hypothetical protein FLJ22690 The Oxford BioMedica clone plH5 represents Hypothetical protein FLJ22690.
  • the protein sequence encoded by Hypothetical protein FLJ22690 is represented in the public databases by the accession NP_078987 and is described in * this patent by Seq ID 205.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_02471 1 and is described in this patent by Seq ID 206.
  • Hypoxia is an important feature of several diseases-, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheumatoid arthritis.
  • Hypothetical protein FLJ22690 is preferentially induced by hypoxia in endothelial cells. We expect this gene product to have a pro-angiogenic effect, and its inhibition to have an anti-angiogenic effect.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Hypothetical protein FLJ22690 is induced in macrophages activated by IL-15,
  • the Oxford BioMedica clone pi G 19 represents Mitochondrion sequence.
  • the protein sequence encoded by Mitochondrion sequence is represented in the public databases by the accession AAH05845 and is described in this patent by Seq ID 207.
  • the nucleotide sequence is represented in the public sequence databases by the accession BC005845 and is described in this patent by Seq ID 208.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates. are also found.
  • the Mitochondrion sequence represented by Seq ID 208 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plH2 represents Fatty acid binding protein 5.
  • the protein sequence encoded by Fatty acid binding protein 5 is represented in the public databases by the accession NP_001435 and is described in this patent by Seq ID 209.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001444 and is described in this patent by Seq ID 210.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types.
  • M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD .
  • Fatty acid binding protein 5 is preferentially induced by hypoxia in monocytes or macrophages.
  • Fatty acid binding protein 5 expressed in macrophages has been shown to play a very important role in the development of atherosclerotic plaques [Layne et al 2001 , FASEB J 15:2733-5], Our demonstration of hypoxic-regulation of this gene not only makes clear how this gene can participate in disease initiation and progression, but provides for a potential route to diagnosis and therapy of atherosclerosis.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Fatty acid binding protein 5 is repressed in macrophages activated by TNFalpha.
  • the Oxford BioMedica clone p 1 G 18 represents Mitochondrion sequence.
  • the protein sequence encoded by Mitochondrion sequence is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession BC001612 and is described in this patent by Seq ID 212.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the Mitochondrion sequence represented by Seq ID 212 is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford BioM edica clone plH4 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA679939 and is described in this patent by Seq ID 214.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 214 is repressed in macrophages activated by IL-17. W e expect it to have an anti-inflammatory role. Hypoxia is frequently found in human tum ours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by the Seq ID 214 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford B ioMedica clone p l H3 represents an unannotated EST.
  • the protein sequence encoded by this EST is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA630167 and is described in this patent by Seq ID 216.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found.
  • the EST represented by Seq ID 216 is up-regulated and also dow n-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
  • the protein sequence encoded by B CL2/adenovirus E 1 B 19kD-interacting protein 3-like is represented in the public databases by the accession NP_004322 and is described in this patent by Seq ID 217.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM _004331 and is described in this patent by Seq ID 218.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the protein sequence encoded by SLC2A 1 is represented in the public databases by the accession NP_006507 and is described in this patent by Seq ID 219.
  • SLC2A 1 is a glucose transporter gene and is also known as GLUT 1. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plP3 represents PDGFB .
  • the protein sequence encoded by PDGFB is represented in the public databases by the accession NP_148937 and is described in this patent by Seq ID 221.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_033016 and is described in this patent by Seq ID 222.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • PDGFB is induced in macrophages activated by LPS and gamma interferon.
  • the Oxford BioMedica clones pl A8 and plA9 represent Lactate dehydrogenase A .
  • the protein sequence encoded by Lactate dehydrogenase A is represented in the public databases by the accession NP_005557 and is described in this patent by Seq ID 223.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005566 and is described in this patent by Seq ID 224.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Lactate dehydrogenase A is repressed in macrophages activated by LPS and gamma interferon and is also repressed in macrophages activated by IL-15.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Lactate dehydrogenase A is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Lactate dehydrogenase A is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • Tissue factor The Oxford BioMedica clone p 1 B 17 represents Tissue factor.
  • the protein sequence encoded by Tissue factor is represented in the public databases by the accession NP_001984 and is described in this patent by Seq ID 225.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001993 and is described in this patent by Seq ID 226.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Tissue factor is preferentially induced by hypoxia in mammary epithelial cells.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Tissue factor is induced in macrophages activated by TNFalpha.
  • Tissue factor is the primary initiator of blood coagulation with structural homology to the cytokine receptor family, and has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Our demonstration of hypoxic regulation leads to a clear undertanding of the possibility of intervention in disease by modulation of Tissue factor activity.
  • the Oxford BioMedica clone plO20 represents VEGF.
  • the protein sequence encoded by VEGF is represented in the public databases by the accession NP_003367 and is described in this patent by Seq ID 227.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003376 and is described in this patent by Seq ID 228.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, VEGF is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone plB2 represents N-myc downstream regulated.
  • the protein sequence encoded by N-myc downstream regulated is represented in the public databases by the accession NP_006087 and is described in this patent by Seq ID 229.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006096 and is described in this patent by Seq ID 230.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • N-myc downstream regulated is preferentially induced by hypoxia in mammary epithelial cells.
  • the Oxford BioMedica clone plB3 represents Proline 4-hydroxylase, alpha polypeptide I.
  • the protein sequence encoded by Proline 4-hydroxylase, alpha polypeptide I is represented in the public databases by the accession NP_000908 and is described in this patent by Seq ID 231.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000917 and is described in this patent by Seq ID 232.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Proline 4-hydroxylase, alpha polypeptide I is repressed in macrophages activated by LPS and gamma interferon, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • Proline 4-hydroxylase, alpha polypeptide I is down-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
  • the protein sequence encoded by B CL2/adenovirus E l B -interacting protein 3 is represented in the public databases by the accession NP_004043 and is described in this patent by Seq ID 233.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004052 and is described in this patent by Seq ID 234.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clones p I B 18 and p l B 19 represent Plasminogen activator inhibitor, type 1.
  • the protein sequence encoded by Plasminogen activator inhibitor, type 1 is represented in the public databases by the accession NP_000593 and is described in this patent by Seq ID 235.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000602 and is described in this patent by Seq ID 236.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Plasm inogen activator inhibitor, type 1 is induced in macrophages activated by LPS and gamma interferon. Plasminogen activator inhibitor, type 1 is repressed in macrophages activated by IL-17.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Plasminogen activator inhibitor, type 1 is induced in m acrophages activated by TNFalpha. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Plasminogen activator inhibitor, type 1 is down-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
  • COX-2 The Oxford BioM edica clone p l N 17 represents COX-2.
  • the protein sequence encoded by COX-2 is represented in the public databases by the accession NP_000954 and is described in this patent by Seq ID 237.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000963 and is described in this patent by Seq ID 238.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • COX-2 is preferentially induced by hypoxia in m amm ary epithelial cells.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • COX-2 is induced in macrophages activated by LPS and gamma interferon.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • COX-2 is induced in macrophages activated by TNFalpha,
  • TNFalpha a known role of COX-2 in prostaglandin synthesis and tumour progression
  • the Oxford BioMedica clone plA24 represents Metallothionein I H .
  • the protein sequence encoded by Metallothionein I H is represented in the public databases by the accession NP_005942 and is described in this patent by Seq ID 239.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005951 and is described in this patent by Seq ID 240.
  • M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis.
  • Metallothionein IH is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, M etallothionein IH is induced in macrophages activated by LPS and gamma interferon.
  • M etallothionein IL The protein sequence encoded by M etallothionein IL is represented in the public databases by the accession NP_002441 and is described in this patent by Seq ID 241.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002450 and is described in this patent by Seq ID 242.
  • Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clone plB l represents Metallothionein 1 G.
  • the protein sequence encoded by Metallothionein 1 G is represented in the public databases by the accession NP_005941 and is described in this patent by Seq ID 243.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005950 and is described in this patent by Seq ID 244.
  • Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFlalpha and EPASl are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia.
  • Metallothionein 1G has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFl alpha.
  • Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis.
  • Metallothionein 1 G is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Metallothionein 1 G is induced in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, M etallothionein 1 G is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • Metallothionein IE functional
  • the protein sequence encoded by Metallothionein IE (functional) is not represented in the public databases by a protein accession.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA872383 and is described in this patent by Seq ID 246.
  • Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioMedica clones pi A l , plA2, pi A3 and pl A4 represent SLC2A3.
  • the protein sequence encoded by SLC2A3 is represented in the public databases by the accession NP_008862 and is described in this patent by Seq ID 247.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006931 and is described in this patent by Seq ID 248.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • SLC2A3 is induced in macrophages treated with the inhibitory cytokine IL-10.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. SLC2A3 is induced in macrophages activated by TNFalpha.
  • the Oxford BioMedica clones pi A 15, pi A 16, pi A 17 and pi A 18 represent Hexokinase-2.
  • the protein sequence encoded by Hexokinase-2 is represented in the public databases by the accession NP_000180 and is described in this patent by Seq ID 249.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000189 and is described in this patent by Seq ID 250.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Hexokinase-2 is repressed in macrophages activated by LPS and gamma interferon.
  • the Oxford BioMedica clones plB 14, plB 15 and pi B 16 represent Interleukin 8.
  • the protein sequence encoded by Interleukin 8 is represented in the public databases by the accession NP_000575 and is described in this patent by Seq ID 251.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000584 and is described in this patent by Seq ID 252.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Interleukin 8 is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Interleukin 8 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clones plA l l and pi A 12 represent GAPDH.
  • the protein sequence encoded by GAPDH is represented in the public databases by the accession NP_002037 and is described in this patent by Seq ID 253.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002046 and is described in this patent by Seq ID 254.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • GAPDH is repressed in macrophages activated by LPS and gamma interferon and is also induced in m acrophages activated by IL- 17 or IL-15.
  • TNFalpha is an inflam m atory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis.
  • GAPDH Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions, GAPDH is induced in m acrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, GAPDH is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioM edica clone pi A 13 represents Phosphoglycerate kinase 1.
  • the protein sequence encoded by Phosphoglycerate kinase 1 is represented in the public databases by the accession NP_000282 and is described in this patent by Seq ID 255
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000291 and is described in this patent by Seq ID 256
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Phosphoglycerate kinase 1 is repressed in macrophages activated by LPS and gam ma interferon.
  • TNFalpha is an inflamm atory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Phosphoglycerate kinase 1 is induced in macrophages activated by TNFalpha.
  • the Oxford B ioM edica clone p i A 14 represents Enolase 1.
  • the protein sequence encoded by Enolase 1 is represented in the public databases by the accession NP_001419 and is described in this patent by Seq ID 257.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001428 and is described in this patent by Seq ID 258.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • Enolase 1 is repressed in macrophages activated by LPS and gamma interferon.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions, Enolase 1 is induced in macrophages activated by TNFalpha.
  • Enolase 1 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone pi A 19 represents Aldolase C
  • the protein sequence encoded by Aldolase C is represented in the public databases by the accession NP_005156 and is described in this patent by Seq ID 259.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005165 and is described in this patent by Seq ID 260.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Aldolase C is induced in macrophages activated by IL-15. Aldolase C is repressed in macrophages activated by IL-15.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Aldolase C is induced in macrophages activated by TNFalpha.
  • Aldolase is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone pi A20 represents Triosephosphate isomerase 1.
  • the protein sequence encoded by Triosephosphate isomerase 1 is represented in the public databases by the accession NP_000356 and is described in this patent by Seq ID 261.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000365 and is described in this patent by Seq ID 262.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Triosephosphate isomerase 1 is repressed in macrophages activated by LPS and gamm a interferon and is also repressed in macrophages activated by IL-15.
  • TNFalpha is an , inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis.
  • Triosephosphate isomerase 1 is induced in macrophages activated by TNFalpha
  • the Oxford BioMedica clone pi A23 represents Metallothionein 2A
  • the protein sequence encoded by Metallothionein 2A is represented in the public databases by the accession NP_005944 and is described in this patent by Seq ID 265.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005953 and is described in this patent by Seq ID 266.
  • M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • HIFlalpha and EPAS l are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases.
  • B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia.
  • Metallothionein 2A has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFlalpha.
  • Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis, Metallothionein 2A is preferentially induced by hypoxia in hepatocytes.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Metallothionein 2A is induced in macrophages activated by LPS and gamma interferon and also induced in macrophages activated by IL-15. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Metallothionein 2A is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clones plB20 and p 1 B 21 represent Osteopontin.
  • the protein sequence encoded by Osteopontin is represented in the public databases by the accession NP_000573 and is described in this patent by Seq ID 267.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000582 and is described in this patent by Seq ID 268.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types.
  • M onocytes and m acrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD , Osteopontin is preferentially induced by hypoxia in monocytes or macrophages and a restricted num ber of other cell types. Osteopontin has been shown recently to play a role in autoimmune disease [Chabas et al, 2001 , Science 294: 1731 -5]. W e present a new association between the hypoxic response and autoimmune disease.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • O steopontin is repressed in m acrophages activated by LPS and gamm a interferon.
  • Hypoxia is frequently found in hum an tum ours where macrophage infiltrates are also found,
  • Osteopontin is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioM edica clones p l C 17 and p 1 C 18 represent Granulin.
  • the protein sequence encoded by Granulin is represented in the public databases by the accession NP_002078 and is described in this patent by Seq ID 269.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002087 and is described in this patent by Seq ID 270.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes.
  • Granulin is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients w ith either ovarian or breast cancer, Granulin is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. The up-regulation of Granulin, which is a known growth factor, is a clinically significant feature of the hypoxic response with clear diagnostic and therapeutic utility.
  • the Oxford B ioM edica clone pl D 8 represents Hypoxia-inducible protein 2.
  • the protein sequence encoded by Hypoxia-inducible protein 2 is represented in the public databases by the accession NP_037464 and is described in this patent by Seq ID 271.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_013332 and is described in this patent by Seq ID 272.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • Hypoxia-inducible protein 2 is induced in m acrophages treated with the inhibitory cytokine IL- 10.
  • Hypoxia-inducible protein 2 is repressed in m acrophages activated by IL-17 and is also repressed in m acrophages activated by IL-15.
  • the O xford B ioM edica clone pi A 10 represents Enolase 2.
  • the protein sequence encoded by Enolase 2 is represented in the public databases by the accession NP_001966 and is described in this patent by Seq ID 273
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001975 and is described in this patent by Seq ID 274.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes.
  • Enolase 2 is repressed in macrophages activated by LPS and gam m a interferon. Hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Enolase 2 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. W e expect it to have an anti-inflamm atory role.
  • the O xford B ioMedica clone pi G24 represents Glycogen synthase 1.
  • the protein sequence encoded by Glycogen synthase 1 is represented in the public databases by the accession NP_002094 and is described in this patent by Seq ID 275.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002103 and is described in this patent by Seq ID 276.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes.
  • macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Glycogen synthase 1 is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15.
  • the O xford BioM edica clone pl G23 represents ALCAM .
  • the protein sequence encoded by ALCAM is represented in the public databases by the accession NP_001618 and is described in this patent by Seq ID 277.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001627 and is described in this patent by Seq ID 278, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • ALCAM In view of the recently-discovered role of ALCAM in angiogenesis [Ohneda et al, 2001 , Blood 2001 Oct 1 ;98(7):
  • the nucleotide sequence is represented in the public sequence databases by the accession BC008022 and is described in this patent by Seq ID 282.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design- of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • the EST represented by Seq ID 282 is repressed in macrophages activated by LPS and gamma interferon. W e expect the product of EST represented by Seq ID 282 to have an anti-inflammatory role,
  • the Oxford BioMedica clone p2A23 represents Chitinase 3-like 2
  • the protein sequence encoded by Chitinase 3-like 2 is represented in the public databases by the accession NP_003991 and is described in this patent by Seq ID 283
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004000 and is described in this patent by Seq ID 284,
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
  • BACHl a novel helicase-Iike protein, interacts directly with BRCA 1 and contributes to its DNA repair function.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the induction by hypoxia of this known transcriptional repressor and potential oncogene [Cantor et al 2001, Cell 105:149-60] is a very significant finding with profound implications for the diagnosis and treatment of cancer.
  • the Oxford B ioM edica clone pi G 15 represents Phosphoglucomutase 1.
  • the protein sequence encoded by Phosphoglucomutase 1 is represented in the public databases by the accession NP_002624 and is described in this patent by Seq ID 287.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002633 and is described in this patent by Seq ID 288. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Phosphoglucomutase 1 is induced in m acrophages treated with the inhibitory cytokine IL-10.
  • Hypothetical protein LOC51014 The Oxford BioM edica clone plF23 represents Hypothetical protein LO C51014.
  • the protein sequence encoded by Hypothetical protein LOC51014 is represented in the public databases by the accession Q9Y3B 3 and is described in this patent by Seq ID 289 ,
  • the nucleotide sequence is represented in the public sequence databases by the accession AF151867 and is described in this patent by Seq ID 290.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found.
  • Hypothetical protein LOC51014 is downregulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
  • the Oxford BioM edica clone p l G8 represents Sin3-associated polypeptide.
  • the protein sequence encoded by Sin3-associated polypeptide is represented in the public databases by the accession NP_003855 and is described in this patent by Seq ID 291.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003864 and is described in this patent by Seq ID 292.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the Oxford BioM edica clone pi G 13 represents AB CA 1.
  • the protein sequence encoded by AB CA 1 is represented in the public databases by the accession NP_005493 and is described in this patent by Seq ID 293.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005502 and is described in this patent by Seq ID 294.
  • Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes.
  • the Oxford BioM edica clone pl G l O represents SEC24 member A .
  • the protein sequence encoded by SEC24 mem ber A is represented in the public databases by the accession CAA 10334 and is described in this patent by Seq ID 295.
  • the nucleotide sequence is represented in the public sequence databases by the accession AJ131244 and is described in this patent by Seq ID 296.
  • Hypoxia is an important feature of several. diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • the O xford B ioM edica clone p l F24 represents Glia-derived nexin.
  • the protein sequence encoded by Glia-derived nexin is represented in the public databases by the accession AAA 35883 and is described in this patent by Seq ID 297.
  • the nucleotide sequence is represented in the public sequence databases by the accession M 17783 and is described in this patent by Seq ID 298.
  • Glia-derived nexin is a glycoprotein that functions as a serine protease inhibitor with activity towards thrombin, trypsin and urokinase.
  • hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
  • M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant.
  • Glia-derived nexin is induced in macrophages activated by LPS and gamm a interferon. Hypoxia is frequently found in hum an tumours w here m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Glia-derived nexin is down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
  • the Oxford BioMedica clone pl G2 represents Postsynaptic density-95.
  • the protein sequence encoded by Postsynaptic density-95 is represented in the public databases by the accession NP_001356 and is described in this patent by Seq ID 299.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001365 and is described in this patent by Seq ID 300.
  • Postsynaptic density-95 belongs to the MAGUK family of cell junction proteins. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.

Abstract

This invention relates to novel methods for the identification of genes and gene products that are implicated in certain disease states. According to the invention, there is provided a method for the identification of a gene that is implicated in a specific disease or physiological condition, said method comprising the steps of comparing: i) the transcriptome or proteome of a first specialised cell type that is implicated in the disease or condition under first and second experimental conditions; with ii) the transcriptome or proteome of a second specialised cell type under said first and said second experimental conditions; and identifying as a gene implicated in the disease or physiological condition, a gene that is differentially regulated in the two specialised cell types under the first and second experimental conditions. The invention also relates to novel genes and gene products identified using these methods.

Description

Analysis m ethod
This invention relates to novel methods for the identification of genes and gene products that are implicated in certain disease states. The invention also relates to novel genes and gene products identified using these m ethods. All publications, patents and patent applications cited herein are incorporated in full by reference.
One of the central goals in the field of gene expression is to understand and elucidate the relationship between a particular disease state and the gene expression pattern that defines and/or causes this disease state. Research has concentrated on differences in expression patterns between diseased and healthy tissues to elucidate the physiological m echanism s of disease. Identified differences in expression patterns provide putative points for therapeutic intervention to reverse the disease phenotype. These differences also provide m arkers that are useful for diagnosis, and identify proteins for further investigation as agents im plicated in the disease in question.
Conventional methods for the elucidation of mechanism s of disease tend to concentrate on the correlation of a disease state w ith altered levels of a particular protein. Such methods include techniques of im m unohistochem istry, the study of differential m RNA expression and the sequence analysis of particular proteins to identify m utations that are associated with a certain disease state.
Recently, research has concentrated on analysis of the transcripto es of organism s and cell types that are considered to be of scientific interest. B y "transcriptome" is meant the exact set of transcripts that are expressed in a cell. The em erging field of nucleic acid arrays is one field in which a large num ber of powerful tools are being generated for the study of transcriptom e variation between different tissue types. These tools are based on techniques originally pioneered by Schena et al, 1995 (Science 270: 467-470) and Fodor et al, 1991 (Science 251 , 767 -773) and facilitate the evaluation of variations in DNA or RN A sequences and of variations in expression levels from tissue samples and allow the identification and genotyping of m utations and polym orphism s in these sequences. The power of one such technique has recently been dem onstrated by Perou et al, (Nature, 2000, 406:747-752), who generated m olecular portraits of the transcriptomes of hum an breast tum ours.
O ver recent years, the so-called "genom ics revolution" has allowed access to large portions of whole genomes, including the human genome. The amount of sequence information now available considerably facilitates the analysis of the results of experiments that aim to elucidate the differences between gene expression in diseased and healthy tissues. As this inform ation increases in scope and becom es m ore readily available, the study of the molecular mechanism of disease, and the elucidation of techniques for combatting these diseases will be considerably facilitated.
How ever, there are notable disadvantages associated w ith all methods that are currently employed for the analysis of hum an disease. M any m ethods currently em ployed utilise established cell lines. Because these cells have been manipulated to allow their immortalisation in cell culture, the physiological situation in these cells is not considered by the present inventors to be generally representative of the authentic situation in equivalent cells in vivo. Furtherm ore, m ost of these methods tend to utilise a global strategy for intervention, often ignoring the intricacies in gene expression that exist between different tissues. There thus rem ains a great need for the establishm ent of novel m ethods for the analysis of gene expression.
According to the invention, there is provided a method for the identification of a gene that is implicated in a specific disease or physiological condition, said method comprising the steps of: a) comparing: i) the transcriptom e or proteome of a first specialised cell type that is implicated in the disease or condition under first and second experim ental conditions; with ii) the transcriptome or proteome of a second specialised cell type under said first and said second experim ental conditions; and b) identifying as a gene implicated in the disease or physiological condition, a gene that is differentially regulated in the two specialised cell types under the first and second experimental conditions.
Using this method, genes have been identified that respond to perturbations of cell physiology in a cell- specific rather than a generic fashion. The method of the invention exhibits significant advantages over conventional m ethods of identifying genes that are implicated in disease.
V arious groups have previously investigated mechanism s of physiological regulation, by comparing gene expression levels in the presence and absence of a physiological stim ulus or challenge. Genes identified in a particular cell type as being expressed at different levels under different conditions are implicated as components of a pathway that is responsive to the altered conditions, or that is regulated differently under the altered conditions. However, these m ethods exhibit a tendency to ignore patterns of gene expression that are physiologically relevant. This inclination is considered to result from a prejudice in the art that dictates that cells respond to changes in certain physiological conditions in a generic fashion, rather than in a cell specific fashion.
B y "implicated in a specific disease or physiological condition" is meant that the gene has been found to possess a distinct role in a pathway that is involved in susceptibility to, generation of or m aintenance of a particular disease phenotype or physiological condition. As will be apparent to the skilled reader, any point in any pathw ay may be the unique point at w hich a cell departs from the normal physiological response and generates a disease phenotype. Often the effect that is m anifested as a disease is the result of a m utation event, in which a mutation occurs in the sequence of a gene encoding a protein that functions in a relevant physiological pathway.
There are num erous examples of diseases and conditions that m ay be studied using the m ethod of the invention. Such pathological conditions include those that result from a change in the intrinsic nature of a cell (usually genetic) or from a change in the cellular microenvironm ent, either of which m ight be recapitulated in a laboratory setting. The m ethods may be applied to any disease or condition that is manifested in, or is generated in a specific cell type.
Examples of such conditions include changes in the cellular microenvironment, exposure to hormones, growth factors, cytokines, chem okines, inflamm atory agents, toxins, m etabolites, pH, pharm aceutical agents, hypoxia, anoxia, ischemia, im balance of any plasm a-borne nutrient [including glucose, am ino acids, co-factors, m ineral salts, proteins and lipids], osm otic stress, temperature [hypo and hyper- thermia], mechanical stress, irradiation [ionising or non-ionising], cell-extracellular m atrix interactions, cell-cell interactions, accumulations of foreign or pathological extracellular components, intracellular and extracellular pathogens [including bacteria, viruses, fungi and mycoplasma] and genetic perturbations [both epigenetic or m ediated by mutation or polymorphism].
Examples of such diseases include cardiovascular disease, atherosclerosis, inflamm atory conditions (including rheum atoid arthritis), cancer, ischemic disease, asthm a, hem atopoietic disorders, neurological diseases including Parkinson's and Alzheimer' s diseases, infectious disease and allergies.
One particular physiological response that has been used herein to illustrate the invention is the cellular response to hypoxia. The term "hypoxia" is intended to refer to an environment of reduced oxygen tension, as compared to the norm al physiological environment for a particular organism , which is termed "normoxia" . The prejudice in this technical field presents the view that there is a general, ubiquitous response to hypoxia, mediated prim arily at the level of m RNA (transcriptional initiation and post- transcriptional stabilisation).
In a variety of hum an diseases, cells are exposed to conditions of low oxygen tension, usually as a result of poor oxygen supply to the diseased area. For instance, tissue oxygenation plays a significant regulatory role in both apoptosis and in angiogenesis (Bouck et al, 1996, Adv . Cancer Res. 69:135-174; Bunn et al, 1996, Physiol. Rev. 76:839-885 ; Dor et al, 1997 , Trends Cardiovasc. M ed., 7 :289-294; Carmeliet et al, 1998, Nature 394:485-490). Apoptosis (see Duke et al, 1996, Sci. American, 80-87 for review) and growth arrest occur when cell growth and viability are reduced due to oxygen deprivation. Angiogenesis (i.e. blood vessel growth, vascularization), is stimulated when hypooxygenated cells secrete factors that stim ulate proliferation and m igration of endothelial cells in an attempt to restore oxygen hom eostasis (for review see Hanahan et al, 1996, Cell, 86 :353-364).
Ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels. For example, solid tum ours typically have a disorganised blood supply, leading to hypoxic regions. O ther disease conditions involving hypoxia include stroke, atherosclerosis, retinopathy, acute renal failure, myocardial infarction, stroke and hair loss. Therefore, apoptosis and angiogenesis as induced by the ischaemic condition are also considered to be involved in these disease states. It is generally considered that understanding the mechanism by w hich cells respond to these diseases m ay be the key to the disease pathology and thus relevant to disease treatment.
In a different but related approach, it is now recognised that angiogenesis is necessary for tum our grow th and that retardation of this process provide a useful tool in controlling m alignancy and retinopathies. For example, neoangiogenesis is seen in m any forms of retinopathy and in tum our growth. The ability to be able to induce tumourigenic cells to undergo apoptosis is an extrem ely desirable goal; particularly in the cancer field, it has been observed that apoptosis and angiogenesis-related genes provide potent therapeutic . targets. It has also been observed that hypoxia plays a critical role in the selection of mutations that contribute to m ore severe tum ourigenic phenotypes (Graeber et al, 1996 Nature, 379(6560):88-91 ).
Early in the history of this field it was discovered that a transcription factor, HIF-l alpha, is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia. This protein is considered a m aster regulator of oxygen homeostasis (see, for example, Semenza, (1998) Curr. Op. Genetics and Dev. 8 :588-594). W here HIF1 alpha is genetically knocked out, the hypoxia-inducible transcription of virtually all glycolytic enzymes has been shown to be inhibited. Glycolysis is an essential process which goes on in all m amm alian cells. This finding is therefore consistent with previous work showing that when cells are exposed to conditions of hypoxia, they up-regulate glycolytic enzymes to enable ATP production, since oxidative phosphorylation is no longer feasible under conditions of low oxygen (W ebster (1987) MolCell.Biochem, 77 : 19-28). Further support for a critical and general role of HIFl alpha in the hypoxic response is dem onstrated by the knockout mouse, which dies at day 10.5 of gestation. The same is true of the knockout of the ARNT protein, the dimerisation partner of HIFl alpha.
For the first time, it is dem onstrated herein that different tissues and cell types exhibit a very different response to hypoxia, at the level of the induction and repression of gene expression. This has allowed the detailed elucidation of the mechanism of this particular physiological response, so paving the way for the development of improved therapeutic agents that target components of the response path ay in particular tissues. Although conventional approaches to the analysis of this mechanism have successfully identified num erous genes, because of the universal prejudice in the art that these components will all be induced/repressed similarly in all cell types, all the approaches suggested have hitherto been limited to the design of therapeutic agents that act in a global fashion.
The m ethods of the present invention therefore extend and add to previous w ork perform ed in this field, in that the discoveries made now allow the design of agents that target the hypoxic response in specific tissues. For example, it is known that brain and heart tissues die very rapidly after ischaem ic insult. B y using the m ethod of the invention, it is quite possible that these tissues will be found to share com m on features in their response to hypoxia, that is different from other cell types. This might allow , for example, the design of a combination cardioprotective and neuroprotective agent effective against this subset of body tissues. Alternatively, the hypoxic response in these tissues m ight be found to be quite different, This information w ould then be taken into account when designing therapeutic countermeasures, in that an agent would be designed for the unique neurological or cardiological tissue concerned.
The m ethod of the invention involves the comparison of the transcriptomes or proteomes of at least tw o specialised cell types under tw o different physiological or genetic conditions. B y "transcriptome" is meant the exact set of transcripts that are expressed in a cell. The transcriptome thus has a qualitative elem ent (the identity of individual gene transcripts) and a quantitative element (the proportion of each unique transcript in the total number of individual transcripts present in the cell at a particular m om ent). B y "proteome" is meant the exact set of protein m olecules that are expressed in a cell.
B y "specialised cell type" is m eant a cell type that has a restricted biochemical capacity and that can be unambiguously identified as possessing a unique set of biochemical and physiological functions, Preferably, the specialised cells are prim ary cells, and not cell lines or whole body tissues, Primary cells are cells that cannot proliferate indefinitely in culture, Prim ary cells can be derived from adult tissue, or from embryo tissue that is differentiated in culture to an adult cell or to a precursor of an adult cell that displays specialised characteristics.
Examples of preferred specialised cell types include cardiom yocytes, endothelial cells, sensory neurons, motor neurons, CNS neurons (all types), astrocytes, glial cells, schwann cells, m ast cells, eosinophils, smooth muscle cells, skeletal muscle cells, pericytes, lymphocytes, tum or cells, m onocytes, m acrophages, foamy m acrophages, granulocytes, synovial cells / synovial fibroblasts, epithelial cells (varieties from all tissues/ organs). Examples of other suitable specialised cell types include vascular endothelial cells, smooth muscle cells (aortic, bronchial, coronary artery, pulmonary artery, etc), skeletal muscle cells, cardiom yocyte cells, fibroblasts (m any types, such as synovial), keratinocytes, hepatocytes, dendritic cells, astrocytes, neurone cells (including mesencephalic, hippocampal, striatal, thalamic, hypothalamic, olfactory bulb, substantia nigra, locus coeruleus, cortex, dorsal root ganglia, superior cervical ganglia, sensory, m otor, cerebellar cells), neutrophils, eosinophils, basophils, m ast cells, m onocytes, m acrophage cells, erythrocytes, megakaryocytes, hem atopoietic progenitor cells, hematopoietic pluripotent stem cells, any stem cells, any progenitor cells, epithelial cells, melanocytes, osteoblasts, osteoclasts, stromal cells, purkinje cells, T-cells, B -cells, synovial cells, pancreatic islet cells (alpha and beta), leukemia cells, lymphom a cells, tum our cells, retinal cells, adrenal chrom affin cells, A s will be apparent to the skilled reader, it is not here possible to provide an exhaustive list of specialised cell types that may be studied according to the methods of the present invention.
Intended as being included within the method of the invention is the possibility of using, as tw o different specialised cell types, two different physiological states of the sam e cell type, for example, activated and resting m acrophages.
The transcriptom es of the specialised cell types are compared under different experimental conditions. The term "experim ental conditions" is used broadly in this context and is intended to embrace any physiological or genetic conditions to w hich a cell type m ay be exposed. The intention of the method is to compare the transcriptomes or proteom es of the cell types under different experimental conditions that have a physiological relevance. Accordingly, the state of the transcriptome or proteome under one set of experim ental conditions will generally act as a control against which the transcriptome or proteom e m ay be compared under a second set of experimental conditions. Any distinct physiologically-relevant conditions may therefore be of interest.
Examples of suitable physiological experim ental conditions include conditions under w hich the cell is subm itted to a physiological, mechanical, temperature, chem ical, toxic or pharmaceutical stress. One example is hypoxia, defined herein as a physiological state in which oxygen dem and by the cell exceeds its supply to the cell. The transcriptome or proteome under this set of experimental conditions may be compared to the transcriptome or proteome under conditions of normoxia, w hen oxygen supply is in concordance with the dem and by the cell.
The transcriptomes or proteomes may also be compared under different genetic conditions. B y "genetic conditions" is meant that the genotype of the compared cell populations contains a different genetic component. This m ay be the presence of one or m ore different, non-endogenous nucleic acid m olecules in the cell, herein referred to collectively as "genetic elem ents" . Such genetic elem ent(s) m ay potentially be incorporated into the genome of the cell, or alternatively may exist as a separate genetic entity, for example, as an extra-chrom osom al elem ent such as a plasm id or episome. Alternatively, the genome m ay have been perturbed by external intervention, for example, to increase or decrease the expression of a particular gene or genes. A num ber of variations on this theme are possible, including the overexpression of a genetic elem ent via the adm inistration of the functional gene, the overexpression of a genetic element via the administration of a regulator of the functional gene (such as, for example, a transcription factor [either natural or artificially constructed via the fusion of a DN A binding dom ain with an activator dom ain]), the inhibition of the expression of a functional gene (for example, using antisense RNA or ribozym es), the inhibition of the expression of a functional gene (for example, using a transdominant protein) and the inhibition of the expression of a functional gene (for example, using a repressor protein that is either natural or artificially constructed from a DNA binding protein fused to a repressor dom ain).
A particular example of a genetic perturbation as envisaged herein, that form s one preferred embodim ent of the m ethod of the present invention, is the so-called "Sm artomics" technology that form s the basis for co-pending, co-owned International patent application PCT/GB O 1 /00758 , According to this technology, a heterologous nucleic acid is introduced into a prim ary cell to augment a specific natural physiological response, "Sm artom ics" m ay be applied to the current invention by m easuring and comparing cellular responses to a heterologous gene in two or m ore distinct cell types, both with and without the natural physiological stim ulus. Lentivirus technology is used to introduce the heterologous nucleic acid m olecule in such a w ay that there is negligible perturbation of endogenous gene expression, For this reason, this technology exhibits significant benefits over conventional technology of a similar nature, since the prior art m ethods are generally invasive, having downstream effects other than the simple introduction of the heterologous nucleic acid m olecule. The Sm artomics technology allows much m ore precise m easurem ents to be taken of the effect of introducing the heterologous nucleic acid.
The method of the invention allows the identification of genes that are implicated in a specific disease or physiological condition. The genes identified in this way are candidate targets for antagonists or agonists that m odulate disease states pertinent to that specialised cell type. This allows the development of selective agonists and antagonists, rather than broad spectrum agonists and antagonists. This approach thus adds value in the selective treatm ent of disease. Furtherm ore the identified genes are associated with regulatory elements that provide alternative and additional candidate targets for exploitation for the delivery of gene products to that cell in a cell-specific fashion. The genes and regulatory elements identified according to the method of the invention can be used directly in therapeutic applications via gene therapy, via recombinant protein m ethods or via chemical mimetics or as targets for the development of agonists and antagonists such as antibodies, small chemical m olecules, peptides, regulatory nucleic acids.
The step of comparison of the transcriptom es or proteomes of the first and second specialised cell types under first and second experimental conditions may be effected using any approach that allows the quantitative comparison of gene or protein expression, and a number of such means will be known to those of skill in the art. Such experim ents have only becom e possible in recent years, due to certain advances in technology that have allowed the large scale, high throughput analysis of gene expression.
One example of a m ethod that allow s the comparison of the transcriptome of a specific cell type with a second or subsequent transcriptom e involves the generation of a set of clones that represent all the transcripts expressed in a cell under the conditions in which the cell is m aintained. This m ay be done by constructing a cDNA library, in which copies of all mRNA transcripts expressed in the cell are cloned into a suitable vector for subsequent analysis.
Such libraries m ay be normalised cDNA libraries, in which the distribution of genes in the library has been biased to reduce the num ber of clones that represent genes with large num bers of transcripts (such as, for exam ple, beta-actin) and thus reduce the repetitive nature of the library. Norm alisation thus acts to reduce the frequency of genes expressed at high levels and to enhance the frequency of genes expressed at low levels (see de Fatim a B onaldo et al, Genome Research 6: 791 -806 (1996)).
Libraries m ay also be subtracted cDNA libraries, in which the distribution of genes is m anipulated to rem ove genes that are expressed in both mRNA populations used to construct the library. The comm ercially-available PCR Select kit (Clontech, Inc) is an example of a system useful to generate such libraries.
cDNA clones generated as reflective of the transcriptome of a specific cell type may then be amplified, and processed to evaluate the identity of the nucleic acid clones. For example, m ultiple clones m ay be picked and used as template for PCR amplification. The PCR products may then be arrayed onto mem branes or glass slides to create nucleic acid arrays, For expression profiling, these arrays are then hybridised to complex nucleic acid probes in order to quantitate the abundance of individual genes contained in the probes.
A recent summ ary of nucleic acid array technology that is useful in the analysis of the transcriptom e of a cell population is provided in Nature Genetics, (1999) (21 suppl; 1 -61 ). There are various types of array technology currently used, including "microarrays", or "chips", which are high density cDNA arrays produced on glass slides, often produced using photolithography . A second type of array is the "macroarray", w hich is an array with sub-m illimetre spot-spot distances produced on a nylon m em brane, One example of this type of array are the nylon-based m icroarrays sold comm ercially by Research Genetics Inc. (term ed Research Genetics Hum an GeneFilters) that each contain 5 ,300 cDNA fragments of known identity . The w hole series of arrays covers some 35,000 cDNA fragm ents. This particular array system (and others like it) allow the identification of transcripts that are down-regulated, as well as those that are up-regulated, since the range of genes used to manufacture the arrays are not biased.
The step of comparison m ay be effected by utilising subtracted cDNA libraries. Using this approach, the transcriptom e of one specialised cell type under first experimental conditions is subtracted against the transcriptom e under second experimental conditions. This reveals the differences in expression under the two experimental conditions tested. When this is performed for both specialised cell types, the differential regulation of gene expression under the two experim ental conditions is revealed.
The step of comparison is through the detection of genes that are differentially regulated in the two specialised cell types examined under the first and second experimental conditions. As an example, a hum an cardiom yoblast (cell type A) and a human m acrophage (cell type B ) m ay be placed at the sam e temperature and at a high oxygen tension (first experimental conditions [1 ]), Cells from the same cell types are also incubated at this temperature, yet under conditions of low oxygen tension (second experim ental conditions [2]). In this simple example, there are then a minim um of four com binations of cell type and condition, A [l ], B [l ], A [2] and B [2], "Snapshots" are taken of the transcriptom es of both cell types under the "norm oxic" and the "hypoxic" experimental conditions, by preparing messenger RNA from all four combinations, Differences in the regulation of genes can then be analysed, for example, using a process of subtractive hybridisation.
The m echanism of transcriptome comparison in the above example may be as follows. Subtracted cDNA libraries are separately prepared for hypoxic m acrophages and cardiom yoblasts; for both cell types, their cDNA under normoxic conditions is subtracted against their cDNA under hypoxic conditions. This might be effected by harvesting RNA from cells both in normoxia and hypoxia, and preparing cDNA . Subtractive hybridization, optionally including suppression PCR , may then be performed to rem ove genes from the hypoxic cell cDN A which are also present in cDNA from norm oxic cells. Insert DNA from these subtracted libraries can then be amplified and arrayed onto duplicate membranes. Quantitative hybridization with pre-library cDNA m aterial (norm oxia and hypoxia) then allows the comparison of differentially-expressed clones in the tw o cell types. The clones representing hypoxia-inducible genes m ay be then be identified, for example, by sequencing. Other techniques that are suitable for the analysis of the transcriptom e of a specific cell type include serial analysis of gene expression (SAGE ; Velculescu et al, Science (1995) 270; 484-487), Selective amplification via biotin- and restriction-mediated enrichm ent (SABRE) (Lavery et al, (1997), PNAS USA 94: p6831 -6836); Differential display (for example, indexing differential display reverse transcriptase polymerase chain reaction (DDRT-PCR ; M ahadeva et al (1998) J. M ol.Biol. 284, 1391 -1398)); representational difference analysis (RD A) (Hubank (1999) M ethods in Enzym ology 303 : 325-349); differential screening of cDNA libraries (see Sagerstrom et al (1997) Annu. Rev. B iochem . 66: 751 -783); "Advanced M olecular B iology" , R .M . Tw ym an (1998) B ios Scientific Publishers, Oxford; "Nucleic Acid Hybridization" , M . L. M . Anderson (1999) B ios Scientific Publishers, O xford); Northern blotting; RNA se protection assays; S l -nuclease protection assays; RT-PCR ; real time RT-PCR (Taq-m an); EST sequencing; massively parallel signature sequencing (MPSS); and sequencing by hybridisation (SBH) (set Drmanac R . et al (1999), M ethods in Enzym ology 303 :165-178). M any of these techniques are review ed in "Comparative gene-expression analysis" Trends B iotechnol. 1999 Feb;17(2):73-8.
M ethods such as these have been applied widely to study mechanism s of biological response. In particular, m icroarrays have been used widely to com pare gene expression levels betw een norm al and diseased tissue. M ore typically, however, comparisons are perform ed to detect changes in gene expression that are associated with specific aspects of disease progression or pathology. For instance, a study of prostate cancer would examine changes associated w ith the step-wise progression to full m alignancy or the dependence on androgens for growth.
Transcriptome analysis is complemented by the analysis of the complete protein make-up of a cell, referred to as proteom ics. The use of tw o dim ensional SD S-PA GE gels in combination with amino acid sequencing by m ass spectrometry is currently the m ost w idely-used technique in this field (see "Proteomics to study genes and genomes" Akhilesh Pandey and M atthias M ann, (2000), Nature 405 : 837- 846). Additionally, the recent developments in the field of protein and antibody arrays now allow the simultaneous detection of a large number of proteins. For example, low -density protein arrays on filter membranes, such as the universal protein array system (Ge H, (2000) Nucleic Acids Res. 28(2), e3) allow im aging of arrayed antigens using standard ELISA techniques and a scanning charge-coupled device (CCD) detector. Im muno-sensor arrays have also been developed that enable the simultaneous detection of clinical analytes. It is now possible using protein arrays, to profile protein expression in bodily fluids, such as in sera of healthy or diseased subjects, as well as in patients pre- and post-drug treatm ent.
Antibody arrays also facilitate the extensive parallel analysis of numerous proteins that are hypothetically implicated in a disease or particular physiological state. A number of methods for the preparation of antibody arrays have recently been reported (see Cahill, Trends in B iotechnology, 2000 7 :47-51 ). It is not the intention here to review studies that have been conducted in this area previously. However, one example of a physiological condition that has already received considerable attention is the response to hypoxia. Several patent applications have now been published that involve an exam ination of the genetic response to hypoxia (see W 000/12139, Quark B iotech, Inc.; W O 00/12525, Quark Biotech, Inc.; W O 99/09049, Quark Biotech, Inc.; W O 99/09046, Quark Biotech, Inc.; W 099/48916, The B oard of Trustees of the Leland Stanford Jr. University). These patent applications generally utilise m ethods of subtractive hybridisation and differential expression gene microarray analysis to examine this genetic response in certain cell lines, The studies have implicated specific genes as being either repressed or induced under hypoxic conditions as compared to their expression under norm oxic conditions. These genes are taught as being useful generally in all cell types, being involved in the (generic) hypoxic response.
Significantly, the present invention extends this work, and, indeed, defines a significant advance over sim ilar work that has been performed on the genetic mechanism s that act in response to other physiological or genetic stimuli. The present inventors, using the novel m ethods disclosed herein, have discovered that far from being generic, the cellular response to m any physiological conditions differs m arkedly betw een different cell types. The cellular response that has been studied in order to illustrate this finding is the response to hypoxia. From these results, it has been inferred herein, quite reasonably, that far from being generic, cellular response mechanism s differ widely, depending on cell type,
This discovery has far-reaching implications as regards the design of therapeutic agents that are effective to counter a disease or physiological condition. For example, an agent that is effective to prevent the drastic effects of hypoxia in a neurone (the effects of w hich include stroke) m ight be totally ineffective in countering the same effects in a cardiom yocyte (chronic ischemic heart disease). Through analysing the mechanism of the hypoxic response in different cell types, it m ay be, in contrast to the example given above, that a particular gene is involved in the hypoxic response in both cardiom yocytes and neurones. W ere this to be the case, this w ould allow the design of a combined m edicament, for example, a com bined cardioprotective and neuroprotective agent. There thus rem ains a great need for the identification of proteins implicated in the physiological mechanism of hypoxia.
According to a further aspect of the invention, there are provided genes and proteins that are identified using a method according to any one of the above-described aspects of the invention, Certain proteins, whose sequences are identified herein as SEQ ID Nos: 1 , 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21 , 23, 25, 27, 29, 31 , 33 , 35, 37, 39, 41 , 43, 45, 47, 49, 51 , 53, 55 , 57, 59, 63, 67, 69, 73, 75, 77, 85 , 87, 89, 91 , 93 , 95, 99, 103 , 113 , 1 15, 1 19, 121 , 129, 131 , 133 , 137, 139, 141 , 145, 151 , 153, 157 , 159, 163 , 169, 181 , 187 , 201 , 205 , 207 and 209, are functionally annotated for the first time. At present, all of these sequences are only identified as "hypothetical proteins" in the public databases. Each and every one of these sequences form s an embodiment of this aspect of the invention.
The invention also includes proteins whose amino acid sequences are encoded by a nucleic acid sequence recited in various cDNAs and ESTs deposited in the public databases, or encoded by a gene identified from such an EST. These cDNAs and ESTs are presented herein as SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216. At present, all of these cDNA and EST sequences are functionally unannotated in the public databases. Each and every one of these sequences forms an embodiment of this aspect of the invention.
One embodiment of this aspect of the invention provides substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67,
69,73,75,77, 85, 87,89,91,93,95,99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 or 209; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96
98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 212, 214 and 216 or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii). The polypeptide sequences recited in SEQ ID Nos: 1,3,5,7,9, 11, 13,15, 17, 19,21,23,25,27,29,31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187,201,205, 207 and 209 were, prior to the present disclosure, unannotated in the literature and public sequence databases. Accordingly, until now, no biological function has been attributed to these polypeptide sequences; each of these sequences is generally labelled in the databases as a "hypothetical protein". The methods of the present invention, described above, have now elucidated a biological function for these polypeptides, in that they have been found to be differentially regulated under physiological conditions of hypoxia.
These discoveries allow the development of regulators, such as small drug molecules, that affect the activity of these polypeptides, so allowing diseases and physiological conditions that are caused by hypoxia, or in which hypoxia has been implicated, to be treated. These discoveries also allow the development of diagnostic agents that are suitable for the detection of hypoxia in biological tissues and, through the identification of mutations and polymorphisms (such as SNPs) within genes coding for the proteins implicated herein, allows the assessment of an individual's risk of being susceptible to diseases and physiological conditions in which hypoxia is implicated.
The biological activity of polypeptides whose sequences are listed in SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 has been found to be hypoxia-regulated. The expression of some of these polypeptides has been found to be induced under conditions of hypoxia, whilst the expression of other polypeptides has been found to be repressed. By "hypoxia-induced" is meant that the polypeptide is expressed at a higher level when a cell is exposed to hypoxic conditions as compared to its expression level under normoxic conditions. By "hypoxia-repressed" is meant that the polypeptide is expressed at a lower level when a cell is exposed to hypoxic conditions as compared to its expression level under normoxic conditions.
The following polypeptides have been found to be hypoxia-induced: those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139 and 141; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142 and 144 or is encoded by a gene identified from an EST recited in any one of these SEQ ID Nos..
The following polypeptides have been found to be hypoxia-repressed: those polypeptides whose amino acid sequence is recited in SEQ ID Nos.: 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 1 88, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos. For the purposes of this document, the term "hypoxia" should be taken to mean an environment of oxygen tension such that the oxygen content is betw een about 5 % and 0.1 % (v/v). In m ost cases, hypoxic tissue will have an oxygen content that is less than or equal to about 2% . The term "normoxia" should be taken to mean conditions comprising a norm al level of oxygen for the environm ent concerned. Norm oxic tissue typically has an oxygen content above about 5 % , The polypeptide sequences whose am ino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 , 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108 , 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158 , 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or whose am ino acid sequence is encoded by a gene identified from an EST recited in any one of these SEQ ID Nos,, w ere also, prior to the present disclosure, unannotated in the literature and public sequence databases, meaning that until now , no biological function has been attributed to these polypeptide sequences.
The sequences in this group fall into a num ber of different categories. The first of these are cDNA clones, for which a protein sequence has not been predicted by the depositor. A second category is expressed sequence tag (EST) sequences that are represented in the UniGene database (http://ww w .ncbi.nlm .nih.gov/UniGene/), which contain m odest or w eak hom ology to known proteins when translated. ESTs are single-pass sequence files of the 5' region of an organism 's expressed genome as accessed via a force cloned cDNA library. EST sequences tend to be short and as a general rule are error-prone. UniGene (see http://ww w .ncbi.nlm .nih.gov/W eb/New sltr/aug96.html for review) is an experimental system for autom atically partitioning these EST sequences into a non-redundant set of gene- oriented clusters. Each UniGene cluster contains sequences that represent a unique gene, as well as related inform ation such as the tissue types in which the gene has been expressed and m ap location. A third category of hits identified by the methods described herein is EST sequences that are contained in Unigene clusters, but w hich are not annotated and exhibit no hom ologies to proteins contained in the public databases. The fourth and final category encompasses singleton EST sequence entries that are not incorporated as entries in the Unigene database and that only appear as single entries in the public databases. The m ethods of the present invention, described above, have now elucidated a biological function for polypeptides that are encoded by genes incorporating cDNA and EST sequences that fall into the four categories set out above, in that these sequences have been found to be differentially regulated under physiological conditions of hypoxia. Such polypeptides m ay have an am ino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 , 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 112, 1 14, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138 , 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198 , 200, 202, 204, 206, 208 , 210, 212, 214 and 216. However, the EST sequences in particular may not be part of the actual coding sequence for a gene, often representing regulatory regions of the gene, or regions that are transcribed, but not translated into polypeptide. Accordingly, this aspect of the invention also includes polypeptides that are encoded by a gene identified from an EST recited in any one of SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148 , 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216 ;
Polypeptides of this aspect of the invention are intended to include fragm ents of polypeptides according to i) or ii) as defined above, provided that the fragment retains a biological activity that is possessed by the full length polypeptide of i) or ii), or has an antigenic determ inant in com m on with the polypeptide of i) or ii). A s used herein, the term "fragment" refers to a polypeptide having an amino acid sequence that is the same as part, but not all, of an amino acid sequence as recited in any one of SEQ ID Nos: 1 , 3 , 5, 7, 9, 1 1 , 13 , 15 , 17, 19, 21 , 23, 25 , 27, 29, 31 , 33, 35, 37, 39, 41 , 43, 45, 47, 49, 51 , 53, 55, 57, 59, 63, 67, 69, 73 , 75, 77, 85, 87, 89, 91 , 93 , 95, 99, 103 , 1 13 , 1 15 , 1 19, 121 , 129, 131 , 133 , 137, 139, 141 , 145, 151 , 153, 157, 159, 163, 169, 181 , 187, 201 , 205, 207 and 209, an am ino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos. 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138 , 140, 142, 144, 146, 148, 150, 152, 154, 156, 158 , 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or an amino acid sequence that is encoded by a gene that is linked to a nucleic acid sequence recited in any one of these SEQ ID Nos. The fragm ents should comprise at least n consecutive amino acids from the sequence and, depending on the particular sequence, n preferably is 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more). Sm all fragm ents may form an antigenic determ inant.
Such fragm ents m ay be isolated fragments, that are not part of or fused to other amino acids or polypeptides, or they m ay be comprised within a larger polypeptide, of which they form a part or region. W hen comprised within a larger polypeptide, a fragment of the invention m ost preferably form s a single continuous region. For instance, certain preferred embodiments relate to a fragm ent having a pre - and/or pro- polypeptide region fused to the am ino term inus of the fragment and/or an additional region fused to the carboxyl term inus of the fragment. However, several fragm ents m ay be comprised within a single larger polypeptide.
The polypeptides of the present invention or their immunogenic fragments (comprising at least one antigenic determinant) can be used to generate ligands, such as polyclonal or m onoclonal antibodies, that are im munospecific for the polypeptides. Such antibodies m ay be employed to isolate or to identify clones that express a polypeptide according to the invention or, for example, to purify the polypeptide by affinity chromatography. Such antibodies m ay also be employed as diagnostic or therapeutic aids, am ongst other applications, as will be apparent to the skilled reader.
The term "immunospecific" m eans that an antibody has substantially greater affinity for a polypeptide according to the invention than their affinity for related polypeptides. As used herein, the term "antibody" is intended to include intact m olecules as well as fragments thereof, such as Fab, F(ab')2 and scFv, which are capable of binding to the antigenic determinant in question,
The invention also includes functional equivalents of a polypeptide of i), ii) or (iii) as recited above, A functionally-equivalent polypeptide according to this aspect of the invention m ay be a polypeptides that is hom ologous to a polypeptide w hose sequence is explicitly recited herein. Two polypeptides are said to be "hom ologous" if the sequence of one of the polypeptides has a high enough degree of identity or sim ilarity to the sequence of the other polypeptide for the skilled person to determ ine that they are similar in origin and function. Preferably, homology is used to refer to sequence identity. "Identity" indicates that at any particular position in the aligned sequences, the am ino acid residue is identical between the sequences. "Similarity" indicates that, at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences. Degrees of identity and sim ilarity can be readily calculated according to methods know.n in the art (see, for example, Computational Molecular B iology, Lesk, A .M ., ed., O xford University Press, New York, 1988; B iocomputing, Inform atics and Genome Projects, Smith, D .W ., ed„ Academic Press, New York, 1993). Advantageously, the BLAST algorithm is employed, with parameters set to default values. The B LAST algorithm is described in detail at http://ww w .ncbi.nih.gov/B LAST/blast_help.html, which is incorporated herein by reference. The search parameters are defined as follows, and are advantageously set to the defined default param eters.
Advantageously, "substantial homology" w hen assessed by B LAST equates to sequences which match w ith an EXPECT value of at least about 7, preferably at least about 9 and most preferably 10 or more. The default threshold for EXPECT in B LAST searching is usually 10. BLAST (B asic Local Alignment Search Tool) is the heuristic search algorithm employed by the programs blastp, blastn, blastx, tblastn, and tblastx; these programs ascribe significance to their findings using the statistical methods of Karlin and Altschul (see http://www.ncbi.nih.gov/BLAST/blast_help.html) with a few enhancements. The BLAST programs were tailored for sequence similarity searching, for example to identify homologues to a query sequence. The programs are not generally useful for motif-style searching. For a discussion of basic issues in similarity searching of sequence databases, see Altschul et al. (1994) Nature Genetics 6:119-129.
The five BLAST programs available at http://www .ncbi.nlm .nih.gov perform the following tasks: blastp compares an amino acid query sequence against a protein sequence database; blastn compares a nucleotide query sequence against a nucleotide sequence database; blastx compares the six-frame conceptual translation products of a nucleotide query sequence (both strands) against a protein sequence database; tblastn compares a protein query sequence against a nucleotide sequence database dynamically translated in all six reading frames (both strands). tblastx compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database.
BLAST uses the following search parameters:
HISTOGRAM Display a histogram of scores for each search; default is yes. (See parameter H in the BLAST M anual). DESCRIPTIONS Restricts the number of short descriptions of matching sequences reported to the number specified; default limit is 100 descriptions. (See parameter V in the manual page). See also EXPECT and CUTOFF.
ALIGNMENTS Restricts database sequences to the number specified for which high-scoring segment pairs (HSPs) are reported; the default limit is 50. If more database sequences than this happen to satisfy the statistical significance threshold for reporting (see EXPECT and CUTOFF below), only the matches ascribed the greatest statistical significance are reported. (See parameter B in the BLAST M anual).
EXPECT The statistical significance threshold for reporting matches against database sequences; the default value is 10, such that 10 m atches are expected to be found merely by chance, according to the stochastic model of Karlin and Altschul (1990). If the statistical significance ascribed to a match is greater than the EXPECT threshold, the match will not be reported. Lower EXPECT thresholds are more stringent, leading to fewer chance matches being reported. Fractional values are acceptable. (See parameter E in the BLAST Manual).
CUTOFF Cutoff score for reporting high-scoring segment pairs. The default value is calculated from the EXPECT value (see above). HSPs are reported for a database sequence only if the statistical significance ascribed to them is at least as high as would be ascribed to a lone HSP having a score equal to the CUTOFF value. Higher CUTOFF values are more stringent, leading to fewer chance matches being reported. (See parameter S in the BLAST Manual). Typically, significance thresholds can be more intuitively managed using EXPECT.
MATRIX Specify an alternate scoring matrix for BLASTP, BLASTX, TBLASTN and TBLASTX. The default matrix is BLOSUM 62 (Henikoff & Henikoff, 1992). The valid alternative choices include: PAM40, PAM 120, PAM250 and IDENTITY. No alternate scoring matrices are available for BLASTN; specifying the M ATRIX directive in BLASTN requests returns an error response.
STRAND Restrict a TBLASTN search to just the top or bottom strand of the database sequences; or restrict a BLASTN, BLASTX or TBLASTX search to just reading frames on the top or bottom strand of the query sequence.
FILTER M ask off segm ents of the query sequence that have low compositional complexity, as determined by the SEG program of Wootton & Federhen (1993) Computers and Chemistry 17:149-163, or segments consisting of short-periodicity internal repeats, as determined by the XNU program of Claverie & States (1993) Computers and Chemistry 17:191 -201 , or, for BLASTN, by the DUST program of Tatusov and Lipman (see http://www.ncbi.nlm.nih.gov). Filtering can eliminate statistically significant but biologically uninteresting reports from the blast output (e.g., hits against common acidic-, basic- or proline-rich regions), leaving the more biologically interesting regions of the query sequence available for specific matching against database sequences.
Low complexity sequence found by a filter program is substituted using the letter "N" in nucleotide sequence (e.g., "NNNNNNNNNNNNN") and the letter "X" in protein sequences (e.g., "XXXXXXXXX").
Filtering is only applied to the query sequence (or its translation products), not to database sequences. Default filtering is DUST for BLASTN, SEG for other programs.
It is not unusual for nothing at all to be masked by SEG, XNU , or both, when applied to sequences in SWISS-PROT, so filtering should not be expected to always yield an effect. Furthermore, in some cases, sequences are masked in their entirety, indicating that the statistical significance of any matches reported against the unfiltered query sequence should be suspect. NCB I-gi Causes NCB I gi identifiers to be shown in the output, in addition to the accession and/or locus name.
M ost preferably, sequence comparisons are conducted using the sim ple B LAST search algorithm provided at http://w w w .ncbi.nlm ,nih,gov/B LAST. Alternatively, sequence hom ology m ay be determined by algorithm s such as FastA , available at http://biology.ncsa.uiuc.edu/B W 30/B W .cgi. FastA is considered to be superior to B LA ST for alignment of short sequences, Advantageously, the FastA algorithm is employed using default param eters at http://biology.ncsa.uiuc,edu/B W 30/BW ,cgi.
Typically, greater than 50% identity between two polypeptides is considered to be an indication of functional equivalence, provided that either the biological activity of the polypeptide is retained or the polypeptides possess an antigenic determinant in common. Preferably, a functionally equivalent polypeptide according to this aspect of the invention exhibits a degree of sequence identity with a polypeptide sequence explicitly identified herein, or with a fragment thereof, of greater than 50% . M ore preferred polypeptides have degrees of identity of greater than 60% , 70% , 80% , 90% , 95% , 98 % or 99% , respectively.
Functionally-equivalent polypeptides according to the invention are therefore intended to include natural biological variants (for example, allelic variants or geographical variations within the species from w hich the polypeptides are derived) and mutants (such as mutants containing amino acid substitutions, insertions or deletions) of the polypeptides whose sequences are explicitly recited herein. Such mutants m ay include polypeptides in which one or m ore of the amino acid residues are substituted with a conserved or non- conserved am ino acid residue (preferably a conserved amino acid residue) and such substituted am ino acid residue may or m ay not be one encoded by the genetic code. Typical such substitutions are among Ala, Val, Leu and He; am ong Ser and Thr; am ong the acidic residues Asp and Glu; among A sn and Gin; among the basic residues Lys and Arg; or am ong the arom atic residues Phe and Tyr. Particularly preferred are variants in which several, i.e. between 5 and 10, 1 and 5, 1 and 3, 1 and 2 or just 1 amino acids are substituted, deleted or added in any combination. Especially preferred are silent substitutions, additions and deletions, which do not alter the properties and activities of the protein. Also especially preferred in this regard are conservative substitutions. "M utant" polypeptides also include polypeptides in which one or more of the amino acid residues include a substituent group. As discussed above, using a m ethod according to the above-described aspects of the invention it has now been discovered, m ost surprisingly, that the response to hypoxia differs between different specialised cell types or between different physiological states of the same cell type. For example, it has been found that in m acrophage cells, different polypeptides are induced/repressed during different physiological states. Furtherm ore, it has been found that a subset of this group of polypeptides are regulated only in activated m acrophage cells. M acrophages possess various biological activities, including cytotoxic effects towards tum our cells and phagocytosis of bacteria or cellular debris. These form an important and potent arm of innate imm unity, and as such must be finely regulated, In the absence of interactions w ith pathogens or other imm une cells, the aforem entioned activities of the m acrophage are greatly reduced (i.e. resting m acrophages). W hen given appropriate stimuli, such as contact with the lipopolysaccharide surface of bacteria, and/or exposure to T-cell derived interferon gamm a, the functional activities of the m acrophage are greatly potentiated (i.e. activated macrophage).
The expression of a further subset of these polypeptides has been found herein to be induced in activated m acrophages under conditions of hypoxia, whilst a still further subset has been found herein to be repressed in activated m acrophages under conditions of hypoxia.
In resting m acrophage cells, it has been found that different polypeptides are induced/repressed during the biological response to hypoxia. For example, it has been found that a subset of this group of polypeptides are regulated only in resting m acrophage cells. The expression of a further subset of these polypeptides has been found herein to be induced in resting m acrophages under conditions of hypoxia, whilst a still further subset has been found herein to be repressed in resting m acrophages under conditions of hypoxia.
According to a further aspect of the invention, there is provided a purified and isolated nucleic acid m olecule that encodes a polypeptide according to any one of the aspects of the invention discussed above. Such a nucleic acid m olecule m ay consist of the nucleic acid sequence as recited in any one of SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178 , 180, 1 82, 184, 186, 1 88, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or form a redundant equivalent or fragment thereof. This aspect of the invention also includes a purified nucleic acid m olecule which hydridizes under high stringency conditions with a nucleic acid m olecule as described above.
According to a further aspect of the invention, there is provided an expression vector that contains a purified and isolated nucleic acid m olecule according to the aspects of the invention described above, The invention also incorporates a delivery vehicle, such as a liposome, comprising a nucleic acid according to the above-described aspects of the invention,
In a further aspect, the invention provides a host cell transformed with a vector of the above-described aspect of the invention. In a still further aspect, the invention provides a ligand that binds specifically to a polypeptide according to the above-described aspects of the invention. The ligand may be an antagonist ligand that inhibits the biological activity of the polypeptide, or may be an agonist ligand that activates the hypoxia-induced activity of the polypeptide to augment or potentiate a hypoxia-induced activity. In a still further aspect of the invention, there is provided a ligand which binds specifically to, and which preferably inhibits the hypoxia-induced activity of, a polypeptide according to any one of the above- described aspects of the invention, Such a ligand may, for example, be an antibody that is immunospecific for the polypeptide in question.
According to a further aspect, the invention provides a polypeptide, a nucleic acid molecule, vector or ligand as described above, for use in therapy or diagnosis of a disease or abnormal physiological condition. Preferably, the disease or abnormal physiological condition that is affected by hypoxia; examples of such diseases include cancer, ischaemic conditions (such as stroke, coronary arterial disease, peripheral arterial disease), reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions (including rheumatoid arthritis), hair loss and wound healing. The undesired celluar process involved in said diseases might include, but is not restricted to; tumorigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis. The undesired biochemical processes involved in said cellular processes might include, but is not restricted to, glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport or nitric oxide synthesis.
According to the invention, a number of known proteins have also been implicated in the biological response to hypoxia. The functions of these proteins are known, meaning that these functions have been annotated in the public databases. The sequences of these proteins are presented in SEQ ID Nos.: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 63, 365, 367, 69, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485 and 487.
According to a further aspect of the invention, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9,
11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 or 209 or any one of SEQ ID Nos.: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339,
341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489 and 491; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of
SEQ ID Nos: 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200,
202, 204, 206, 208, 210, 212, 214 and 216, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii); for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
The invention also provides a purified and isolated nucleic acid molecule that encodes a polypeptide according to this aspect of the invention, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology. The sequences of these molecules are provided in SEQ ID Nos.: 218, 220, 222, 224, 226, 228, 230, 232 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484 486 and 488. As described above for the EST nucleic acid sequences annotated herein, this aspect of the invention includes redundant equivalents and fragm ents of the sequences explicitly recited in SEQ ID Nos.: 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478 , 480, 482, 484, 486 and 488, and purified nucleic acid molecules w hich hybridize under high stringency conditions w ith such nucleic acid molecules, and vectors containing such nucleic acid m olecules for use in the diagnosis or therapy of tum ourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
This aspect of the invention also includes ligands which bind specifically to, and which preferably inhibit the hypoxia-induced activity of, a polypeptide listed in SEQ ID Nos.: 217, 219, 221 , 223, 225, 227, 229, 231 , 233 , 235, 237, 239, 241 , 243 , 245 , 247, 249, 251 , 253, 255 , 257, 259, 261 , 263 , 265, 267, 269, 271 , 273, 275, 277, 279, 281 , 283 , 285 , 287, 289, 291 , 293 , 295, 297, 299, 301 , 303 , 305, 307, 309, 31 1 , 313 , 315, 317, 319, 321 , 323 , 325 , 327, 329, 331 , 333 , 335 , 337, 339, 341 , 343 , 345 , 347, 349, 351 , 353, 355 , 357, 359, 361 , 363 , 365 , 367, 369, 371 , 373, 375 , 377, 379, 381 , 383, 385 , 387, 389, 391 , 393, 395, 397, 399, 401 , 403, 405, 407, 409, 41 1 , 413, 415, 417, 419, 421 , 423, 425 , 427, 429, 431 , 433, 435 , 437, 439, 441 , 443 , 445, 447, 449, 451 , 453, 455, 457, 459, 461 , 463, 465, 467, 469, 471 , 473, 475, 477 , 479, 481 , 483, 485 and 487, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
The invention also provides a pharm aceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a a polypeptide, a nucleic acid m olecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable carrier.
The invention also provides a vaccine composition comprising a polypeptide, or a nucleic acid molecule as described above.
The invention also provides a method of treating a disease in a patient in need of such treatment by adm inistering to a patient a therapeutically effective amount of a polypeptide, a nucleic acid m olecule, vector, ligand or pharmaceutical composition as described above. For diseases in which the expression of the natural gene or the activity of the polypeptide is lower in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, ligand, compound or composition administered to the patient should be an agonist. For diseases in w hich the expression of the natural gene or activity of the polypeptide is higher in a diseased patient w hen compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid m olecule, vector, ligand, compound or composition adm inistered to the patient is an antagonist. B y the term "agonist" is meant herein, any polypeptide, peptide, synthetic m olecule or organic m olecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzym atic activity. B y the term "antagonist" is m eant herein, any polypeptide, peptide, synthetic molecule or organic m olecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharm acological receptor. The invention also provides for the use of a polypeptide, nucleic acid molecule, vector, ligand or pharm aceutical composition according to any one of the above-described aspects of the invention in modifying the response of a cell to conditions of hypoxia.
The invention also provides a polypeptide, nucleic acid m olecule, vector, ligand or pharm aceutical composition according to any one of the above-described aspects of the invention, for use in the m anufacture of a medicament for the treatm ent of a hypoxia-regulated condition.
The invention also provides a m ethod of monitoring the therapeutic treatment of disease or physiological condition in a patient, comprising m onitoring over a period of time the level of expression or activity of polypeptide, nucleic acid m olecule, vector or ligand in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease or physiological condition.
The invention also provides a method of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by adm inistering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or m ore of the nucleic acid molecules as described above. The invention also provides a method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of the aspects of the invention described above in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition. Such a method of diagnosis may be carried out in vitro. One example of a suitable method comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex. A further example of a suitable method m ay comprises the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid m olecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 , 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98 , 100, 102, 104, 106, 108, 1 10, 112, 1 14, 1 16, 1 18, 120 , 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268 , 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478 , 480, 482, 484, 486 and 488, and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; w herein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of the hypoxia-related condition .
A still further example of a suitable method may comprise the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid prim er under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid m olecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 , 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 44Q, 442, 444, 446, 448 , 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486 and 488, and the primer; b) contacting a control sample with said primer under the same conditions used in step a); c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; wherein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the amplified nucleic acid in the control sample is indicative of the hypoxia-related condition.
A still further example of a suitable method m ay comprised the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of the above-described aspects of the invention from said tissue sample; and c) diagnosing the patient for the hypoxia-related condition by detecting the presence of a m utation which is associated w ith the hypoxia-related condition in the nucleic acid m olecule as an indication of the hypoxia-related condition. This method may comprise the additional step of amplifying the nucleic acid m olecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
Particular hypoxia-related conditions that may be diagnosed in this fashion include cancer, ischaemia, reperfusion, retinopathy, neonatal stress, preeclapm sia, atherosclerosis, rheum atoid arthritis, undesired hair loss, cardiac arrest or stroke, for example, caused by a disorder of the cerebral, coronary or peripheral circulation. In a further aspect, the invention provides a m ethod for the identification of a compound that is effective in the treatment and/or diagnosis of a hypoxia-regulated condition, comprising contacting a polypeptide, nucleic acid m olecule, or ligand according to any one of the above-described aspects of the invention with one or more compounds suspected of possessing binding affinity for said polypeptide, nucleic acid molecule or ligand, and selecting a compound that binds specifically to said nucleic acid m olecule, polypeptide or ligand.
According to a still further aspect of the invention, there is provided a kit useful for diagnosing a hypoxia- regulated condition, comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of the aspects of the invention described above; a second container containing primers useful for amplifying said nucleic acid m olecule; and instructions for using the probe and primers for facilitating the diagnosis of the hypoxia-regulated condition. The kit may additionally comprise a third container holding an agent for digesting unhybridised RNA ,
To facilitate in the diagnosis of the hypoxia-regulated condition using one of the methods outlined above, in a further aspect, the invention provides an array of at least tw o nucleic acid m olecules, wherein each of said nucleic acid m olecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of the aspects of the invention described above. Such an array may contain nucleic acid m olecules that either correspond to the sequence of, are complem entary to the sequence of, or hybridise specifically to at least 2, 3 , 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 92a, 93, 94, 95,96,97,98,99, 100, 101,102, 103, 104, 105,106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 215, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295 or more of the nucleic acid molecules implicated in a hypoxia-regulated condition as recited above. The nucleic acid molecules on the array may consist of oligonucleotides of between twelve and fifty nucleotides, more preferably, between forty and fifty nucleotides. Alternatively, the nucleic acid molecules on the array may consist of PCR-amplified cDNA inserts where the nucleic acid molecule is between 300-2000 nucleotides.
In a related aspect, again useful for diagnosis, the invention provides an array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia-regulated condition as described above. The invention also provides an array of polypeptides, comprising at least two polypeptide species as recited above, wherein each polypeptide species is implicated in a hypoxia-regulated condition, or is a functional equivalent variant or fragment thereof.
Kits useful in the diagnostic methods of the invention may comprise such nucleic acid, antibody and/or polypeptide arrays.
According to the invention, a kit may also comprise one or more antibodies that bind to a polypeptide as recited above, and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide.
According to a still further aspect of the invention, there is provided a genetically-modified non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of the aspects of the invention described above, Preferably, said genetically-modified animal is a transgenic or knockout animal. The invention also provides a method for screening for a compound effective to treat a hypoxia-regulated condition, by contacting a non-hum an genetically-m odified anim al as described above with a candidate compound and determ ining the effect of the compound on the physiological state of the animal.
As discussed in som e detail above, ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels. One particular example of an ischaemic disease pathology is m yocardial ischaemia, which encompasses several chronic and acute cardiac pathologies that involve the deprivation of the m yocardium of its blood supply, usually through coronary artery occlusion, A key component of ischaemia is hypoxia. Following transient ischaemia, the affected tissue m ay be subjected to reperfusion and re-oxygenation, and this is of significance in its own right.
Ischaemia/reperfusion is well known to induce cell death in m yocardial tissue by apoptosis, leading to impaired function of the myocardium and infarction. M any of the specific m olecules required to execute the process of apoptosis are known, but not all of these m olecules have been characterised in detail. Cell death may also proceed by a distinct process called necrosis, which unlike apoptosis, is not initiated and controlled by specific and dedicated cellular and biochemical mechanism s (see Nicotera et al, B iochem Soc Symp. 1999; 66 :69-73). There is substantial evidence that apoptotic cell death occurs either during or after m yocardial ischaemia (Kajstura et al, Lab Invest. 1996; 74(1 ):86-l 07 ; Cheng et al, Exp Cell Res. 1996; 226(2):316-27 ; Fliss and Gattinger, Circ Res. 1996 ; 79(5):949-56 ; Veinot et al, Hum Pathol. 1997 ; 28(4):485-92 ; B ialik et al, J Clin Invest. 1997 ; 100(6): 1363-72 ; Gottlieb et al, J Clin Invest. 1994; 94(4):1621 -8 ; Gottlieb and Engler, Ann N Y A cad Sci, 1999 ; 874:412-26). In the laboratory, apoptosis is also induced by subjecting cardiac m yocytes to hypoxia (Tanaka et al, Circ Res. 1994 Sep;75(3):426-33 ; Long et al, J Clin Invest. 1997 99(1 1 ): 2635-43).
Clearly, there is a significant clinical application were a successful m ethod to inhibit apoptosis in ischaemic m yocardial tissue to be devised. A specific and effective treatment requires identifying biochemical target(s), w hich are responsible for m ediating apoptosis, specifically in ischaem ic m yocardial cells. One target w hich plays a comm on role in mediating apoptosis in m any cell types, namely p53 , is not involved in apoptosis resulting from m yocardial ischaemia (Bialik et al, J Clin Invest. 1997 ; 100(6): 1363-72). Others have shown that inhibiting key mediators of apoptosis, caspases, provides protection against lethal reperfusion injury, following m yocardial ischaemia in rat models (M ocanu et al, B r J Pharm acol. 2000; 130(2): 197-200; Yaoita et al, Circulation. 1998 97(3): 276-81 ; Holly et al, J M ol Cell Cardiol. 1999 31 (9): 1709-15). However, this approach lacks specificity, since the caspases play a key role in mediating apoptosis in the majority of mamm alian cell types, where it is usually beneficial. An approach that involves modulating the activity of molecules shown specifically to mediate apoptosis in ischaemic cardiac cells, would present a distinct advantage in both specificity and efficacy.
It has now been discovered that a polypeptide encoded by a gene identified from the EST recited in SEQ ID No 86, having the Protein accession number BAB 15101 (encoded by Homo sapiens cDNA: FLJ21620 fis, clone COL07838 Nucleotide accession AK025273) is regulated by hypoxia. Other public domain sequences corresponding to this gene include Homo sapiens cDNA: FLJ23265 fis, clone COL06456 Nucleotide accession AK026918. Accordingly, when referring in the present specification to the EST recited in SEQ ID No 86, it is intended that these gene and protein sequences are also embraced. This gene was identified using Research Genetics Human GeneFilters arrays, which contain an EST corresponding to the gene (accession number R00332). In the art, the gene is now termed EGL nine (C.elegans) homolog 3.
There are no reports that describe the function of this human gene. However, a high degree of amino acid homology is observed between the protein encoded by this gene, and a rat protein called "Growth factor responsive smooth muscle protein" or "SM20" (Nucleotide accession U06713; Protein accession A53770). An alignment of single letter amino acid sequences is shown below. Over the highlighted region there is 97% amino acid similarity and 96% amino acid identity.
A53770 (1 ) MTLRSRRGFLSFLPG RPPRRWLRISKRGPPTSHWASPA GGRT HYSCR BAB15101 (1)
51 100
A53770 (51) SQSGTPFSSEFQATFPAFAAKVARGPW PQWEPPARLSASP CVRSGQA BAB15101 (!)
101 150
A53770 (101) LGACTLGVPRLGSVSEjMPLGHIMRLbLEKIALEYIVPC BE -GFCYliDNFJ BAB15101 (1) PLGHIMRLDLEEIMJEYIVPCLBEVOFCYLDNFJ
151 " " " 200
A53770 (151) ^GIWGDC ERWQLHYNGALRDGQLAGPMG¥SERH RQDOITWIG©l' BAB15101 (35) GEWGDC E QLHC pALRDGQIAGPRAGVSKRHLRGDQITWlGG^
201 _ _ 250
A53770 (201) E^CE- IMST&^ BAB15101 (85) EEGCEA1 SFLLSLIDR V YCGSRLGΪCY YVEERSKAMVAGYPGHGTGYVR
251 300
A53770 (251) OTDNP»GDGPGITCIYXL N DMLHGG%RIFPEGKSFVAD¥EPIFDR
Figure imgf000030_0001
A53770 (351) ALAKEJ BAB15101 (235) A TED The high degree of amino acid similarity suggests that the hum an protein B AB 15101 has an equivalent biochemical function to the rat protein A53770 ("Growth factor responsive smooth m uscle protein" or "SM20"). Recent publications have shown that SM20 functions to promote apoptosis in neurons (Lipscom b et al, J Neurochem 1999; 73(l ):429-32; Lipsco b et al, J Biol Chem 2000 Nov 1 ; [epub ahead of print]). Significantly, SM 20 has been shown to be expressed at high levels in the heart (W ax et al. J Biol Chem 1994; 269(17): 13041 -7).
It has also been discovered that a polypeptide encoded by a gene identified from the EST recited in SEQ ID No 90, having the Protein accession number CAB 81622, is regulated by hypoxia. The encoding hum an gene has been annotated in the UniGene database as "Similar to rat sm ooth muscle protein SM - 20" ; the nucleotide sequence is contained within the nucleotide accession AL 1 17352. M ore recently, a longer fragment of this gene has been cloned, nam ed c l orfl 2, or EGLN 1 (Nucleotide accession AAG34568 ; Protein accession AAG34568). Accordingly, when referring in the present specification to the EST recited in SEQ ID No 90, it is intended that these gene and protein sequences are also embraced.
This distinct hum an gene, encoding a protein related to SM 20 and EGLN 3 (BAB 15101 ), is also induced in response to hypoxia. This gene was identified using Research Genetics Hum an GeneFilters arrays, which contain an EST corresponding to the gene (accession number H56028).
Independently to this, a fragm ent of this gene has been cloned from a cDNA library derived from hypoxic hum an cardiom yoblasts, and it has been shown that the gene is increased in expression in response to hypoxia in this cell type (see Table 1 herein ; penultimate row). The nucleotide sequence of this cDNA fragm ent is referred to herein as SEQ ID No 90a.
In the light of this novel discovery reported herein that these human equivalents of SM20 are induced by hypoxia, it is herein proposed that in cardiac ischaemia, the resulting apoptosis is due at least in part, to increased expression of these genes.
The therapeutic modulation of the activity of EGLN3 (B AB 15101 ), c l orfl 2 (AAG34568), CAB 81622, SM 20 and other equivalent proteins and encoding genes therefore provides a novel means for the treatm ent of m yocardial ischaem ia, through the alteration of the propensity of m yocardial cells to undergo apoptosis. For example, a suitable treatm ent may involve altering the susceptibility of ischaem ic myocardial tissue to subsequent reperfusion and re-oxygenation, or m ay involve m odulating the susceptibility of chronic ischaemic myocardial tissue (including forms of angina) to later m ore severe ischaem ia, w hich would result in m yocardial infarction. It is submitted that, by w ay of analogy, cerebral ischaem ia m ay be treated using the same principle.
These data provide the first connection between these related genes and the physiological response to hypoxia. Recently published research papers have identified that the protein products of these genes can act as proline hydroxylases (see Bruick RK et al Science. 2001 294:1337-40 and Epstein A C et al Cell. 107 :43-54). This is consistent with our observations that certain proline hydroxylases are induced in response to hypoxia and the genes EGLN 1 and EGLN3 are part of the hypoxia response. For example, two genes encoding proline hydroxylases have been identified herein as being increased in expression in response to hypoxia (proline 4-hydroxylase, alpha polypeptide 1 ; SeqID : 231/232, proline 4-hydroxylase, alpha polypeptide II; SeqID : 349/ 350). This identified a functional significance of proline hydroxylation as a response to hypoxia, A preferred embodim ent of the invention thus includes methods for modulating the biological response to hypoxia by modulating the proline hydroxylase activity of the EGLN3 (B AB 15101 ), cl orfl 2 (AAG34568), CAB 81622 and SM 20 proteins. Furtherm ore, a number of bacteria, such as moraxella, are thought to be involved in the initiation of inflam matory diseases. M any bacteria contain, w ithin their genom e, genes encoding proteins that share homology to the EGLN family of prolyl hydroxylases. We therefore propose that these bacterial genes m ay initiate a hypoxic like response at the site of infection thereby causing localised inflamm ation. The resulting inflam m atory infiltrate could then cause the tissue to become hypoxic thereby continuing the cycle of hypoxia response.
As discussed in detail above, fragments and functional equivalents of the EGLN 3 (BAB 15101 ), cl orfl 2 (AAG34568), CAB 81622, SM 20 and other equivalent proteins are included within the present invention, in addition to ligands that bind specifically to these proteins. Furtherm ore, the invention also em braces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid m olecules and host cells transformed with these vectors.
The therapeutic and diagnostic applications discussed above are also equally relevant to this aspect of the invention. For example, sm all molecule inhibitors of the EGLN 3 (B AB 15101 ), c l orfl 2 (AAG34568), CAB 81622, SM 20 and equivalent proteins and encoding genes are envisaged for utility as pharmaceutical agents, particularly in m odulating the proline hydroxylase activity of the EGLN3 and cl orfl 2 proteins. Truncated or chimeric inhibitory derivatives of the encoding genes, or distinct genes that encode regulators of the B AB 15101 , A AG34568 , CAB 81622 and SM 20 encoding genes, are also envisaged for utility for gene therapy.
An alignment of the amino acid sequences of rat SM 20 (Accession A53770), its human equivalent (Accession BAB 15101 ; SEQ ID No: 85) and this distinct human homologue (Accession CAB 81622 or AAG34568 ; SEQ ID No: 89) is shown below :
1 50
BAB15101 (1)
A53770 (1) AAG34568 (1) MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQD Consensus (1)
51 100
BAB15101 (1
A53770 (1 I4TLRSRRGFLSFLPGLRPPRRWLRISKRGPPT3HWASP AL AAG34568 (51 K HK VCQGSEGALGHGVGPHQHSGPAPPAAVPPPR GAREPRKAAARR
Consensus (51 G L PP A
101 150
BAB15101 (1
A53770 (41 GGRITLHYSCRSQSGTPFSSEFQATFPAFAAKVARGPWLPQWEPPAR— - AAG34568 (101 DNA'SGDAJAKGKV AKPPADPAAAASPCRAAAGGQGSAVAAEAEPGKEΞPP
Consensus (101 S A A P A A P AA A G L EP
Figure imgf000033_0001
201 _ 250
BAB15101 (22 PLHEVGF^YLDNFLGEVVGDCVLER^KQX.HCTGALRDGQLAGPRAGVS R
A53770 (138 bLHEVGFCYLDNFLGEλAGDCVLERy'KQLIΪYNGALRCGQ AGPRAGVSKR AAG34568 (201 Crøκroiθ dDFLGKETGQQIGpEpR jHDTGKFTl)GQIjVSQKS--DSSp
Consensus (201 CLHEVGFCYLDNFLGEWGDCVLERVKQLH TGALRDGQLAGPRAGVSKR
251 300
BAB15101 (72 HLRGDQjlTW GWSΞGCEAlSFJ'LELIDRLVLYCGSRteKYYWE'RSM
A53770 (188 HLRGDQilTWIGGNEEGCEAfrNFJLLSLIDRLVLYCGSRΪGKYYVKEp.s'KAM AAG34568 (250 D^RGDK T IEGKEPGCETiGLtMSStoDLlRHCNGKLGSYKlNG^TKAM
Consensus (251 HLRGDQITWIGGNEEGCEAI FLLSLIDRLVLYCGSRLGKYYVKERSKAM
301 350
BAB15101 (122 imCYPGNGTGYWH?DNPHGDGRCITCIYYLNM«DAlCLHGGl--RIFPEG
A53770 (238 ACYPGHGTGi^HVDKPNGDGRClKIYYLNiaI|[froAKLHG VI.RlFPEG AAG34568 (300 VACYPGMGTGYVRH?PHPMGDGRCVrClYYIiHKD^DASVSGGILRIgPEGj
Consensus (301 VACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKN DAXLHGGILRIFPEG
Figure imgf000033_0002
BAB15101 (222 feKkFRNLTRKTESALTED
A53770 (338 SKEFR LTRKTESAJLAKD AAG34568 (400 OTYLTGEKGTOVE^NKPSDSVGKDVF
Consensus (401 K FRNLTRKTESAL D
From this sequence alignment, a highly conserved region of amino acid sequence may be noted, the consensus of which is as follows:
KAIWACYPGNGTGWRHVDNPNGDGRCITCIYYLI^^ SDRR PHEVQPSYATRYAMTV YFDAEERAEAKKK This consensus sequence, and variants thereof, m ay be used in the identification of other proteins that are implicated in the biological response to hypoxia. This aspect of the invention therefore provides a substantially purified polypeptide comprising the consensus sequence:
KAMVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEG SFIADVEPIFDRLLFF SDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKK, or a variant thereof.
The invention also provides a substantially purified polypeptide comprising the consensus sequence: KAJWACYPGNGTGYVRΪTVDNPNGDGRCITCIYYL NWDAKLHGGILRIFPEGKSFIADVEPIFDRLLFF SDRRNPHEVQPSYATRYAMTV YFDAEERAEAK , or a variant thereof, in the treatment or diagnosis of a hypoxia-related disease or condition.
Neither this consensus dom ain nor any proteins that contain this dom ain have been previously associated with the cellular response to hypoxia/ischaem ia. Searches of the public databases indicate that the hum an genom e contains several genes that encode proteins that contain this consensus sequence, These proteins m ay have similar functions or may function in the sam e biochemical pathway, potentially with an antagonistic effect.
By "variant" is m eant a variation of the consensus sequence given above, that exhibits a degree of hom ology with the consensus sequence above a certain threshold level of identity or sim ilarity, Degrees of identity and similarity can be readily calculated according to methods known in the art (see, for example, Computational Molecular B iology, Lesk, A .M ., ed„ Oxford University Press, New York, 1988; B iocomputing. Informatics and Genom e Projects, Smith, D .W ., ed., Academ ic Press, New York, 1993). Typically, greater than 50% identity between two sequences is considered to be an indication of functional equivalence. Preferably, a variant consensus according to this aspect of the invention exhibits a degree of sequence identity with the consensus sequence given above, of greater than 50% . M ore preferred polypeptides have degrees of identity of greater than 60% , 70% , 80% , 90% , 95 % , 98 % or 99% , respectively.
As discussed in detail above, fragm ents and functional equivalents of these proteins are included within the present invention, in addition to ligands that bind specifically to these proteins. Furtherm ore, the invention also em braces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid m olecules and host cells transformed with these vectors. The therapeutic and diagnostic applications discussed above are also equally relevant to this aspect of the invention. The polypeptide referred to above as that encoded by SEQ ID No 91 is a specific protein that is termed "Sem aphorin 4b" . The gene encoding this protein is regulated (activated) by conditions of hypoxia. The Sem aphorin 4b protein is encoded by a gene identified from the EST recited in SEQ ID N o 92. The unequivocal and accurate full length cDNA sequence is provided herein as SEQ ID No 92a. The accurate presumptive amino acid sequence is provided herein as SEQ ID No 91 . This protein, functionally- equivalent variants of this protein, the encoding nucleic acid m olecules and ligands that regulate the activity and/or expression of this gene and protein are claimed above in the context of their role in hypoxia and hypoxia-related disorders.
Sem aphorins are a large family of proteins, characterised by the 500 am ino acid sema dom ain (Puschel et al., 1995, Neuron, 14(5): 941 -8; Tam agnone and Com oglio, 2000, Trends Cell Biol., 10(9): 377-83). Early work showed a role in the guidance of axons during brain development, and the regulation of cell migration. M ore recently, specific members of this large fam ily have been associated with cancer (B ram billa et al., Am J Pathol., 2000, 156(3): 939-50), rheum atoid arthritis (Mangasser-Stephan et al., Biochem B iophys Res Commun ., 1997, 234(1 ): 153-6), the imm une system (Spriggs, Curr Opin Immunol., 1999, 1 1 (4): 387-91 ) including B -lymphocyte functions (Hall et al„ Proc Natl Acad Sci U S A, 1996, 93(21 ): 1 1780-5) and angiogenesis (Miao et al., J Cell B iol., 1999, 146(1 ): 233-42). This is perhaps not surprising considering that cell m igration / trafficking is a key part of inflamm ation, angiogenesis and tumour metastasis.
There are at least distinct 25 hum an sem aphorin genes and the significance/ utility of many of these remains untested. This includes the Sem aphorin 4b protein, which is unpublished and until now has not been assigned a full and accurate amino acid sequence.
W e have m ade experim ental discoveries which link the expression of Sem aphorin 4b to factors (hypoxia, gamma IFN and superoxide radicals) that are associated w ith a variety of human ischaemic and inflammatory diseases. In particular, a key response of cells to hypoxia is to stim ulate angiogenesis, and a key part of inflamm ation is the recruitment and trafficking of im m une cells. In light of our discoveries, and what is know n about other specific members of the sem aphorin family, it is herein proposed that Sem aphorin 4b is a regulator of these cellular functions, and thus provides a novel target for therapeutic intervention . This paves the way for the developm ent of therapeutic agents that either potentiate or antagonise functions of Semaphorin 4b. Such agents are likely to be highly valuable in the treatment of hum an disease.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, recombinant DNA technology and immunology, which are within the skill of those working in the art. M ost general molecular biology, microbiology recombinant DNA technology and immunological techniques can be found in Sambrook et al, Molecular Cloning, A Laboratory Manual (1989) Cold Harbor-Laboratory Press, Cold Spring Harbor, N.Y . or Ausubel et al, Current protocols in molecular biology (1990) John Wiley and Sons, N .Y ,
Unless defined otherwise, all technical and scientific term s used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
A. Polypeptides
The term "polypeptide" as used herein, refers to a chain (may be branched or unbranched) of two or more amino acids linked to each other by means of a peptide bond or modified peptide bond (isosteres), The term polypeptide encompasses but is not limited to oligopeptides, peptides and proteins. The polypeptide of the invention may additionally be either in a mature protein form or in a pre-, pro- or prepro-protein form that requires subsequent cleavage for formation of the active mature protein. The pre-, pro-, prepro- part of the protein is often a leader or secretory sequence but may also be an additional sequence added to aid protein purification (for example, a His tag) or to conform a higher stability to the protein. A polypeptide according to the invention may also include modified amino acids, that is, amino acids other than those 20 that are gene-encoded. This modification may be a result of natural processes such as post-translational processing or by chemical modification. Examples of modifications include acetylation, acylation, amidation, ADP-ribosylation, arginylation, attachment of a lipid derivative or phosphatidylinositol, γ-carboxylation, covalent attachment of a flavin or haeme moiety, a nucleotide or nucleotide derivative, cyclisation, demethylation, disulphide bond formation, formation of covalent crosslinks, formylation, glycosylation, GPI anchor formation, hydroxylation, iodination, lipid attachment, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemisation, selenoylation, sulphation, and ubiquitination. M odification of the polypeptide can occur anywhere within the molecule including the backbone, the amino acid side-chains or at the N- or C- terminals,
A polypeptide according to the invention may either be isolated from natural sources (for example, purified from cell culture), or be a recombinantly produced polypeptide, or a synthetically produced polypeptide or a combination of all the above.
Antibodies A polypeptide according to the invention, its functional equivalents and/or any immunogenic fragments derived from the polypeptide may be used to generate ligands including immunospecific monoclonal or polyclonal antibodies, or antibody fragments. These antibodies can then be used to isolate or identify clones expressing the polypeptide of the invention or to purify the polypeptide by affinity chrom atography. Further uses of these immunospecific antibodies m ay include, but are not limited to, diagnostic, therapeutic or general assay applications. Examples of assay techniques that employ antibodies are im m unoassays, radioim munoassays (RIA) or enzym e linked imm unosorbent assay (ELISA). In these cases, the antibodies m ay be labelled with an analytically-detectable reagent including radioisotopes, a fluorescent m olecule or any reporter molecule.
The term "im munospecific" as used herein refers to antibodies that have a substantially higher affinity for a polypeptide of this invention compared with other polypeptides. The term "antibody" as used herein refers to a m olecule that is produced by anim als in response to an antigen and has the particular property of interacting specifically with the antigenic determinant that induced its form ation. Fragm ents of the aforem entioned m olecule such as Fab, F(ab')2 and scFv, which are capable of binding the antigen determinant, are also included in the term "antibody" . Antibodies may also be modified to make chimeric antibodies, where non-hum an variable regions are joined or fused to human constant regions (for example, Liu et al, PNAS, USA, 84, 3439 (1987)). Particularly, antibodies may be modified to make them less im m unogenic to an individual in a process such as hum anisation (see, for example, Jones et al, Nature, 321 , 522 (1986); Verhoeyen et al, Science, 239, 1534 (1988); Kabat et al, J. Imm unol, 147, 1709 (1991 ); Queen et al, PNA S , USA , 86, 10029 (1989); Gorm an et al, PNAS , USA, 88 , 34181 (1991 ) and Hodgson et al, B io/Technology, 9 , 421 (1991 )). The term "humanised antibody", as used herein, refers to antibody m olecules in which the am ino acids of the CDR (com plementarity-determining region) and selected other regions in the variable dom ains of the heavy and/or light chains of a non-hum an donor antibody have been substituted with the equivalent amino acids of a human antibody, The humanised antibody therefore closely resembles a hum an antibody, but has the binding ability of the donor antibody. Antibodies may also have a "bispecific" nature, that is, the antibody has two different antigen binding domains, each dom ain being directed against a different epitope. Specific polyclonal antibodies m ay be m ade by im m uno-challenging an anim al with a polypeptide of this invention. Com m on anim als used for the production of antibodies include the m ouse, rat, chicken, rabbit, goat and horse. The polypeptide used to immuno-challenge the animal may be derived by recombinant DNA technology or may be chem ically-synthesised. In addition, the polypeptide may be conjugated to a carrier protein. Com m only used carriers to which the polypeptides may be conjugated include, but are not lim ited to B SA (bovine serum albumin), thyroglobulin and keyhole limpet haem ocyanin. Serum from the im muno-challenged anim al is collected and treated according to known procedures, for example, by immunoaffinity chrom atography.
Specific monoclonal antibodies can generally be made by methods known to one skilled in the art (see for example, Kohler, G . and M ilstein, C, Nature 256, 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, 77 -96 in M onoclonal Antibodies and Cancer Therapy, Alan R . Liss, Inc. (1985) and Roitt, I. et al, Im munology, 25.10, M osby-Year B ook Europe Limited (1993)), Panels of m onoclonal antibodies produced against the polypeptides of the invention can be screened for various properties, i.e., for isotype, epitope, affinity, etc. against which they are directed. Alternatively, genes encoding the m onoclonal antibodies of interest m ay be isolated from hybridom as, for instance using PCR techniques known in the art, and cloned and expressed in appropriate vectors.
Phage display technology m ay be utilised to select the genes encoding the antibodies that have exhibited an immunspecific response to the polypeptides of the invention (see M cCafferty, J., et al, (1990), Nature 348, 552-554; M arks, J. et al, (1992) B iotechnology 10, 779-783).
Ligands
The polypeptides of the invention m ay also be used to search for interacting ligands. M ethods for doing this include the screening of a library of compounds (see Coligan et al, Current Protocols in Immunology 1 (2); Chapter 5 (1991 ), isolating the ligands from cells, isolating the ligands from a cell-free preparation or natural product mixtures. Ligands to the polypeptide may activate (agonise) or inhibit (antagonise) its activity. Alternatively, compounds m ay affect the levels of the polypeptide present in the cell, including affecting gene expression, mRNA stability and the degree of post-translational modification of the encoded protein. The invention thus em braces m ethods for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a polypeptide, a nucleic acid molecule or host cell according to any one of the embodiments of the invention described herein with one or m ore compounds suspected of possessing binding affinity for said polypeptide or nucleic acid m olecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide, or that affects the level of gene expression, mRNA stability or the degree of post-translational modification of the encoded protein. Ligands to the polypeptide form a further aspect of the invention, as discussed in more detail above. Preferred "antagonist" ligands include those that bind to the polypeptide of this invention and strongly inhibit any activity of the polypeptide. Preferred "agonist" ligands include those that bind to the polypeptide and strongly induce activity of the polypeptide of this invention or increases substantially the level of the polypeptide in the cell. As defined above, the term "agonist" is meant to include any polypeptide, peptide, synthetic m olecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity . The term "antagonist" is m eant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharmacological receptor.
Ligands to a polypeptide according to the invention may come in various forms, including natural or modified substrates, enzymes, receptors, small organic molecules such as small natural or synthetic organic molecules of up to 2000Da, preferably 800Da or less, peptidomimetics, inorganic molecules, peptides, polypeptides, antibodies, structural or functional mimetics of the aforementioned.
B. Nucleic acid molecules
Preferred nucleic acid molecules of the invention are those which encode the polypeptide sequences recited in any one of SEQ ID Nos.1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43,45,47,49,51,53,55,57,59,63,67,69,73,75,77,85,87,89,91,93,95,99,103,113,115,119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209. Examples of such nucleic acid molecules include those listed in SEQ ID Nos.2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, homologous nucleic acids and nucleic acids that are complementary to these nucleic acid molecules, Nucleic acid molecules of this aspect of the invention may be used in numerous methods and applications, as described generally herein, A nucleic acid molecule preferably comprises of at least n consecutive nucleotides from any one of the sequences disclosed in SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, where n is 10 or more. A nucleic acid molecule of the invention also includes sequences that are complementary to the nucleic acid molecule described above (for example, for antisense or probing purposes).
A nucleic acid molecule according to this aspect of the invention may be in the form of RNA, such as mRNA, DNA, such as cDNA, synthetic DNA or genomic DNA. The nucleic acid molecule may be double-stranded or single-stranded. The single-stranded form may be the coding (sense) strand or the non- coding (antisense) strand. A nucleic acid molecule may also comprise an analogue of DNA or RNA, including, but not limited to modifications made to the backbone of the molecule, such as, for example, a peptide nucleic acid (PNA). The term "PNA" as used herein, refers to an antisense molecule that comprises an oligonucleotide of at least five nucleotides in length linked to a peptide backbone of amino acid residues, preferably ending in lysine. The terminal lysine confers solubility to the composition. PNAs may be pegylated to extend their lifespan in a cell, where they preferentially bind complementary single- stranded DNA and RNA and stop transcript elongation (Nielsen, P.E, et al. (1993) Anticancer Drug Des. 8:53-63).
A nucleic acid m olecule according to this aspect of the invention can be isolated by cloning, purification or separation of the molecule directly from a particular organism , or from a library, such as a genomic or cDNA library. The m olecule m ay also be synthesised, for example, using chemical synthetic techniques such as solid phase phosphoramidite chem ical synthesis. RNA m ay be synthesized in vitro or in vivo by transcription of the relevant DNA molecule,
Due to the degeneracy of the genetic code, differing nucleic acid sequences may encode the same polypeptide (or mature polypeptide). Thus, nucleic acid molecules included in this aspect of the invention include any m olecule comprising a variant of the sequence explicitly recited. Such variants m ay include variant nucleic acid m olecules that code for the same polypeptide (or mature polypeptide) as that explicitly identified, that code for a fragment of the polypeptide, that code for a functional equivalent of the polypeptide or that code for a fragment of the functional equivalent of the polypeptide. Also included in this aspect of the invention, are variant nucleic acid molecules that are derived from nucleotide substitutions, deletions, rearrangem ents or insertions or multiple combinations of the aforem entioned. Such m olecules m ay be naturally occurring variants, such as allelic variants, non-naturally occurring variants such as those created by chemical mutagenesis, or variants isolated from a species, cell or organism type other than the type from w hich the sequence explicitly identified originated. Variant nucleic acid m olecules may differ from the nucleic acid molecule explicitly recited in a coding region, non-coding region or both these regions.
Nucleic acid m olecules m ay also include additional nucleic acid sequence to that explicitly recited, for example, at the 5' or 3 ' end of the molecule. Such additional nucleic acids may encode for a polypeptide w ith added functionality compared with the original polypeptide whose sequence is explicitly identified herein. An example of this would be an addition of a sequence that is heterologous to the original nucleic acid sequence, to encode a fusion protein. Such a fusion protein may be of use in aiding purification procedures or enabling techniques to be carried out where fusion proteins are required (such as in the yeast two hybrid system ). A dditional sequences m ay also include leader or secretory sequences such as those coding for pro-, pre- or prepro- polypeptide sequences. These additional sequences may also include non-coding sequences that are transcribed but not translated including ribosome binding sites and termination signals. A nucleic acid m olecule of the invention m ay include m olecules that are at least 70% identical over their entire length to a nucleic acid molecule as explicitly identified herein in SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 , 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14, 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188 , 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216. Preferably, a nucleic acid molecule according to this aspect of the invention comprises a region that is at least 80% identical over its entire length to a nucleic acid m olecule as explicitly identified herein in these SEQ ID Nos., preferably at least 90% , m ore preferably at least 95 % and m ost preferably at least 98 % or 99% identical. Further preferred embodiments include nucleic acid m olecules that encode polypeptides that retain substantially the same biological function or activity as the polypeptide explicitly identified herein. The term s "hom ology" and "identity" should be given the meanings described in detail above with respect to polypeptide analysis. Preferably, nucleotide homology and identity are assessed using the blastn program available at http://www .ncbi.nlm .nih, gov. The nucleic acid m olecules of the invention can also be engineered using m ethods generally known in the art. These methods include but are not lim ited to DNA shuffling; random or non-random fragm entation (by restriction enzym es or shearing methods) and reassem bly of fragments; insertions, deletions, substitutions and rearrangements of sequences by site-directed mutagenesis (for example, by PCR). These alterations m ay be for a num ber of reasons including for ease of cloning (such as introduction of new restriction sites), altering of glycosylation patterns, changing of codon preferences, splice variants changing the processing, and/or expression of the gene product (the polypeptide) in general or creating fusion proteins (see above).
Hybridisation
Nucleic acid m olecules of the invention m ay also include antisense m olecules that are partially complementary to a nucleic acid m olecule as explicitly identified herein in SEQ ID Nos.: 2, 4, 6, 8, 10 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 1 10, 1 12, 1 14 1 16, 1 18, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198 200, 202, 204, 206, 208, 210, 212, 214 and 216, and which therefore will hybridise to the encoding nucleic acid m olecules. These antisense m olecules, including oligonucleotides, can be designed to recognise, specifically bind to and prevent transcription of a target nucleic acid encoding a polypeptide of the invention, as will be known by those of ordinary skill in the art (see Cohen, J.S ., Trends in Pharm . Sci., 10, 435 (1989), Okano, J. Neurochem . 56, 560 (1991 ); O 'Connor, J. Neurochem 56, 560 (1991 ); Lee et al, Nucleic Acids Res 6, 3073 (1979); Cooney et al, Science 241 , 456 (1988); Dervan et al, Science 251 , 1360 (1991 ).
The term "hybridisation" used herein refers to any process by which a strand of nucleic acid binds with a complementary strand of nucleic acid by hydrogen bonding, typically forming W atson-Crick base pairs. As carried out in vitro, one of the nucleic acid populations is usually immobilised to a surface, whilst the other population is free. The two molecule types are then placed together under conditions conducive to binding.
The phrase "stringency of hybridisation" refers to the percentage of complementarity that is needed for duplex formation. "Stringency" thus refers to the conditions in a hybridization reaction that favour the association of very similar molecules over association of molecules that differ. Conditions can therefore exist that allow not only nucleic acid strands with 99-100% complementarity to hybridise, but sequences with lower complementarity (for example, 50%) to also hybridise. High stringency hybridisation conditions are defined herein as overnight incubation at 42°C in a solution comprising 50% formamide, 5XSSC (150mM NaCl, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5x Denhardts solution, 10% dextran sulphate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1 X SSC at approximately 65°C, Low stringency conditions involve the hybridisation reaction being carried out at 35°C (see Sambrook et al [supra]). Preferably, the conditions used for hybridization are those of high stringency.
Some trans- and cis-acting factors that may affect the binding of two complementary strands include strand length, base composition (GC pairs have an extra hydrogen bond and are thus require more energy to separate than AT pairs) and the chemical environment. The presence of monovalent cations (such as Na+) stabilises duplex formation whereas chemical denaturants such as formamide and urea destabilise the duplex by disruption of the hydrogen bonds. Use of compounds such as polyethylene glycol (PEG) can increase reassociation speeds by increasing overall DNA concentration in aqueous solution by abstracting water molecules. Denhardt's reagent or BLOTTO are chemical agents often added to block non-specific attachment of the liquid phase to the solid support. Increasing the temperature will also increase the stringency of hybridisation, as will increasing the stringency of the washing conditions following hybridisation (Sambrook et al. [supra]).
Numerous techniques exist for effecting hybridisation of nucleic acid molecules. Such techniques usually involve one of the nucleic acid populations being labelled. Labelling methods include, but are not limited to radiolabelling, fluorescence labelling, chemiluminescent or chromogenic labelling or chemically coupling a modified reporter molecule to a nucleotide precursor such as the biotin-streptavidin system . This can be done by oligolabelling, nick-translation, end-labelling or PCR amplification using a labelled polynucleotide. Labelling of RNA m olecules can be achieved by cloning the sequences encoding the polypeptide of the invention into a vector specifically for this purpose. Such vectors are known in the art and m ay be used to synthesise RNA probes in vitro by the addition of an appropriate RNA polym erase such as T7, T3 or SP6 and labelled nucleotides.
Various kits are commercially available that allow the labelling of molecules, Examples include those made by Pharm acia & Upjohn (Kalamazoo, M I); Promega (M adison W I); and the U .S . B iochem ical Corp . (Cleveland, OH), Hybridisation assays include, but are not lim ited to dot-blots, Southern blotting, Northern blotting, chrom osome in situ hybridisation (for example, FISH [fluorescence in situ hybridisation]), tissue in situ hybridisation, colony blots, plaque lifts, gridded clone hybridisation assays, DNA microarrays and oligonucleotide microarrays. These hybridisation methods and others, may be used by a skilled artisan to isolate copies of genomic DNA , cDN A , or RN A encoding homologous or orthologous proteins from other species.
The invention therefore also embodies a process for detecting a nucleic acid m olecule according to the invention, comprising the steps of: (a) contacting a nucleic probe with a biological sample under hybridising conditions to form duplexes: and (b) detecting any such duplexes that are form ed. The term "probe" as used herein refers to a nucleic acid m olecule in a hybridisation reaction whose m olecular identity is known and is designed specifically to identify nucleic acids encoding homologous genes in other species. Usually, the probe population is the labelled population, but this is not alw ays the case, as for example, in a reverse hybridisation assay.
One example of a use of a probe is to find nucleic acid molecules with an equivalent function to those that are explicitly identified herein, or to identify additional fam ily members in the same or other species. This can be done by probing libraries, such as genomic or cDNA libraries, derived from a source of interest, such as a human, a non-human anim al, other eukaryote species, a plant, a prokaryotic species or a virus. The probe m ay be natural or artificially designed using methods recognised in the art (for example, Ausubel et al, [supra]). A nucleic acid probe w ill preferably possess greater than 15, m ore preferably greater than 30 and m ost preferably greater than 50 contiguous bases complementary to a nucleic acid molecule explicitly identified herein.
In m any cases, isolated DNA from cDN A libraries will be incomplete in the region encoding the polypeptide, norm ally at the 5' end. M ethods available for subsequently obtaining full-length cDNA sequence include RACE (rapid amplification of cDNA ends) as described by Frohman et al, (Proc. Natl.
Acad. Sci. USA 85, 8998-9002 (1988)), and restriction-site PCR, w hich uses universal primers to retrieve unknown nucleic acid sequence adjacent to a known locus (Sarkar, G. (1993) PCR M ethods Applic, 2:318-322). "Inverse PCR" m ay also be used to amplify or to extend sequences using divergent prim ers based on a known region (Triglia, T. et al, (1988) Nucleic Acids Res. 16 :8186). Another m ethod which may be used is "capture PCR" , which involves PCR amplification of DNA fragm ents adjacent to a know n sequence in hum an and yeast artificial chrom osome DNA (Lagerstrom , M . et al, (1991 ) PCR M ethods Applic, 1 :1 1 1 -1 19). Another m ethod which m ay be used to retrieve unknown sequences is that of Parker, J.D , et al, (1991 ); Nucleic Acids Res. 19:3055-3060). Additionally, one may use PCR, nested primers, and libraries, such as the PromoterFinder™ library (Clontech, Palo Alto, CA) to walk genomic DNA , This latter process avoids the need to screen libraries and is useful in finding intron/exon junctions. W hen screening for full-length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. Also, random -primed libraries are preferable, in that they will contain more sequences that contain the 5' regions of genes. Use of a randomly prim ed library m ay be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA . Genomic libraries m ay be useful for extension of sequence into 5' non-transcribed regulatory regions. In one embodim ent of the invention, a nucleic acid m olecule according to the invention m ay be used for chrom osom e localisation, In this technique, a nucleic acid molecule is specifically targeted to, and can hybridise with, a particular location on an individual hum an chrom osome, The m apping of relevant sequences to chromosomes is an important step in the confirm atory correlation of those sequences with the gene-associated disease, Once a sequence has been m apped to a precise chromosom al location, the physical position of the sequence on the chromosom e can be correlated with genetic map data. Such data are found in, for example, M cKusick, Mendelian Inheritance in M an (available on-line through Johns Hopkins University W elch M edical Library), The relationships between genes and diseases that have been m apped to the same chrom osom al region are then identified through linkage analysis (coinheritance of physically adjacent genes). This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localised by genetic linkage to a particular genom ic region, any sequences m apping to that area m ay represent associated or regulatory genes for further investigation. The nucleic acid m olecule may also be used to detect differences in the chromosom al location due to translocation, inversion, etc. am ong norm al, carrier, or affected individuals. Nucleic acid m olecules of the present invention are also valuable for tissue localisation. Such techniques facilitate the determ ination of expression patterns of the polypeptide in tissues by detection of the mRNAs that encode them . These techniques include in situ hybridisation techniques and nucleotide amplification techniques, such as PCR. Results from these studies provide an indication of the normal functions of the polypeptide in the organism, as well as highlighting the involvement of a particular gene in a disease state or abnormal physiological condition.
In addition, comparative studies of the normal expression pattern of mRNAs with that of mRNAs encoded by a mutant gene provide valuable insights into the role of mutant polypeptides in disease. Such inappropriate expression may be of a temporal, spatial or quantitative nature.
Vectors
The nucleic acid molecules of the present invention may be incorporated into vectors for cloning (for example, pBluescript made by Stratagene) or expression purposes. Vectors containing a nucleic acid molecule explicitly identified herein (or a variant thereof) form another aspect of this invention. The nucleic acid molecule may be inserted into an appropriate vector by any variety of well known techniques such as those described in Sambrook et al [supra]. Generally, the encoding gene can be placed under the control of a control element such as a promoter, ribosome binding site or operator, so that the DNA sequence encoding the desired polypeptide is transcribed into RNA in the transformed host cell.
Vectors may be derived from various sources including, but not limited to bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses for example, baculoviruses and SV40 (simian virus), vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses, lentiviruses and retroviruses, or combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, including cosmids and phagemids. Human, bacterial and yeast artificial chromosomes (HACs, BACs and YACs respectively) may also be employed to deliver larger fragments of DNA than can be contained and expressed in a plasmid.
Examples of retroviruses include but are not limited to: murine leukaemia virus (MLV), hum an immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukaemia virus (Mo-MLV), FBR murine osteosarcoma virus (FBR M SV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukaemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29), and Avian erythroblastosis virus (AEV). A detailed list of retroviruses may be found in Coffin et al ("Retroviruses" 1997 Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763).
Lentiviruses can be divided into primate and non-primate groups. Examples of primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto-immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV). The non- primate lentiviral group includes the prototype "slow virus" visna/maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV) and the more recently described feline immunodeficiency virus (FIV) and bovine immunodeficiency virus (BIV). A distinction between the lentivirus family and other types of retroviruses is that lentiviruses have the capability to infect both dividing and non-dividing cells (Lewis et al 1992 EM B O . J 1 1 : 3053 -3058 ; Lewis and Em erm an 1994 J. Virol. 68 : 510-516). In contrast, other retroviruses - such as M LV - are unable to infect non-dividing cells such as those that m ake up, for example, m uscle, brain, lung and liver tissue.
A vector m ay be configured as a split-intron vector. A split intron vector is described in PCT patent applications W O 99/15683 and W O 99/15684.
If the features of adenoviruses are combined with the genetic stability of retroviruses/lentiviruses then essentially the adenovirus can be used to transduce target cells to become transient retroviral producer cells that could stably infect neighbouring cells. Such retroviral producer cells engineered to express an antigen of the present invention can be implanted in organism s such as anim als or humans for use in the treatment of angiogenesis and/or cancer.
Poxvirus vectors are also suitable for use in accordance with the present invention. Pox viruses are engineered for recom binant gene expression and for the use as recombinant live vaccines. This entails the use of recombinant techniques to introduce nucleic acids encoding foreign antigens into the genome of the pox virus. If the nucleic acid is integrated at a site in the viral DNA which is non-essential for the life cycle of the virus, it is possible for the new ly produced recombinant pox virus to be infectious, that is to say to infect foreign cells and thus to express the integrated DNA sequence, The recombinant pox virus prepared in this w ay can be used as live vaccines for the prophylaxis and/or treatment of pathologic and infectious disease.
For vaccine delivery, preferred vectors are vaccinia virus vectors such as M VA or NYVAC . M ost preferred is the vaccinia strain modified virus ankara (M VA) or a strain derived therefrom . Alternatives to vaccinia vectors include avipox vectors such as fowlpox or canarypox known as ALVAC and strains derived therefrom which can infect and express recombinant proteins in hum an cells but are unable to replicate.
B acterial vectors may be also used, such as salmonella, listeria and mycobacteria.
Vectors containing the relevant nucleotide sequence m ay enter the host cell by a variety of methods well known in the art and described in m any standard laboratory m anuals (such as Sam brook et al, [supra], Ausubel et al, [supra], Davis et al, B asic M ethods in M olecular Biology (1986)). M ethods include calcium phosphate transfection, cationic lipid-mediated transfection, DEAE-dextran mediated transfection, electroporation, microinjection, scrape loading, transduction, and ballistic introduction or infection.
Host cells
The choice of host cells is . often dependent on the vector type used as a carrier for the nucleic acid molecule of the present invention. Bacteria and other microorganisms are particularly suitable hosts for plasmids, cosmids and expression vectors generally (for example, vectors derived from the pBR322 plasmid), yeast are suitable hosts for yeast expression vectors, insect cell systems are suitable host for virus expression vectors (for example, baculovirus) and plant cells are suitable hosts for vectors such as the cauliflower mosaic virus (CaMV) and tobacco mosaic virus (TM V). Other expression systems include using animal cells (for example, with the LentiVectors™, Oxford BioMedica) as a host cell or even using cell-free translating systems. Some vectors, such as "shuttle vectors" may be maintained in a variety of host cells. An example of such a vector would be pEG 202 and other yeast two-hybrid vectors which can be maintained in both yeast and bacterial cells (see Ausubel et al, [supra] and Gyuris, J., Cell, 75, 791 - 803).
Examples of suitable bacterial hosts include Streptococci, Staphylococci, Escherichia coli, Streptomyces and Bacillus subtilis cells. Yeast and fungal hosts include Saccharomyces cerevisiae and Aspergillus cells. M ammalian cell hosts include many immortalised cell lines available from the American Type Culture Collection (ATCC) such as CHO (Chinese Hamster Ovary) cells, HeLa cells, BHK (baby hamster kidney) cells, monkey kidney cells, C 127, 3T3, BHK, HEK 293, Bowes melanoma and human hepatocellular carcinoma (for example, Hep G2) cells. Insect host cells that are used for baculovirus expression include Drosophila S2 and Spodoptera Sf9 cells. Plant host cells include most plants from which protoplasts be isolated and cultured to give whole regenerated plants. Practically, all plants can be regenerated from cultured cells or tissues, including but not limited to all major species of sugar cane, sugar beet, cotton, fruit and other trees, legumes and vegetables.
Expression systems
Also included in present invention are expression vectors that comprise a nucleic acid molecule as described above. Expression vectors and host cells are preferably chosen to give long term , high yield production and stable expression of the recombinant polypeptide and its variants.
Expression of a polypeptide can be effected by cloning an encoding nucleic acid molecule into a suitable expression vector and inserting this vector into a suitable host cell. The positioning and orientation of the nucleic acid molecule insert with respect to the regulatory sequences of the vector is important to ensure that the coding sequence is properly transcribed and translated. Alternatively, control and other regulatory sequences may be ligated onto the nucleic acid molecule of this invention prior to its insertion into the expression vector. In both cases, the sequence of the nucleic acid molecule may have to be adjusted in order to effect correct transcription and translation (for example, addition of nucleotides may be necessary to obtain the correct reading frame for translation of the polypeptide from its encoding nucleic acid molecule).
A nucleic acid m olecule of the invention may comprise control sequences that encode signal peptides or leader sequences. These sequences may be useful in directing the translated polypeptide to a variety of locations within or outside the host cell, such as to the lumen of the endoplasmic reticulum, to the nucleus, to the periplasmic space, or into the extracellular environment. Such signals may be endogenous to the nucleic acid molecules of the invention, or may be a heterologous sequence. These leader or control sequences may be removed by the host during post-translational processing.
A nucleic acid molecule of the present invention m ay also comprise one or more regulatory sequences that allow for regulation of the expression of polypeptide relative to the growth of the host cell. Alternatively, these regulatory signals may be due to a heterologous sequence from the vector. Stimuli that these sequences respond to include those of a physical or chemical nature such as the presence or absence of regulatory compounds, changing temperatures or metabolic conditions. Regulatory sequences as described herein, are non-translated regions of sequence such as enhancers, promoters and the 5' and 3' untranslated regions of genes. Regulatory sequences interact with host cellular proteins that carry out translation and transcription. These regulatory sequences may vary in strength and specificity. Examples of regulatory sequences include those of constitutive and inducible promoters. In bacterial systems, an example of an inducible promoter is the hybrid lacZ promoter of the Bluescript phagemid (Stratagene, LaJolla, CA) or pSportlTM plasmid (Gibco BRL). The baculovirus polyhedrin promoter m ay be used in insect cells.
An example of a preferred expression system is the lentivirus expression system , for example, as described in International patent application W 098/17815.
Detection of uptake of vectors by the host organism
Various methods are known in the art to detect the uptake of a nucleic acid or vector molecule by a host cell and/or the subsequent successful expression of the encoded polypeptide (see for example Sambrook et al, [supra]).
Vectors frequently have marker genes that can be easily assayed. Thus, vector uptake by a host cell can be readily detected by testing for the relevant phenotype. Markers include, but are not limited to those coding for antibiotic resistance, herbicide resistance or nutritional requirements. The gene encoding dihydrofolate reductase (DHFR) for example, confers resistance to methotrexate (W igler, M . et al. (1980) PNAS 77:3567-70) and the gene npt confers resistance to the aminoglycosides neom ycin and G-418 (Colbere-Garapin , F. et al (1981 ) J. M ol. Biol. 150: 1 -14). Additional selectable genes have been described, examples of which will be clear to those of skill in the art. M arkers however, only indicate that a vector has been taken up by a host cell but does not distinguish between vectors that contain the desired nucleic acid molecule and those that do not. One method of detecting for the said nucleic acid m olecule is to insert the relevant sequence at a position that will disrupt the transcription and translation of a m arker gene. These cells can then be identified by the absence of a m arker gene phenotype. Alternatively, a m arker gene can be placed in tandem with a sequence encoding a polypeptide of the invention under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
M ore direct and definitive methods to detect the presence of the nucleic acid molecule of the present invention include DNA -DNA or DNA -RNA hybridisation with a probe comprising the relevant antisense molecule, as described above. M ore direct methods to detect polypeptide expression include protein bioassays for example, fluorescence activated cell sorting (FAC S), immunoassay techniques such as ELISA or radioim m unoassays.
Alternative methods for detecting or quantitating the presence of the nucleic acid m olecule or polypeptide of this invention include membrane, solution or chip-based technologies (see Hampton, R . et al, (1990) Serological M ethods, a Laboratory M anual, APS Press, St Paul, M N) and M addox, D .E. et al, (1983) J. Exp. M ed, 158, 1211 -1216).
Transgenic animals
In another embodiment of this invention, a nucleic acid m olecule according to the invention may be used to create a transgenic anim al, most commonly a rodent, The m odification of the animal' s genome m ay either be done locally, by m odification of som atic cells or by germ line therapy to incorporate inheritable modifications. Such transgenic animals may be particularly useful in the generation of animal models for drug molecules effective as modulators of the polypeptides of the present invention.
Polypeptide purification
A polypeptide according to the invention m ay be recovered and purified from recombinant cell cultures by methods including, but not limited to cell lysis techniques, ammonium sulphate precipitation, ethanol precipitation, acid extraction, anion or cation chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chrom atography, high perform ance liquid chrom atography (HPLC) or fast perform ance liquid chrom atography (FPLC). The polypeptide may need refolding after purification or isolation and many well known techniques are available that will help regenerate an active polypeptide conform ation.
M any expression vectors are com m ercially available that aid purification of the relevant polypeptide. These include vectors that join the sequence encoding the polypeptide to another expressed sequence creating a fused protein that is easier to purify. W ays in which these fused parts can facilitate purification of the polypeptide of this invention include fusions that can increase the solubility of the polypeptide, joining of metal chelating peptides (for example, histidine-tryptophan modules) that allow for purification with imm obilised metals, joining of protein A dom ains w hich allow for purification with immobilised immunoglobulins and the joining of the dom ain that is utilised in the FLAGS extension/affinity purification system (Immunex Corp., Seattle, W A). Fusion of the polypeptide of this present invention with a secretion signal polypeptide m ay also aid purification. This is because the medium into which the fused polypeptide has been secreted can subsequently be used to recover and purify the expressed polypeptide, If necessary, these extraneous polypeptides often comprise a cleavable linker sequence which allow s the polypeptide to be isolated from the fusion. Cleavable linker sequences between the purification dom ain and the polypeptide of the invention include those specific for Factor Xa or for enterokinase (Invitrogen, San Diego, CA). One such expression vector provides for expression of a fusion protein containing the polypeptide of the invention fused to several histidine residues preceding a thioredoxin or an enterokinase cleavage site. The histidine residues facilitate purification by IM A C (immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp. Purif. 3 : 263-281 ), while the thioredoxin or enterokinase cleavage site provides a means for purifying the polypeptide from the fusion protein. A discussion of vectors that contain fusion proteins is provided in Kroll, D .J. et al. (1993 ; DNA Cell Biol. 12:441 -453). Assays
Another aspect of this invention includes assays that m ay be carried out using a polypeptide or nucleic acid molecule according to the invention. Such assays m ay be for m any uses including the development of drug candidates, for diagnostic purposes or for the gathering of inform ation for therapeutics.
If the polypeptide is to be expressed for use in screening assays, generally it is preferred that it be produced at the surface of the host cell in which it is expressed. In this event, the host cells m ay be harvested prior to use in the screening assay, for example using techniques such as fluorescence activated cell sorting (FA CS) or im munoaffinity techniques. If the polypeptide is secreted into the medium , the m edium can be recovered in order to recover and purify the expressed polypeptide. If polypeptide is produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
The polypeptide of the invention can be used to screen libraries of compounds in any of a variety of drug screening techniques. Such compounds m ay activate (agonise) or inhibit (antagonise) the level of expression of the gene or the activity of the polypeptide of the invention and form a further aspect of the present invention. Examples of suitable com pounds are those w hich are effective to alter the expression of a natural gene which encodes a polypeptide of the invention or to regulate the activity of a polypeptide of the invention.
Agonist or antagonist compounds m ay be isolated from , for example, cells, cell-free preparations, chemical libraries or natural product mixtures. These agonists or antagonists may be natural or modified substrates, ligands, enzymes, receptors or structural or functional mim etics. For a suitable review of such screening techniques, see Coligan et al., Current Protocols in Immunology l (2):Chapter 5 (1991 ).
Potential agonists or antagonists include small organic m olecules, peptides, polypeptides and antibodies that bind to the polypeptide of the invention and thereby m odulate its activity. In this fashion, binding of the polypeptide to normal cellular binding molecules may be potentiated or inhibited, such that the norm al biological activity of the polypeptide is enhanced or prevented.
The polypeptide of the invention that is employed in such a screening technique m ay be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. In general, such screening procedures m ay involve using appropriate cells or cell membranes that express the polypeptide that are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response. The functional response of the cells contacted with the test compound is then compared with control cells that were not contacted with the test compound. Such an assay may assess whether the test compound results in a signal generated by activation of the polypeptide, using an appropriate detection system . Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist in the presence of the test compound is observed.
Alternatively, simple binding assays m ay be used, in which the adherence of a test compound to a surface bearing the polypeptide is detected by means of a label directly or indirectly associated w ith the test compound or in an assay involving competition with a labelled competitor. In another embodiment, competitive drug screening assays m ay be used, in which neutralising antibodies that are capable of binding the polypeptide specifically compete with a test compound for binding, In this m anner, the antibodies can be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide. Assays may also be designed to detect the effect of added test compounds on the production of mRNA encoding the polypeptide in cells, For example, an ELISA m ay be constructed that measures secreted or cell-associated levels of polypeptide using monoclonal or polyclonal antibodies by standard methods known in the art, and this can be used to search for compounds that may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues. The formation of binding complexes between the polypeptide and the compound being tested may then be measured.
Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the polypeptide of interest (see International patent application W O 84/03564). In this method, large numbers of different small test compounds are synthesised on a solid substrate, which may then be reacted with the polypeptide of the invention and washed. One way of immobilising the polypeptide is to use non-neutralising antibodies. Bound polypeptide m ay then be detected using methods that are well known in the art. Purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques.
A polypeptide according to the invention may be used to identify membrane-bound or soluble receptors, through standard receptor binding techniques that are known in the art, such as ligand binding and crosslinking assays in which the polypeptide is labelled with a radioactive isotope, is chemically modified, or is fused to a peptide sequence that facilitates its detection or purification, and incubated with a source of the putative receptor (for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids), The efficacy of binding may be measured using biophysical techniques such as surface plasmon resonance and spectroscopy. Binding assays may be used for the purification and cloning of the receptor, but may also identify agonists and antagonists of the polypeptide, that compete with the binding of the polypeptide to its receptor. Standard methods for conducting screening assays are well understood in the art.
A typical polypeptide-based assay might involve contacting the appropriate cell(s) or cell membrane(s) expressing the polypeptide with a test compound. In such assays, a polypeptide according to the invention may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. Any response to the test compound, for example a binding response, a stimulation or inhibition of a functional response may then be compared with a control where the cell(s) or cell membrane(s) was/were not contacted with the test compound. A binding response could be measured by testing for the adherence of a test compound to a surface bearing a polypeptide according to the invention. The test compound may aid polypeptide detection by being labelled, either directly or indirectly. Alternatively, the polypeptide itself may be labelled, for example, with a radioisotope, by chemical modification or as a fusion with a peptide or polypeptide sequence that will facilitate polypeptide detection. Alternatively, a binding response may be measured, for example, by performing a competition assay with a labelled competitor or vice versa. One example of such a technique is a competitive drug screening assay, where neutralising antibodies that are capable of specifically binding to the polypeptide compete with a test compound for binding. In this manner, the antibodies may be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide. Alternative binding assay methods are well known in the art and include, but are not limited to, cross-linking assays and filter binding assays. The efficacy of binding may be measured using biophysical techniques including surface plasmon resonance and spectroscopy.
High throughput screening is a type of assay which enables a large number of compounds to be searched for any significant binding activity to the polypeptide of interest (see patent application WO84/03564). This is particularly useful in drug screening. In this scenario, many different small test compounds are synthesised on to a solid substrate. The polypeptide is then introduced to this substrate and the whole apparatus washed. The polypeptide is then immobilised by, for example, using non-neutralising antibodies. Bound polypeptide may then be detected using methods that are well known in the art. Purified polypeptide may also be coated directly onto plates for use in the aforementioned drug screening techniques.
Assay methods that are also included within the term s of the present invention are those that involve the use of the genes and polypeptides of the invention in overexpression or ablation assays. Such assays involve the manipulation of levels of these genes/polypeptides in cells and assessment of the impact of this manipulation event on the physiology of the manipulated cells. For example, such experiments reveal details of signaling and metabolic pathways in which the particular genes/polypeptides are implicated, generate information regarding the identities of polypeptides with which the studied polypeptides interact and provide clues as to methods by which related genes and proteins are regulated.
Another aspect of this invention provides for any screening kits that are based or developed from any of the aforementioned assays.
C. Pharmaceuticals
A further aspect of the invention provides a pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharm ceutically-acceptable carrier. A composition containing a polypeptide, nucleic acid molecule, ligand or any other compound of this present invention (herein known as X) is considered to be "substantially free of impurities" (herein known as Y) when X makes up more than 85% mass per mass of the total [X+Y] mass. Preferably X comprises at least 90% of the total X+Y m ass. More preferably X comprises at least 95% , 98% and m ost preferably 99% of the total X+Y m ass.
Carriers
Carrier m olecules m ay be genes, polypeptides, antibodies, liposom es or indeed any other agent provided that the carrier does not itself induce toxicity effects or cause the production of antibodies that are harm ful to the individual receiving the pharm aceutical composition. Further examples of known carriers include polysaccharides, polylactic acids, polyglycolic acids and inactive virus particles. Carriers m ay also include pharmaceutically acceptable salts such as m ineral acid salts (for example, hydrochlorides, hydrobromides, phosphates, sulphates) or the salts of organic acids (for example, acetates, propionates, malonates, benzoates). Pharm aceutically acceptable carriers may additionally contain liquids such as water, saline, glycerol, ethanol or auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like. Carriers m ay enable the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions to aid intake by the patient. A thorough discussion of pharm aceutically acceptable carriers is available in Rem ington's Pharmaceutical Sciences (M ack Pub. Co., N J. 1991 ).
Dosage
The am ount of component X in the composition should also be in therapeutically effective am ounts. The phrase "therapeutically effective am ounts" used herein refers to the am ount of agent needed to treat, ameliorate, or prevent (for example, when used as a vaccine) a targeted disease or condition. An effective initial method to determ ine a "therapeutically effective amount" m ay be by carrying out cell culture assays (for example, using neoplastic cells) or using anim al models (for example, mice, rabbits, dogs or pigs). In addition to determining the appropriate concentration range for X to be therapeutically effective, animal models may also yield other relevant information such as preferable routes of administration that w ill give maximum effectiveness. Such information may be useful as a basis for patient administration. A "patient" as used in herein refers to the subject who is receiving treatment by adm inistration of X. Preferably, the patient is human, but the term may also include animals.
The therapeutically-effective dosage will generally be dependent on the patient' s status at the time of adminstration, Factors that may be taken into consideration w hen determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug com binations, reaction sensitivities and the patient' s tolerance or response to the therapy. The precise amount can be determined by routine experimentation but m ay ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 m g/kg (m ass of drug compared to mass of patient) to 50 m g/kg, preferably 0.05 mg/kg to 10 m g/kg. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
Routes of administration
Uptake of a pharmaceutical composition of the invention by a patient may be initiated by a variety of methods including, but not limited to enteral, intra-arterial, intrathecal, intramedullary, intramuscular, intranasal, intraperitoneal, intravaginal, intravenous, intraventricular, oral, rectal (for example, in the form of suppositories), subcutaneous, sublingual, transcutaneous applications (for example, see W O98/20734) or transdermal means.
Gene guns or hyposprays may also be used to administer the pharmaceutical compositions of the invention. Typically, the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. Direct delivery of the compositions can generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue, The compositions can also be administered into a lesion, Dosage treatment may be a single dose schedule or a multiple dose schedule.
Inhibition of excessive activity
If a particular disease state is partially or completely caused by an inappropriate excess in the activity of a polypeptide according to the invention, several approaches are available for inhibiting this activity.
One approach comprises administering to a patient an inhibitor compound (antagonist) along with a pharmaceutically acceptable carrier in an amount effective to inhibit the function of the polypeptide, such as by blocking the binding of a ligand, substrate, enzyme, receptor, or by inhibiting a second signal, and thereby alleviating the abnormal condition. Such an antagonist molecule may, for example, be an antibody. Most preferably, such antibodies are chimeric and/or humanised to minimise their immunogenicity, as previously described. In another approach, soluble form s of the polypeptide that retain binding affinity for the ligand, substrate, enzyme, receptor, in question, may be administered to the patient to compete with the biological activity of the endogenous polypeptide, Typically, the polypeptide may be administered in the form of a fragment that retains a portion that is relevant for the desired biological activity.
In an alternative approach, expression of the gene encoding the polypeptide can be inhibited using expression blocking techniques, such as by using antisense nucleic acid molecules (as described above), either internally generated or separately administered. M odifications of gene expression may be effected by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5' or regulatory regions (signal sequence, promoters, enhancers and introns) of the gene encoding the polypeptide. Similarly, inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J.E, et al. (1994) In: Huber, B .E. and B .I. Carr, Molecular and Immunologic Approaches, Futura Publishing Co., Mt. Kisco, NY). The complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes. Such oligonucleotides may be administered or may be generated in situ from expression in vivo, Gene silencing approaches may also be undertaken to down-regulate endogenous expression of a gene. RNA interference (RNAi) (Elbashir, SM et al., Nature 2001 , 411 , 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed, Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA, reducing or ablating target protein expression. In addition, expression of a polypeptide according to the invention may be prevented by using a ribozyme specific to the encoding mRNA sequence for the polypeptide. Ribozymes are catalytically active RNAs that can be natural or synthetic (see for example Usman, N, et al, Curr. Opin. Struct. B iol (1996) 6(4), 527-33). Synthetic ribozymes can be designed to specifically cleave mRNAs at selected positions thereby preventing translation of the mRNAs into functional polypeptide. Ribozymes may be synthesised with a natural ribose phosphate backbone and natural bases, as normally found in RNA molecules. Alternatively the ribozymes may be synthesised with non-natural backbones, for example, 2'-0-methyl RNA, to provide protection from ribonuclease degradation and may contain modified bases.
Efficacy of the gene silencing approaches assessed above may be assessed through the measurement of polypeptide expression (for example, by Western blotting), and at the RNA level using TaqMan-based methodologies.
RNA molecules may be modified to increase their intracellular stability and half-life, Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of non-traditional bases such as inosine, queosine and butosine, as well as acetyl-, methyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine and uridine that are not as easily recognised by endogenous endonucleases. Activation of a polypeptide activity
If a particular disease state is partially or completely due to a lowered level of biological activity from a polypeptide according to the invention, various m ethods m ay be used. An example of such a m ethod includes administering a therapeutically effective am ount of compound that can activate (i.e. an agonist) or cause increased expression of the polypeptide concerned. A dm inistration of such a compound m ay be via any of the methods described previously.
Gene Therapy
Another aspect of the present invention provides for gene therapy methods involving nucleic acid molecules identified herein. Gene therapy m ay be used to affect the endogenous production of the polypeptide of the present invention by relevant cells in a patient. For example, gene therapy can be used perm anently to treat the inappropriate production of a polypeptide by replacing a defective gene with the corrected therapeutic gene.
Treatment m ay be effected either in vivo or ex vivo. Ex vivo gene therapy generally involves the isolation and purification of the patient' s cells, introduction of the therapeutic gene into the cells and finally, the introduction of the genetically-altered cells back into the patient, In vivo gene therapy does not require the isolation and purification of patient cells prior to the introduction of the therapeutic gene into the patient. Instead, the therapeutic gene can be packaged for delivery into the host. Gene delivery vehicles for in vivo gene therapy include, but are not lim ited to, non-viral vehicles such as liposom es, replication-competent and replication-deficient viruses (for example, adenovirus as described by Berkner, K.L., in Curr. Top. M icrobiol. Immunol., 158, 39-66 (1992)) or adeno-associated virus (AAV) vectors as described by M uzyczka, N „ in Curr. Top. M icrobiol. Immunol., 158, 97-129 (1992) and U .S . Patent No . 5,252,479. Alternatively, "naked DNA" may be directly injected into the bloodstream or muscle tissue as a form of in vivo gene therapy.
One example of a strategy for gene therapy including a nucleic acid molecule of this present invention m ay be as follow s. A nucleic acid molecule encoding a polypeptide of the invention is engineered for expression in a replication-defective or replication-competent vector, such as a retroviral vector. This expression construct m ay then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding the polypeptide, such that the packaging cell now produces infectious viral particles containing the gene of interest. These producer cells may be administered to a patient for engineering cells in vivo and expression of the polypeptide in vivo (see Chapter 20, Gene Therapy and other M olecular Genetic-based Therapeutic Approaches, (and references cited therein) in Hum an M olecular Genetics (1996), T Strachan and A P Read, B IOS Scientific Publishers Ltd). Genetic delivery of antibodies that bind to polypeptides according to the invention may also be effected, for example, as described in International patent application WO98/55607.
Vaccines
A further embodiment of the present invention provides that the polypeptides or nucleic acid molecules identified may be used in the development of vaccines. Where the aforementioned polypeptide or nucleic acid molecule is a disease-causing agent, vaccine development can involve the raising of antibodies against such agents. Where the aforementioned polypeptide or nucleic acid molecule is that is upregulated, vaccine development can involve the raising of antibodies or T cells against such agents (as described in W O00/29428). Vaccines according to the invention may either be prophylactic (i.e. prevents infection) or therapeutic (i.e. treats disease after infection). Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid, usually in combination with pharmaceutically-acceptable carriers as described above. Additionally, these carriers may function as immunostimulating agents ("adjuvants"). Furthermore, the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H, pylori, and other pathogens.
Vaccination processes may involve the use of heterologous vectors eg: prime with MVA and boost with DNA,
Since polypeptides may be broken down in the stomach, vaccines comprising polypeptides are preferably administered parenterally (for instance, subcutaneous, intramuscular, intravenous, or intradermal injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents.
The vaccine formulations of the invention may be presented in unit-dose or multi-dose containers. For example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.
The technology referred to as jet injection (see, for example, www.powderject.com) may also be useful in the formulation of vaccine compositions. In accordance with this aspect of the present invention, polypeptides can be delivered by viral or non-viral techniques. Non-viral delivery systems include but are not limited to DNA transfection methods. Here, transfection includes a process using a non-viral vector to deliver a antigen gene to a target mammalian cell. Typical transfection methods include electroporation, nucleic acid biolistics, lipid-mediated transfection, compacted nucleic acid-m ediated transfection, liposom es, immunoliposomes, lipofectin, cationic agent-m ediated, cationic facial amphiphiles (CFA s) (Nature B iotechnology 1996 14; 556), multivalent cations such as sperm ine, cationic lipids or polylysine, 1 , 2,-bis (oleoyloxy)-3- (trim ethylam m onio) propane (DOTAP)-cholesterol complexes (W olff and Trubetskoy 1998 Nature B iotechnology 16: 421 ) and combinations thereof.
Viral delivery systems include but are not limited to adenovirus vectors, adeno-associated viral (AAV) vectors, herpes viral vectors, influenza, retroviral vectors, lentiviral vectors or baculoviral vectors, Venezuelan equine encephalitis virus (VEE), poxviruses such as: canarypox virus (Taylor et al 1995 Vaccine 13 :539-549), entom opox virus (Li Y et al 1998 XHth International Poxvirus Symposium pl 44. Abstract), penguine pox (Standard et al. J Gen Virol. 1998 79: 1637-46) alphavirus, and alphavirus based DNA vectors.
In addition to the use of polypeptide-based vaccines, this aspect of the invention includes the use of genetically-based vaccines, for example, those vaccines that are effective through eliciting the expression of a particular gene (either endogenous or exogenously derived) in a cell, so targeting this cell for destruction by the im mune system of the host organism .
A number of suitable methods for vaccination and vaccine delivery system s are described in International patent application W 000/29428.
D. Diagnostics
Another aspect of the present invention provides for the use of a nucleic acid m olecule identified herein as a diagnostic reagent.
For example, a nucleic acid molecule may be detected or isolated from a patient' s tissue and used for diagnostic purposes. "Tissue" as defined herein refers to blood, urine, any matter obtained from a tissue biopsy or any matter obtained from an autopsy, Genomic DNA from the tissue sample may be used directly for detection of a hypoxia-related condition. Alternatively, the DNA may be amplified using methods such as polymerase chain reaction (PCR), the ligase chain reaction (LCR), strand displacem ent amplification (SDA), or other amplification techniques (see Saiki et al, Nature, 324, 163-166 (1986); B ej, et al, Crit. Rev. B iochem . Molec. B iol., 26, 301 -334 (1991 ); B irkenmeyer et al, J, Virol. M eth., 35, 1 17-126 (1991 ) and B runt, J., B io/Technology, 8, 291 -294 (1990)). Such diagnostics are particularly useful for prenatal and even neonatal testing.
A method of diagnosis of disease using a polynucleotide m ay comprise assessing the level of expression of the natural gene and comparing the level of encoded polypeptide to a control level measured in a norm al subject that does not suffer from the disease or physiological condition that is being tested. The diagnosis m ay comprise the following steps: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid molecule of the invention and the probe; b) contacting a control sample with said probe under the sam e conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of differing levels of the hybrid complex in the patient sample compared to levels of the hybrid complex in the control sam ple is indicative of the dysfunction. A further aspect of the invention comprises a diagnostic method comprising the steps of: a) obtaining a tissue sample from a patient being tested for disease; b) isolating a nucleic acid m olecule according to the invention from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation in the nucleic acid molecule which is associated w ith disease. To aid the detection of nucleic acid molecules in the above-described methods, an amplification step, such as PCR , m ay be included. An example of this includes detection of deletions or insertions indicative of the dysfunction by a change in the size of the amplified product in comparison to the norm al genotype. Point mutations can be identified by hybridising amplified DNA to labelled RNA of the invention or alternatively, labelled antisense DNA sequences of the invention, Perfectly m atched sequences can be distinguished from mismatched duplexes by RNase digestion or by assessing differences in m elting temperatures. The presence or absence of the mutation in the patient m ay be detected by contacting DNA with a nucleic acid probe that hybridises to the DNA under stringent conditions to form a hybrid double- stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion corresponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation in the corresponding portion of the DNA strand.
Point mutations and other sequence differences between the reference gene and "mutant" genes can be identified by other well-known techniques, such as direct DNA sequencing or single-strand conform ational polym orphism , (see Orita et al, Genomics, 5, 874-879 (1989)). For example, a sequencing primer may be used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabelled nucleotides or by automatic sequencing procedures with fluorescent-tags. Cloned DNA segm ents m ay also be used as probes to detect specific DNA segments. The sensitivity of this m ethod is greatly enhanced when combined with PCR . Further, point mutations and other sequence variations, such as polymorphism s, can be detected as described above, for example, through the use of allele-specific oligonucleotides for PCR amplification of sequences that differ by single nucleotides. DNA sequence differences m ay also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (for example, M yers et al, Science (1985) 230:1242). Sequence changes at specific locations m ay also be revealed by nuclease protection assays, such as RNase and S I protection or the chemical cleavage method (see Cotton et al, PNA S . USA (1985) 85 : 4397-4401 ). In addition to conventional gel electrophoresis and DNA sequencing, mutations such as microdeletions, aneuploidies, translocations, inversions, can also be detected by in situ analysis (see, for example, Keller et al, DNA Probes, 2nd Ed„ Stockton Press, New York, N .Y ., USA (1993)), that is, DNA or RNA sequences in cells can be analysed for mutations without need for their isolation and/or imm obilisation onto a membrane. FISH is presently the m ost comm only applied method and num erous review s of FISH have appeared (see, for example, Trachuck et al, Science, 250, 559-562 (1990), and Trask et al, Trends, Genet., 7, 149-154 (1991)).
Arrays
In another embodim ent of the invention, an array of oligonucleotide probes comprising a nucleic acid molecule according to the invention can be constructed to conduct efficient screening of genetic variants, mutations and polym orphism s. Array technology m ethods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability (see for example: M .Chee et al, Science (1996), Vol 274, pp 610-613).
In one embodiment, the array is prepared and used according to the methods described in W 095/1 1995 (Chee et al); Lockhart, D . J. et al (1996) Nat. Biotech. 14: 1675-1680); and Schena, M . et al (1996) PNAS 93 : 10614-10619). Oligonucleotide pairs m ay range from two to over one million. The oligomers are synthesized at designated areas on a substrate using a light-directed chemical process. The substrate may be paper, nylon or other type of m embrane, filter, chip, glass slide or any other suitable solid support. In another aspect, an oligonucleotide m ay be synthesized on the surface of the substrate by using a chem ical coupling procedure and an ink jet application apparatus, as described in PCT application W 095/251 1 16 (B aldeschweiler et al). In another aspect, a "gridded" array analogous to a dot (or slot) blot m ay be used to arrange and link cDNA fragm ents or oligonucleotides to the surface of a substrate using a vacuum system , therm al, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), m aterials (any suitable solid support), and machines (including robotic instrum ents), and may contain 8, 24, 96, 384, 1536 or 6144 oligonucleotides, or any other number between two and over one million which lends itself to the efficient use of commercially-available instrumentation .
D iagnostics using polypeptides or mRNA In addition to the m ethods discussed above, diseases m ay be diagnosed by methods comprising determ ining, from a sam ple derived from a subject, an abnormally decreased or increased level of polypeptide or mRNA . Decreased or increased expression can be measured at the RNA level using any of the methods w ell known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR , RT-PCR, RN ase protection, Northern blotting and other hybridization methods.
Assay techniques that can be used to determ ine levels of a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art and are discussed in some detail above (including radioimmunoassays, competitive-binding assays, W estern Blot analysis and ELISA assays). One example of this aspect of the invention provides a diagnostic method which comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the form ation of a ligand-polypeptide complex; and (b) detecting said complex.
Protocols such as ELISA , RIA , and FAC S for measuring polypeptide levels m ay additionally provide a basis for diagnosing altered or abnorm al levels of polypeptide expression. Norm al or standard values for polypeptide expression are established by combining body fluids or cell extracts taken from norm al m amm alian subjects, preferably humans, with antibody to the polypeptide under conditions suitable for complex form ation The am ount of standard complex form ation m ay be quantified by various methods, such as by photom etric means.
Antibodies which specifically bind to a polypeptide of the invention m ay be used for the diagnosis of conditions or diseases characterised by expression of the polypeptide, or in assays to m onitor patients being treated with the polypeptides, nucleic acid molecules, ligands and other compounds of the invention. Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for the polypeptide include methods that utilise the antibody and a label to detect the polypeptide in hum an body fluids or extracts of cells or tissues. The antibodies may be used w ith or without modification, and may be labelled by joining them , either covalently or non-covalently, with a reporter m olecule. A wide variety of reporter m olecules known in the art m ay be used, several of which are described above.
Quantities of polypeptide expressed in subject, control and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease. Diagnostic assays m ay be used to distinguish between absence, presence, and excess expression of polypeptide and to m onitor regulation of polypeptide levels during therapeutic intervention. Such assays m ay also be used to evaluate the efficacy of a particular therapeutic treatment regimen in anim al_studies, in clinical trials or in m onitoring the treatment of an individual patient.
Diagnostic kits
A diagnostic kit of the present invention m ay comprise:
(a) a nucleic acid molecule of the present invention ;
(b) a polypeptide of the present invention; or (c) a ligand of the present invention.
In one aspect of the invention, a diagnostic kit m ay comprise a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to the invention; a second container containing primers useful for amplifying the nucleic acid m olecule; and instructions for using the probe and primers for facilitating the diagnosis of disease. The kit m ay further comprise a third container holding an agent for digesting unhybridised RNA .
In an alternative aspect of the invention, a diagnostic kit m ay comprise an array of nucleic acid molecules, an array of antibody m olecules, and/or an array of polypeptide molecules, as discussed in m ore detail above.
Such kits will be of use in diagnosing a disease or susceptibility to disease, particularly inflamm ation, oncology, or cardiovascular disease.
Various aspects and embodiments of the present invention w ill now be described in more detail by way of example, with particular reference to polypeptides regulated differentially under hypoxic conditions as opposed to norm oxic conditions. It w ill be appreciated that m odification of detail m ay be made without departing from the scope of the invention. Brief description of the Figures
Figure 1 show s a scatter plot, showing normalised signal intensities in hypoxia versus norm oxia, with each dot representing a single gene.
Figure 2: Hypoxia responses am plified by HIFl alpha overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1 ). Error bars represent standard error of the mean. Figure 3: Hypoxia responses amplified by EPAS l overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1 ). Error bars represent standard error of the mean.
Figure 4: Hypoxia responses amplified by HIFlalpha / EPAS l overexpression. Data shown is the average of 4 repeat experiments. Values represent fold change as compared to untreated cells (condition 1). Error bars represent standard error of the mean.
Figure 5 shows genes that are induced by hypoxia to a greater degree in resting macrophages, as compared to activated macrophages. Error bars show the standard deviation from both repeat experiments and multiple exposures from single experiments. These data are not shown in table form. All bars are ratios of mRNA expression in hypoxia/ normoxia. These are calculated separately for resting (light bars) and activated (dark bars) macrophages, and do not illustrate differences resulting from activation in normoxia,
Figure 6 shows genes which are induced by hypoxia to a greater degree in activated m acrophages, compared to resting macrophages, Figure 7 shows genes that are repressed by hypoxia to a greater degree in activated macrophages,
For Figures 8, 9a, 9c, 10-32a, 32d and 33-52, mRNA levels, determined from a custom gene array, of particular genes are shown on the Y-axis, expressed as a value as compared to the median expression level of this gene throughout all samples. Eleven primary human cell types as shown on the x-axis were cultured in normoxia (black), or exposed to hyopxia for 6hr (grey) or 18hr (white). Figure 8: Ecotropic viral integration site 2A (Seq ID :475/476).
Figure 9a: Novel PI-3-kinase adapter (Seq ID:79/80); Image clone accession R62339.
Figure 9b: TaqM an Real-time Q-RT-PCR data for Novel PI-3-kinase adapter (Seq ID :79/80); Image clone accession R62339.
Figure 9c: IMAGE clone ace R59598 (Syk). Figure 10: Regulator of G-protein signalling 1 (Seq ID :375/376)
Figure 1 1 : GM2 ganglioside activator protein (Seq ID:389/390)
Figure 12: Hypothetical protein PRO0823 (Seq ID .21/22)
Figure 13: CYP1 (cytochro e P450, subfamily XXVIIB) (Seq ID:339/340)
Figure 14: Alpha-2-macroglobulin (Seq ID :405/406) Figure 15: Interleukin 1 receptor antagonist (Seq ID :357/358) Figure 16: SCYA3L (Seq ID:469/470)
Figure 17: CFFM4 (Seq ID:433/434)
Figure 18: Pleckstrin (Seq ID:431/432)
Figure 19: CYP1B1 (SeqID :325/326) Figure 20: CYP1B1 (SeqID : 137/138)
Figure 21: Hypothetical protein FLJ13511 (SeqID : 163/164)
Figure 22: Hematopoietic Zinc finger protein (SeqID:17/18)
Figure 23: Osteopontin (SeqID :267/268)
Figure 24: Osteopontin (SeqID :267/268) Figure 25: Adipophilin (SeqID :313/314)
Figure 26: Adipophilin (SeqID :313/314)
Figure 27: Adipophilin (SeqID :313/314)
Figure 28: Adipophilin (SeqID :313/314)
Figure 29: Hypothetical protein FLJ22690 (SeqID :205/206) Figure 30: cDNA DKFZp586E1624 (SeqID: 65/66)
Figure 31: EST (SeqID :197/198)
Figure 32a: EGL nine (C.elegans) homolog 3 (SeqID :85/86)
Figure 32b: Gene expression profiles in macrophages with and without activation, mRNA levels, determined from a custom gene array, of clorf 12 are shown on the Y-axis, expressed as a value compared to the mean value of a set of control genes on each array (per-chip normalisation). All cells were human macrophages, cultured either without cytokines or with IL-10 or with the combination of IFND andLPS in normoxia and hypoxia,
Figure 32c: Gene expression profiles in macrophages with and without activation. mRNA levels, determined from a custom gene array, of EGLN3 are shown on the Y-axis, expressed as a value compared to the mean value of a set of control genes on each array (per-chip normalisation). All cells were human macrophages, cultured either without cytokines or with IL-10 or with the combination of IFNQ andLPS in normoxia and hypoxia.
Figure 32d:Clorfl2 (SeqID: 89.90) Figure 32e: The effect of EPAS/ HIF overexpression on expression of the gene C 1 orf 12 EGLN genes using a custom gene array. mRNA expression levels of the gene cl0RF12 as determined by the custom array, in response to hypoxia and adenoviral over-expression of HIF or EPAS are shown. Experimental conditions are as follows: #1 no adeno / normoxia; #2 empty adeno (low dose)/ normoxia; #3 empty adeno (high dose)/ normoxia; #4 empty adeno (low dose)/ hypoxia; #5 empty adeno (high dose)/ hypoxia; #6 HIF-1 adeno (low dose)/ hypoxia; #7 HIF-1 adeno (high dose)/ hypoxia; #8 EPAS adeno (low dose)/ hypoxia; #9 EPAS adeno (high dose)/ hypoxia. Error bars are the standard error of the mean.
Figure 32f: The effect of EPAS/ HIF overexpression on expression of the gene EGLN3 gene using a custom gene array. mRNA expression levels of the gene EGLN3 as determined by the custom array, in response to hypoxia and adenoviral over-expression of HIF or EPAS are shown. Experimental conditions are as follows: #1 no adeno / normoxia; #2 empty adeno (low dose)/ normoxia; #3 empty adeno (high dose)/ normoxia; #4 empty adeno (low dose)/ hypoxia; #5 empty adeno (high dose)/ hypoxia; #6 HIF-1 adeno (low dose)/ hypoxia; #7 HIF-1 adeno (high dose)/ hypoxia; #8 EPAS adeno (low dose)/ hypoxia; #9 EPAS adeno (high dose)/ hypoxia. Error bars are the standard error of the mean, Figure 32g: The effect of EPAS/ HIF overexpression on expression of the EGLN3 gene using AffyMetrix Hu95 ver2 GeneChips. mRNA expression levels of the gene in response to hypoxia and adenoviral over- expression of HIF or EPAS are shown, Graphs show the mean of two replicate arrays, with error bars as standard deviation. Above each graph, data values are shown, including the normalised values and raw values (the AffyMetrix average difference parameter) and Present/ Absent flags, Figure 32h: The effect of EPAS/ HIF overexpression on expression of the clorf 12 gene using AffyMetrix Hu95 ver2 GeneChips, mRNA expression levels of the gene in response to hypoxia and adenoviral over- expression of HIF or EPAS are shown. Graphs show the mean of two replicate arrays, with error bars as standard deviation. Above each graph, data values are shown, including the normalised values and raw values (the AffyMetrix average difference parameter) and Present/ Absent flags. Figure 32i: Flag immunocytochemistry in HEK293T cells
Figure 32j: Human Cardiomyocyte Caspase Activity after 72 hours transduction with EIAV-ELG9- Homolog 3
Figure 33: Novel Metallothionein (SeqID :83/84)
Figure 34: Hypothetical protein hqp0376 (SeqID:337/338) Figure 35: Metallothionein 2A (SeqID :265/266)
Figure 36: Metallothionein 1G (SeqID :243/244)
Figure 37: Metallothionein IH (SeqID : 239/240) Figure 38: Hepcidin antimicrobial peptide (SeqID :141/142)
Figure 39: EST (SeqID : 117/118)
Figure 40: Hypothetical protein FLJ22622 (SeqID :129/130)
Figure 41 : TRIP-Br2 (SeqID :31/32) Figure 42: Tumor protein D52 (SeqID :301/302)
Figure 43: Semaphorin 4b (SeqID :91/92/92a)
Figure 44: Dec-1 (SeqID :371/372)
Figure 45: Calgranulin A (SeqID:447/448)
Figure 46: ERO l (S. cerevisiae)-like (SeqID :67/68) Figure 47: Hypothetical protein FLJ20500 (SeqID :25/26)
Figure 48: N-myc downstream regulated (SeqID :229/230)
Figure 49: Decidual protein induced by progesterone (SeqID :387/388)
Figure 50: Integrin, alpha 5 (SeqID :379/380)
Figure 51 : Tissue factor (SeqID :225/226) Figure 52: COX-2 (SeqID :237/238)
Figure 53: Genes up-regulated by macrophage activation. Normalised mRNA levels in the 6 experimental conditions (#1 no cytokines/ normoxia, #2 no cytokines/ hypoxia, #3 IL-10/ normoxia, #4 IL-10/ hypoxia, #5 LPS/IFN/ normoxia, #6 LPS/IFN/ hypoxia) are shown as values referenced to the median value of that gene throughout all 6 experimental conditions. Error bars show the standard error of the mean. Figure 54: Genes downregulated by macrophage activation (I)
Figure 55: Genes downregulated by macrophage activation (II)
Figure 56: Genes downregulated by macrophage activation (III)
Figure 57 shows an RNase protection assay for the gene encoding Semaphorin 4b.
Figure 58 shows a Northern blot showing the size of the mRNA and tissue distribution for the Semaphorin 4b gene. Examples
Summary
Subtracted cDNA libraries were separately prepared for hypoxic m acrophages and cardiom yoblasts. This involved harvesting RNA from cells both in norm oxia and hypoxia, and preparing cDNA . Subtractive hybridization / suppression PCR w as then perform ed to rem ove genes from the hypoxic cell cDNA , which are also present in cDNA from norm oxic cells. Insert DNA from the libraries was PCR amplified and arrayed onto duplicate membranes. Quantitative hybridizations with pre-library cDNA material (norm oxia and hypoxia) were done to identify clones in the libraries that actually contain hypoxia inducible genes. The insert DNA was then sequenced. This procedure was done independently for macrophage and cardiom yoblast. The hypoxia inducible genes identified from these different cell types differed widely, with only a m inority of these. genes being identified from both cell types.
To characterise the differences between the two tissues further, arrays were produced containing all confirmed hypoxia-inducible genes from the m acrophage library. Replicate arrays were hybridised with cDNA from normoxic and hypoxic cardiom yoblasts to allow quantitative evaluation of these genes in the cardiomyoblast. This revealed quantitative differences in the hypoxia induced activation these genes in the two cell types.
Example la: Comparison of the hypoxic-response between human macrophages and cardiomyoblasts by a subtraction cloning / array screening approach M ethods / Results
To isolate hum an m acrophage, monocytes were derived from peripheral blood of healthy hum an donors. 100ml bags of buffy coat from the B ristol B lood Transfusion Centre were mixed with an equal volume of RPM I1640 m edium (Sigm a). This was layered on top of 10ml ficol-paque (Pharm acia) in 50ml centrifuge tubes and centrifuged for 25 min at 800 x g. The interphase layer w as removed, w ashed in M ACS buffer (phosphate buffered saline pH 7.2, 0.5 % bovine serum albumin, 2mM EDTA) and resuspended at 80 microliter per 10n7 cells. To this 20 m icroliter CD 14 M icrobeads (M iltenyi Biotec) were added, and the tube incubated at 4 degrees for 15 m in. Following this one wash was performed in MACS buffer at 400 x g and the cells were resuspended in 3 ml M ACS buffer and separated on an LS+ M ACS Separation Column (M iltenyi Biotec) positioned on a midi-M ACS magnet (Miltenyi Biotec). The column w as washed with 3 x 3ml MACS buffer. The column was removed from the magnet and cells were eluted in 5 ml M ACS buffer using a syringe. Cells were washed in culture m edium (AIM V (Sigma) supplem ented with 2% hum an AB serum (Sigm a), and resuspended at 2 x 10n5 cells per ml in the same medium and placed in large teflon-coated culture bags (Sud-Laborbedarf Gm bH, 82131 Gauting, Germ any) and transferred to a tissue culture incubator (37 degrees, 5 % C02) for 7-10 days. During this period m onocytes spontaneously differentiate to m acrophages. This is confirmed by examining cell m orphology using phase contrast microscopy. Cells are removed from the bags by placing at 4 degrees for 30 min and emptying the contents. The cells are then washed and resuspended in culture medium at 5 x 105 cell/m l and plated out in Primeria 10 cm tissue culture petri dishes (Falcon Becton Dickinson) at 5 x 10n6 cells per dish. Culture is continued for 16-24hr to allow cell adherence, prior to experimentation involving hypoxia.
As an alternative prim ary cell type hum an cardiom yoblast cultures were established. Cells derived from the ventricular tissue of newborn or foetal hearts were purchased from BioWhittaker (CC-2582). Growth conditions were used to allow m aximum expansion of the cells in vitro, by using a m edium rich in grow th factors. Under such conditions cardiom yoblast-like cells predom inate (the developmental precursor of cardiom yocytes). This has been previously described by Goldm an and W urzel (In Vitro Cell. Dev. Biol. 28A : 109-1 19 (1992)) and Goldman et al, (1996, Exp.Cell.Res. 228(2): 237-245). For these cultures, cells were seeded at l xlO6 per T150 flask in human smooth muscle growth m edium (TCS CellWorks ZHM -3935) and were expanded in the same medium up to a maximum number of 4 passages. The grow th medium is purchased pre-prepared, and includes in the form ula, 5% fetal bovine serum , insulin, epiderm al grow th factor and fibroblast grow th factor. Prior to experimentation involving hypoxia, cells were plated onto 10 cm tissue culture petri dishes and allowed to reach confluency. For experimentation with hypoxia, for all cell types, an equal number of identical culture dishes were divided into two separate incubators: One at 37 degrees, 5% C02, 95% air (=Normoxia) and the other at 37 degrees, 5% C02, 94.9% Nitrogen, 0,1 % Oxygen (=Hypoxia), After 6 hours culture under these conditions, the dishes were removed from the incubator, placed on a chilled platform , washed in cold PB S and total RNA w as extracted using RNazol B (Tel-Test, Inc; distributed by Biogenesis Ltd) following the manufacturer' s instructions, Polyadenylated mRNA w as extracted from the total RNA using a commercial kit following the manufacturer' s instructions (Promega; PolyATract mRNA isolation System IV).
The hypoxia period of 6 hr was previously determined to be sufficient to allow the induction of known hypoxia-regulated genes, as determined by RNase protection assays. During these preliminary studies it was noted that m acrophages, cardiomyoblasts and an additional control cell type, Jurkat T-cells, showed different patterns of gene induction in response to hypoxia:
Known Hypoxia-inducible gene level of hypoxia-induced increase in m RNA levels
Macrophage Myoblast T-cell phosphoglycerate kinase-1 none none high
(PGK) • vascular endothelial growth factor-A high low high
(VEGF) solute carrier family 2, member 1 high low high
(Glut-1)
Separate subtracted cDNA populations were generated from mRNA extracted from hypoxic macrophages and hypoxic cardiomyoblasts, using a combination of two kits, purchased from Clontech Laboratories- SMART PCR cDNA synthesis kit and PCR Select cDNA subtraction kit. The manufacturer's instructions were followed for both kits. All diagnostic steps were followed as recommended by the manufacturers. All PCR reactions were done using an Applied Biosystems 9700 with 96-well block, using Applied Biosystems plastics. Driver and tester populations used for subtraction were as below:
subtracted cDNA tester driver
Subtracted macrophage macrophage (hypoxia) macrophage (normoxia)
Subtracted cardiomyoblast cardiomyoblast (hypoxia) cardiomyoblast (normoxia)
The final subtracted cDNA samples were evaluated by performing RT-PCR using the following primers for human beta actin: sense: TCACCCACACTGTGCCCATCTACGA antisense: CAGCGGAACCGCTCATTGCCAAATGG
This showed that an additional 5 cycles of PCR were required to achieve similar levels of beta actin product from subtracted compared to unsubtracted cDNA, indicating a significant reduction in the representation of a non-regulated gene in the subtracted cDNA. Glyceraldehyde 3-Phosphate dehydrogenase PCR primers, as contained in the kit, were not used.
The three subtracted cDNA populations were ligated into a plasmid vector (pCRII, Invitrogen) to generate libraries, which were transformed into E.coli (INVαF', Invitrogen) and plated out onto agar, supplemented with ampicillin and X-Gal, according to standard methods.
Colonies that are white indicate the presence of a recombinant plasmid, and these were picked into individual wells of 96-well plates containing 100 microliters LB -Ampicillin, and given 3-8 hr growth at 37 degrees. In this way, for each library, up to 15 x 96-well plates of clones were generated. To screen clones for the presence of differentially expressed genes, replicate arrays of plasmid insert DNA were generated on nylon m embranes: Firstly, PCR was performed using nested PCR primers 2R and 1 , which flank the cDNA insert of each clone (sequence described in the PCR Select kit). The reaction mix also contains 200 uM d(A ,T,C,G)TP, Advantage2 polym erase mix (Clontech Laboratories) and supplied l Ox buffer, 40 ul reactions were set up in 96-well PCR reaction plates and inoculated with 0.5 ul bacteria from the library plates. 23 cycles of PCR were performed (95 degrees 10 sec; 68 degrees 2 m in), and a selection of wells were checked on an agarose gel. In this m anner a 96-well plate of insert DNA was generated for each 96-well plate of bacterial clones. Arrays of insert DNA were generated by transferring 4ul of each well to 384-w ell plates (Genetix), and denaturing the DNA by adding 4ul 0.4M NaOH and incubating at 37 degrees for 15 minutes. Brom ophenol blue w as added to the wells to allow visualisation of arraying. A 384-pin replicator (Genetix) was used to spot sm all volum es of denatured insert DNA onto dry nylon membranes (Hybond N+, AmershamPharmacia).
By repeating this operation from the same 384-well plate onto several membranes, matched pairs of m em branes were produced, suitable for array screening. A fragment of the beta actin gene was spotted at specific positions of the arrays. Following spotting, the membranes w ere left at room temperature for 2 hr, re-denatured by placing on chrom atography paper wetted w ith 0.3 M NaOH, neutralised by placing on chromatography paper wetted with 0,5 M Tris pH 7.5 , dried at room temperature for 2 hr and crosslinked by exposing to 2000 joules UV radiation. Prior to hybridisation, residual salts were rem oved from the arrays, by w ashing in hot 0.5 % SD S . M atched pairs of m embranes were hybridised w ith subtracted cDNA samples; from hypoxic and norm oxic cells, to determine the abundance of the genes corresponding to each spotted clone in the cDNA samples. Because the cDNA probes were subtracted, large differences in the hybridisation signal for individual spots were apparent, which can be identified by eye. Prior to probe labelling, subtracted cDNA samples were digested with Rsal and run through Qiagen Qiaquick PCR purification columns to remove adapter sequences added during the PCR Select procedure. 25 ng cDNA w as labelled with 33P using a commercial kit following the manufacturer's instructions (Promega, Prime-a-gene kit), and unincorporated label was rem oved using BioRad Biospin-6 columns following adding 2.5ug yeast tRNA carrier,
Pre-hybridisation, hybridisation and washes were performed essentially according to the Research Genetics GeneFilters protocol, but supplem enting the hybridisation mixture with 10 ug of a cocktail of oligonucleotides complementary to the Clontech PCR Select nested PCR primers (equimolar mix of prim ers 1 and 2R and their reverse complements). Hybridized arrays were exposed to X-ray film or were exposed to a phosphorim ager (M olecular D ynamics, Storm) and clones showing gross differences in the hybridization signals with hypoxic compared to norm oxic cDNA probes were identified. This procedure was used to process all clones originally picked from the primary libraries and PCR amplified. The selected clones were grouped together onto a single array (referred to here as a secondary array), and vtere re-screened with cDNA probes which had not been subtracted, to allow a m ore quantitative though less sensitive, evaluation of the relative abundance of the genes in hypoxia vs. norm oxia.
In this case, probes were ds cDNA generated from the Clontech SM ART cDNA synthesis kit (labelled using the Prom ega Prime-a-gene kit) or w ere total RNA (labelled according to the Research Genetics GeneFilters protocol), and hybridisations were done according to the Research Genetics GeneFilters protocol.
H ybridization signals were measured using a phosphorim ager and were processed with ArrayVision (Im aging Research Inc) softw are using m ultiple beta-actin spots to norm alise the quantitation and individual spot background correction. At this stage, the inserts of clones showing consistent up- regulation in hypoxia were sequenced using the 2R primer.
The identity of the genes were determ ined using B LAST at the NCB I (NLM , NIH) against the non- redundant data base collection. W here significant m atches to human genes were not m ade, the hum an EST database was used, For both EST and non-EST hits, identifier numbers w ere also obtained from the UniGene database. The above strategy was used independently for libraries derived from macrophages and from cardiomyoblasts. B y screening a relatively large num ber of clones (several thousand per library), single genes were identified from m ultiple clones from any individual library. M ultiple clones covered either the same or different regions of the genes.
In the above manner, certain hypoxia-inducible genes were identified from clones only derived from the cardiom yoblast library. These genes are listed in Table 1. Certain hypoxia-inducible genes were identified from clones only derived from the macrophage libraries. These genes are listed in Table 2. Certain hypoxia-inducible genes were identified from clones derived from both m acrophage and m yoblast libraries, These genes are listed in Table 3.
It can be seen that Table 3 contains m any less genes than either Tables 1 and 2; demonstrating that these cell types have large differences in the genes induced by hypoxia. Importantly, the subtracted libraries for m acrophage and cardiom yoblast were constructed in parallel. Therefore, m ajor differences in the spectrum of genes isolated from these libraries are likely to be due to differences in the starting m aterial, rather than due to technical differences in the production of the libraries. Importantly, the genes contained in these tables were confirmed to be hypoxia-regulated in the relevant cell type(s) by the described two- stage array hybridisation screening process.
From Table 3 it is clear that although this subset of genes was found in subtracted libraries from both hypoxic macrophages and cardiomyoblasts, the fold-induction obtained between hypoxia and normoxia, for the different tissues differs widely. For the first 5 genes in this table, the hypoxia response is greater for m acrophages, w hereas for the last 2 genes it is greater for cardiom yoblasts.
To test whether genes isolated only in the macrophage-derived subtracted libraries are not responsive to hypoxia in cardiom yoblast, cardiom yoblast cDNA isolated from normoxic and hypoxic cells was hybridised to an array of macrophage-derived clones. These data are presented as a scatter plot, showing norm alised signal intensities in hypoxia versus norm oxia, with each dot representing a single gene on the array, This plot is presented in Figure 1 . A gene that is not affected by hypoxia will localise around the y=x line, running diagonally through the centre of the graph, From the figure, it can be seen that most genes lie in this region, even though all the genes were responsive to hypoxia in the m acrophage (Table 2), There is a subset of genes that lie beneath this region (x>y), representing induction of these genes by hypoxia in the cardiom yoblast.
Sequence data for the cDNA inserts of clones from our custom subtracted cDNA libraries is available. These are usually short fragments of 300-1000 bp. Some have been resequenced to obtain an accurate full insert sequence (see document "gene sequences/analysis").
Several of the genes presented in Tables 1 -3 encode hypothetical proteins of unknown function and others have no database matches with protein coding sequence. The work presented here provides some functional annotation for these genes, and potential applications for the treatment of disease. Certain genes, in particular the glycolytic enzymes and transporters, have been hypothesised previously as forming part of the generic hypoxia response. The data provided herein provide solid, validating data for these hypotheses. It w as surprising to note that cells from our cultures of hum an ventricle-derived cells, show ing a cardiomyoblast-like phenotype, do not support significant induction of the following genes: Lactate dehydrogenase A „ Enolase 1 , Phosphoglycerate kinase 1 , Triosephosphate isomerase 1 , These genes have been identified as being targets of the "ubiquitous" transcription factor HIF-1 alpha ("HIF-1 : mediator of physiological and pathophsiological responses to hypoxia" J.Appl.Physiol 88: 1474-1480 (2000)). Example lb: Preparation of custom array
To confirm the findings presented in Example l a, and to obtain more accurate and additional data, both the subtracted cDNA'library clones and the IM A GE clones identified from the Research Genetics Human GeneFilters have now been fabricated by the authors into an independently produced and verified gene array (referred to herein as the "custom gene array"), composed of PCR-amplified insert DNA . The methods used to produce this array are common in the art, but the key points are summarised below .
Clones from the subtracted cDNA library were PCR amplified as defined in Example l a. In m any cases, there were multiple cDNA clones corresponding to different regions of the same gene, and all these were represented on the custom gene array. IM AGE clones were obtained from the UK M RC HGM P Resource Centre (Hinxton, Cam bridge CB 10 1 SB , UK) and were re-isolated as individual colonies and sequenced to verify the correct identity of the clone. In the m ajority of cases, the same IM AGE clone identified from the Research Genetics Hum an GeneFilters was selected, but in some instances these clones were not available and alternatives were selected, corresponding to the same gene. Additional genes, with well-defined roles in various disease processes relevant to hypoxia, were also represented on the array, as derived from IM AGE clones. It is well established in the literature that genes with similar functions are often co-regulated at the mRNA level, as determined by microarray data clustering methods (Iyer VR et al, Science, 1999 283 (5398):83-7 ; Eisen M B et al Proc Natl Acad Sci U S A, 1998 95(25):14863 -8). This allow s associations to be m ade between genes of unknown function (as present in the current specification) to genes of well defined function, in order to add significance to the former.
Norm alisation is a key issue in array analysis. The custom gene array is a single colour type array, and contains a selection of additional IM AGE clones corresponding to genes which w ere empirically determined not to be affected by hypoxia and which are highly expressed in a wide range of hum an tissues and cell types. During data analysis, spot intensities were divided by the mean of all the reference genes shown below , each of which was present in quadruplicate on each array.
Gene IMA GE clone Ace.
FLJ1 1 102 fis clone PLACE 1005646 AA464704 matrix Gla protein AA 155913 guanine nucleotide binding protein alpha stimulating 1 R43581
DKFZp434A 1319 W 74725 cDNA FLJ23280 fis clone HEP07194 AA669443 beta actin (in house clone) EFl a-like protein AI817566 ribosomal protein L37a W91881
IM A GE clone plasm id miniprep DNA was prepared and PCR amplified with flanking vector primers of the sequences GTTTTCCCAGTCACGA CGTTG and TGAGCGGATAACAATTTCACACAG. This was then purified and concentrated by ethanol precipitation, and the presence of a single band and DNA concentration were determined by agarose gel electrophoresis and by digital imaging methods,
Purified PCR product corresponding to all the clones (IMAGE and non-IMAGE) were normalised to 0,5 mg/ ml by dilution, Arrays were fabricated onto Hybond N+ (Amersham) membranes using a BioRobotics TAS arrayer (Biorobotics, Cambridge CB37LW , UK) with a 500 micron pin tool, Using 384-well source plates and a 2x2 arraying format this array was relatively low density, thereby eliminating problems of spot-to-spot signal bleed. Also the large pin size and high source plate DNA concentration improves the sensitivity of detection. Post-arraying denaturation/ neutralisation was essentially as described by Bertucci F et al, 1999 (Oncogene 18: 3905-3912).
Total RNA was extracted from cells using RNeasy (Qiagen) and 7 microgram s RNA was labelled with 100 microCi 33P dCTP using 2 micrograms poly dT (10-20 mer) as primer in a reverse transcription reaction. First strand RNA was then degraded under alkaline contitions, and this was then neutralised with Tris HCl pH 8.0, and the labelled cDNA was purified using BioRad BioSpin-6 chromatography columns. Pre-hybridisation was performed in 4 ml Research Genetics MicroHyb solution supplemented with lOmicrograms poly dA (10-20 mer) and 10 micrograms Cot-1 DNA, at 45 degrees for 2-3 hours. The cDNA was then denatured by heating and added to the pre-hybridisation, which was continued for 18- 20hr. Washing steps were done as follows: 2xSSC/ 1 % SDS 2x20min at 50 degrees and 0.5xSSC/ 1 % SDS lOmin at 55 degrees. Arrays were exposed to Amersham Low Energy phosphor screens for 24hr and scanned using a phosphorimager at 50 micron resolution. Image analysis was done using ArrayVision software (Imaging Research Inc). Tab delimited data files were exported and a full analysis performed using GeneSpring software (Silicon Genetics).
Using the described methodology a dynamic range of detection of 4 logs and a sensitivity of at least 1 / 50,000 is obtained, as determined by spike doping titration experiments. Having several technical differences compared to the Research Genetics Human GeneFilters as used in the initial filing, data from the custom gene array is expected to be quantitatively different.
Example lc: Hypoxia regulation of gene expression in macrophages by exposing cells to hypoxia +/- additional signal amplification.
The transcription factor HIF- lα, is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia. This protein is considered a master regulator of oxygen hom eostasis (see, for example, Semenza, (1998) Curr. Op, Genetics and Dev. 8:588-594). Although HIF- la is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPASl) or HIF-2a, which shares 48% sequence identity with HIF-la (Tian H, et al. Genes Dev. 1997 11 :72-82.). Evidence suggests that EPAS 1 is especially important in mediating the hypoxia-response in certain cell types, and it is clearly detectable in human macrophages, suggesting a role in this cell type (Griffiths et al., 2000, Gene Ther„ 7(3):255-62).
As supporting evidence for the hypoxic regulation of the genes contained within this specification, adenoviral vectors were used to overexpress HIF-l a and EPAS l in primary human macrophages prior to exposure to hypoxia, in order to amplify the response. Because the role of these transcription factors as mediators of the hypoxia response is very well established, any further increases in the inducibility of specific genes resulting from this approach represents credible supporting evidence that those genes are responsive to hypoxia. A commercially available system was used herein to produce adenoviral particles involving the adenoviral transfer vector AdApt, the adenoviral genome plasmid AdEasy and the packaging cell line Per-c6 (Crucell, Leiden, The Netherlands). The standard manufacturer's instructions were followed. Three derivatives of the AdApt transfer vector have been prepared, named AdApt ires-GFP, AdApt HIF- la-ires-GFP and AdApt EPAS l -ires-GFP. In these vectors, for convenience, AdApt was modified such that inserted genes (i.e. HIF-l a or EPAS l) expressed from the powerful cytomegalovirus (CMV) promoter were linked to the green fluorescent protein (gfp) marker, by virtue of an internal ribosome entry site (ires). Therefore presence of green fluorescence provides a convenient indicator of viral expression of HIF-l a or EPAS l in transduced mammalian cells. The control vector AdApt ires-GFP was used to allow discrimination between effects of the inserted genes (i.e. HIF-la or EPASl) to that of potential non-specific effects of adenoviral transduction or GFP expression. Standard subcloning methods we e used to construct the adenoviral constructs as described in detail elsewhere (see co-pending, co- owned International patent application PCT/GB01/00758; Example 2).
The adenoviral transfer vectors AdApt HIF-la-ires-GFP and AdApt EPAS l -ires-GFP, were verified prior to production of adenoviral particles, for their ability to drive expression of functionally active HIF-la or EPASl protein from the CMV promoter in mammalian cells. This was achieved by transient transfection luciferase-reporter assays as described (Boast K et al Hum Gene Ther. 1999 Sep 1 ;10:2197-208).
Using the aforementioned Introgene adenoviral system, caesium-banded, pure adenoviral particles were produced for each of the vectors AdApt ires-GFP, AdApt HIF-la-ires-GFP and AdApt EPAS l-ires-GFP. Following the Introgene manual, adenoviral preparations were quantitated by spectrophotometry, yielding values of viral particles (VP) per milliliter.
Primary human macrophages isolated as described above, were washed and resuspended in DMEM (Gibco, Paisley, UK) supplemented with 4% fetal bovine serum (Sigma). 5xl06 cells were plated into nine individual 10cm Primeria (Falcon) tissue culture dishes containing medium plus adenovirus as shown below (experimental design), to give a total volume of 10 ml per plate. Tw o doses of adenovirus were used; 5.3xl 08 viral particles / ml (low) and 1.6x l 09 viral particles / m l (high). These am ounts were chosen following a series of titration experiments. Following culture for 16 hr, during w hich the m acrophages adhere to the plate and are infected by the adenoviral particles, the medium was rem oved and replaced by IM D M medium (Gibco, Paisley, UK) supplemented with 2% hum an AB serum . A further 24 hr period of culture was allowed prior to experim entation, to allow gene expression from the transduced adenovirus. Gene transduction was verified by visually assessing gfp expression and expression of the viral HIF-la and EPASl genes was determined by real time quantitative RT-PCR using an AB I Prism 7700 TaqM an and CyberGreen protocol. For the high doses of virus, the total levels of HIF-l a or EPA S l mRNA present in the transduced cells were increased by 10-30 fold.
For experimentation with conditions of hypoxia, identical culture dishes were divided into two separate incubators: One at 37 degrees, 5% C02, 95% air (=Norm oxia; equivalent to 20% Oxygen) and the other at 37 degrees, 5 % C02, 94.9% Nitrogen, 0.1 % Oxygen (=Hypoxia). After 6 hours culture under these conditions, the dishes were removed from the incubator, placed on a chilled platform , washed in cold PB S and total RNA was extracted using RNeasy (Qiagen) following the manufacturer' s instructions.
Experim ental design
Condition Adenovirus Adenovirus Oxygen
(type) am ount (% )
(low=5.3> • 10s vp/ml high= 1.6x 109 vp/ml)
1 none none 20
2 AdApt ires-GFP low 20 3 AdApt ires-GFP high 20 4 AdApt ires-GFP low 0.1 5 AdApt ires-GFP high 0.1 6 AdApt HIF-l a-ires-GFP low 0.1 7 AdApt HIF-l a-ires-GFP high 0.1 AdApt EPA S l -ires-GFP low 0,1 AdApt EPA S l -ires-GFP high 0.1
RNA samples from the experimental conditions shown above were each hybridised to individual copies of the Custom gene array and processed as described earlier. To ensure reproducible data, this was repeated so each RNA sample was hybridised to 4 separate arrays. Therefore a total of 36 arrays were used for this experiment. Data analysis was done taking the mean signal of each spot from the four array replicates of each RNA sample. W hen displayed graphically, standard error of the mean is displayed as the error bar. Expression values were calculated so that they represent the fold-change ratio as compared to condition#l , i.e. untreated cells.
For genes shown in Table 4 it can be seen that in cells transduced by the control adenovirus AdApt ires- GFP there is a response to hypoxia (conditions 4,5) as compared to in normoxia (conditions 2,3). However this response is significantly greater when the natural hypoxia response is amplified by overexpression of HIF-l alpha from the adenovirus AdApt HIF-l a-ires-GFP (conditions 6,7). Furthermore, this effect is usually dependent on the amount of HIFlalpha overexpression (i.e. greater in condition 7 compared to 6), This same data is displayed graphically in Figure 2, It can be seen that these genes encode metallothionein proteins, One of these (Nucleotide Seq ID No. 84; Protein Seq ID No. 83) is a novel member of the matallothionein family. Several metallothionein genes are known in the art to be activated by hypoxia, supporting the usefulness of this data.
For genes shown in Table 5 and Figure 3 it can be seen that in cells transduced by the control adenovirus AdApt ires-GFP there is a response to hypoxia (conditions 4,5) as compared to in normoxia (conditions 2,3). However this response is significantly greater when the natural hypoxia response is amplified by overexpression of EPAS 1 from the adenovirus AdApt EPAS 1 -ires-GFP (conditions 8,9),
In the case of the protein encoded by Seq ID No. 24, results are available independently for two separate cDNA clones representing non-overlapping regions of the same full length gene.
In the case of the protein encoded by Seq ID No. 86 (EGL nine (C.elegans) homolog 3), additional evidence is described above in support of the function of this protein. Furthermore, real time quantitative RT-PCR analysis of this gene using an ABI Prism 7700 TaqM an and CyberGreen protocol, has been performed, to verify and more accurately quantitate the upregulation of EGL nine (C.elegans) homolog 3 in response to hypoxia and EPASl adenoviral overexpression. The main difference between the array- based and real time quantitative RT-PCR methodologies is that the latter is far more sensitive and therefore can detect expression in the off-state (here normoxia) for weakly expressed genes. This data has shown an induction ratio of 819-fold for EGL nine (C.elegans) homolog 3 in response to hypoxia with additional EPAS l expression, from RNA generated from an independent experiment. This data was normalised to beta actin.
Similarly another weakly-expressed EPAS l -induced gene,' Semaphorin 4b (Seq ID No. 91/92; see additional discussion above) has been determined using real time quantitative RT-PCR methodology, showing an actin-normalised induction ratio of 30.1 is found (data not shown). For the gene shown in Table 6 and Figure 4 it can be seen that in cells transduced by the control adenovirus AdApt ires-GFP, there is a negative response to hypoxia (conditions 4,5) as compared to in normoxia (conditions 2,3). However, this response is significantly greater when the natural hypoxia response is amplified by overexpression of HIF1 alpha or EPAS l (conditions 6,7,8,9).
Example 2: Differences in the hypoxia responses of resting and activated macrophages.
Macrophages accumulate at hypoxic areas in various disease states, including cancer, rheumatoid arthritis, atherosclerosis and wound healing, At these sites macrophages activation is liable to occur, such as in response to T-cell derived gamma interferon. For instance, in atherosclerotic plaques there is an accumulation of both T-cells and macrophages, and these are known to interact with one another (reviewed in Lusis AJ, Atherosclerosis, Nature, 2000 Sep 14;407(6801):233-41).
It is well established that the macrophage has a significant role in the pathology of the above diseases involving hypoxia, and that most functions of the macrophage (including inflammatory functions) are greatly increased following activation. Therefore any therapeutic strategy aimed at the hypoxic macrophage, needs to also consider the effects of macrophage activation and possible cross talk between the responses to macrophage activation and hypoxia,
2.1: Research Genetics Human GeneFilters
This work was carried out using Research Genetics Human GeneFilters, which contain DNA derived from clones of the IMAGE cDNA collection, representing genes of varying degrees of characterisation. A series of 6 arrays of human genes were used (GeneFilters GF200-205), potentially covering a total of 31 ,104 genes. Generally, single genes are represented only once in these arrays. However, sometimes IMAGE clones initially thought to represent separate genes, upon re-analysis were found to be different regions of the same gene. Here we have presented data for all clones individually, though they possess the same UniGene ID and gene name. An example is Hypothetical protein FLJ20037.
The methodology for Research Genetics arrays is similar in principle to that described for the array screening of clones from subtracted libraries. There are several attributes to this method: Relatively small amounts of RNA can be labelled to make cDNA probes, in a single step reaction, and probes are labelled with the same chemical group (33P), so there are no errors introduced as a result of using different dyes, which may differ in stability etc. Using a Phosphorimager allows detection over a wide range of intensities (over 4 logs). Overall it is interesting to note a recent study, which has favourably re-evaluated the performance of the nylon based array, as compared with the glass-based microarray method (Bertucci F et al, Hum Mol Genet 8:1715-1722 (1999)). Experiments were done essentially as described in the Research Genetics GeneFilters protocol. Duplicate copies of each array from the same production batch, were used and hybridised in parallel with labelled RNA isolated from norm oxic and hypoxic prim ary hum an m acrophages. Hybridised arrays were scanned twice using a M olecular D ynamics Storm phosphorimager, and both im ages were analysed to ensure reproducibility. Furtherm ore, the experiments were repeated using the same RNA samples, but with different array lot numbers, again to ensure reproducibility.
Analysis was performed using Research Genetics Pathways software, with norm alisation using the 'all data points' option. Analyses w ere output as spreadsheets and filtered to remove data points where the signal intensity w as less than 4-fold above the general background for the experimental condition with the higher signal (hypoxia or norm oxia depending on whether hypoxia causes induction or repression). Sometimes expression in the lower state was not significantly above background, and the ratio will therefore be underestimated. R atios were calculated by normalised signal intensity in hypoxia divided by norm oxia. Changes were verified visually from the original array im ages.
In this manner, comparisons were made betw een normoxia and hypoxia in resting m acrophages. The whole procedure was then repeated for activated m acrophages, to investigate possible differences in the response to hypoxia. It is possible that potential differences for certain genes could be correlated w ith changes in expression resulting from activation, prior to challenge w ith hypoxia, To explore this possibility, comparisons were made between resting and activated macrophages, both in normoxia. Since some of the genes we have identified as being activated by hypoxia have very low hybridisation signals in normoxia (for both resting and activated macrophages), this comparison w as not possible.
W e have found various patterns of gene expression changes occurring in response to hypoxia, related to the activation state of m acrophages, which are presented below . Such a range of responses, specific to various subsets of genes, was not expected, and contradicts a view that the hypoxia response is a largely a generic mechanism . Table 7 shows genes that are induced by hypoxia to a similar degree in resting and activated m acrophages.
Table 8 shows genes that are induced by hypoxia to a greater degree in resting m acrophages, as compared to activated macrophages. These data are presented illustratively in Figure 5.
Data from Table 8/Figure 5 reveals several unexpected observations. A) From the final column it can be seen that m acrophage activation in the absence of hypoxia, causes induction of many of these genes. This suggests that the signalling pathways resulting from activation and hypoxia might converge to a single transcriptional regulator, causing macrophage activation to pre-empt the response to subsequent hypoxia. This is exemplified m ost strikingly for Interleukin 8, which is dramatically induced in response to macrophage activation, but shows no additional response to hypoxia.
B) Genes in row s 11 , 13 and 14 have no response to hypoxia following macrophage activation, though there is not a preceding large increase in expression in response to macrophage activation alone. This suggests that in the activated macrophage, the necessary signalling pathway or transcriptional regulator is not functional.
C) Although Table 8 was produced electronically, without selecting genes based on their names, it can be seen that genes encoding proteins of the metallothionein family feature strongly.
Table 9 shows genes which are induced by hypoxia to a greater degree in activated macrophages, compared to resting m acrophages. These data are presented illustratively in Figure 6,
In Table 7, there are several genes for which hypoxia/ normoxia ratios were only obtained for activated macrophages, such as Cox-2 (see row 47), For these genes, macrophage activation usually increases expression of the gene to detectable levels, thus allowing the study of subsequent changes in response to hypoxia. It is likely that these genes are not significantly expressed in resting macrophages irrespective of hypoxia, and therefore the hypoxia response is probably specific to activated macrophages,
Certain genes respond to hypoxia by decreasing mRNA expression (repression), and these genes therefore have hypoxia/normoxia ratios of < 1.0. This phenomenon is known in the field of hypoxia, although the mechanism is obscure. Data is presented in tables 7-9, which unexpectedly shows that this hypoxia- induced repression for specific genes is not a generic process, but is dependent on the cellular context. In Table 10/ Figure 7, genes are presented that are hypoxia-repressed to a greater degree in activated (column 7) compared with resting (column 8) macrophages. Prior to any hypoxic challenge, these gene are induced to varying degrees, in response to macrophage activation (column 9), suggesting a shared mechanism for these separate responses. From Table 10, genes in rows 1-6 show that macrophage activation is necessary to obtain any response to hypoxia. In resting m acrophages, these genes are not responsive to hypoxia at all.
Strikingly, Table 10/ Figure 7 shows that seven separate genes encoding chemokine proteins (Monocyte chemotactic protein 1 , Macrophage inflammatory protein lb, Monocyte chemotactic protein 3 and Small inducible cytokine A3, Monocyte chemotactic protein 2, Macrophage inflammatory protein 2a and Macrophage inflammatory protein 2 precursor) are more strongly repressed in activated macrophages as compared to resting macrophages. These genes are also among the most inducible in response to activation alone, in normoxia (column 9). These findings are of potential utility in view of the great significance of chemokines to inflammatory disease. For example, macrophage chemotactic factor 1 (Table 10, row 19) is key to the pathological role of the macrophage in atherosclerosis ("Chemokines and atherosclerosis" Reape TJ and Groot PHE, Atherosclerosis 147: 213-225, 1999).
Genes in rows 20-30 of Table 10, were not detectably expressed in resting macrophages, irrespective of hypoxia. Table 11 shows other genes that were down-regulated in response to hypoxia in macrophages. Example 3: Tissue-specific hypoxia regulation of gene expression by an analysis of a series of prim ary human cell cultures.
Equivalent cultures of non-immortalised, non-transformed primary human cells of 10 distinct types, were cultured in either normoxia or were exposed to hypoxia for 6 hr and 18 hr, and gene expression changes were determined. To the inventors' knowledge, this is the first time that such a study has been reported, Moreover, unlike the vast majority of information in the public domain relating to genes responsive to hypoxia, all of these cells were human and were cultured without any modifications following isolation from the human donors. By using primary cells rather than cell lines or immortalised cultures, the findings of this work more accurately represents the situation in the human body.
Most cell types were obtained from Clonetics (distributed by BioW hittaker, W alkersville, MD) and cultured according to the manufacturer's recommendations, unless where otherwise shown, #l :adipocyte
(Clonetics CC-2568; derived from subcutaneous adult adipose tissue), #2:cardiomyocyte (Clonetics CC-
2582; derived from fetal tissue; prior to experimentation cultured in minimal medium : DMEM , 4% Horse serum), #3:endothelial (TCS CellW orks ZHC-2101 human umbilical vein endothelial cells), #4:fibroblast
(Clonetics CC-2511 dermal fibroblasts derived from adult tissue), #5:hepatocyte (Clonetics CC-2591 , derived from adult tissue), #6:macrophage (derived from human blood as described elsewhere in the specification), #7:mammary epithelial (Clonetics CC-2551 ; derived from adult tissue), #8:monocyte
(derived from human blood as described elsewhere in the specification but without the 7 day differentiation culture period), #9:neuroblastoma (neuroblastoma-derived cell line SH-SY5Y), #10:renal epithelial (Clonetics CC-2556; derived from fetal tissue), #11 skeletal muscle myocyte (Clonetics CC- 2561 ; derived from adult tissue). A non-primary cell type (#9) was used to represent neurons, since primary human neurons are difficult to source. Therefore a total of 11 cell types are compared. It should be noted that RNA from hepatocytes at the 16hr timepoint of hypoxia was not available for this work.
Genes which were induced or repressed preferentially in particular cell tyρe(s) were identified by hybridisation of the RNA samples to the custom gene array, as described in Examples lb and lc. Each RNA sample was hybridised to duplicate or triplicate arrays, to ensure reproducible data, and was analysed using GeneSpring software. Data from replicate arrays were merged during analysis to generate mean values. Data normalisation was achieved per-array using the aforementioned list of control genes, such that differences in RNA labelling or hybridisation due to experimental variation were corrected by referencing each gene to the mean value of the reference genes on the same array. Also, for each gene, expression values were obtained which represent the value in each experimental condition (e.g. macrophages 6hr hypoxia) as compared to the median of value of that gene throughout the full range of experimental conditions (i.e. from all cell types). This transformation does not alter the relative values of any gene between the different experimental conditions, and is done since these is no obvious single reference experimental condition to create ratio values. This is common in microarray data analysis.
Table 12 shows the full dataset of this analysis. From this it can be seen that certain genes respond to hypoxia differently, depending on the particular cell type. This information is valuable in identifying biological targets for the development of therapeutic and diagnostic products. Not only does it indicate a particularly significant role for these genes in the specific cell type implicated in a disease, but it also identifies that any therapeutic product is less likely to produce problematic toxicological effects. Data shown in Table 12 and the derived figures, are reproducible, and are an accurate determination of mRNA expression levels. This m ay be confirmed by independent means, such as quantitative real time RT-PCR.
Certain genes from Table 12 will be presented for illustration. Genes with a greater response in monocytes or macrophages
Since monocytes and macrophages are similar cell types, the latter derived from the former, they will be analysed together,
Expression profiles of 11 genes showing hypoxia-induced changes in gene expression which are most pronounced in monocytes or macrophages are shown in Figures 8-18, These genes correspond to: Seq ID :339/340 CYP1 (cytochrome P450, subfamily XXVIIB)
Seq ID:357/358 interleukin 1 receptor antagonist
Seq ID :375/376 Regulator of G-protein signalling 1
Seq ID :389/390 GM2 ganglioside activator protein
Seq ID :405/406 Alpha-2-macroglobulin Seq ID :475/476 Ecotropic viral integration site 2A =
Seq ID :433/434 high affinity immunoglobulin epsilon receptor beta (CFFM4)
Seq ID:431/432 Pleckstrin
Seq ID :469/470 cytokine effector of inflammatory response SCYA3L
Seq ID:79/80 Novel PI-3-kinase adapter Seq ID :21/22 Hypothetical protein PRO0823
It will be appreciated that the majority of these genes have a known biological function in immunity/ inflammation, consistent with the known function of the monocyte/ macrophage. Further to this knowledge, this data identifies that in hypoxic disease sites where monocyte/ macrophages make up a significant proportion of the cell types, such as in rheumatoid arthritis synovial membranes, that these genes are possible therapeutic targets.
Ecotropic viral integration site 2A (Seq ID:475/476)
For example, the gene illustrated in Figure 8, Ecotropic viral integration site 2A (Seq ID :475/476) is induced in hypoxic monocytes to a level over 25 times higher than the median expression level of this gene throughout the other cell types. This gene, of unknown function, is located on Chromosome 17ql 1.2 close to genes with immune functions. Presented elsewhere in this specification is data showing that expression of Ecotropic viral integration site 2A is downregulated in response to the inflammatory cytokine interferon gamm a. These novel data provide evidence that Ecotropic viral integration site 2A is a novel target for inflammatory conditions involving hypoxia and monocytes.
Novel PI-3-kinase adapter Seq ID:79/80 Clone plE9 (EST accession R62339).
Another example, in Figure 9a, is Seq ID :79/80 (EST accession R62339). It is seen that in hypoxic macrophages, this gene is expressed at 6-fold higher levels than the median expression level of this gene throughout the other cell types. Therefore, the levels of the encoded protein in hypoxic monocytes/ macrophages, as found at various disease sites, are likely to be higher than in other cell types not involved in the disease process or present at the site of disease. This illuminates a novel utility of this gene as a target for the development of therapeutic products for diseases involving monocytes/ macrophages and hypoxia,
The data that led to the generation of this Figure are as follows:
Cell type Oxygen Normalised expression (clone plE9 / SeqlD:79/80) adipocyte normoxia 1 ,54 adipocyte hypoxia 6hr 0.89 adipocyte hypoxia 18hr 1.48 cardiomyocyte normoxia 1.18 cardiomyocyte hypoxia 6hr 1.80 cardiomyocyte hypoxia 18hr 1.53 endothelial normoxia 0.68 endothelial hypoxia 6hr 0.82 endothelial hypoxia 18hr 0.60 fibroblast normoxia 0.60 fibroblast hypoxia 6hr 0.64 fibroblast hypoxia 18hr 0.73 hepatocyte normoxia 0.92 hepatocyte hypoxia 6hr 1.62 macrophage normoxia 4.20 macrophage hypoxia 6hr 3.97 macrophage hypoxia 18hr 6.19 ammary epithelial normoxia 0.25 mammary epithelial hypoxia 6hr 0.42 mamm ary epithelial hypoxia 18hr 0.18 m onocyte norm oxia 2.33 m onocyte hypoxia 6hr 3.63 m onocyte hypoxia 18hr 5.01 neuroblastom a norm oxia 0.93 neuroblastom a hypoxia 6hr 0.80 neuroblastoma hypoxia 18hr 0.85 renal epithelial norm oxia 0.57 renal epithelial hypoxia 6hr 0,61 renal epithelial hypoxia 18hr 0.61 skeletal m yocyte normoxia 1.58 skeletal myocyte hypoxia 6hr 1.37 skeletal m yocyte hypoxia 18hr 1.17
To substantiate the array-based data, the same RNA samples were examined by real time quantitative RT- PCR . The advantages of this m ethod are that it is m ore sensitive and because two gene-specific primers are used, the data will be more specific to the gene in question.
RNA from the above samples (except for the hepatocyte RNA w hich w as unavailable) was Dnase I- treated prior to reverse transcription to rem ove possible contaminating genomic DNA and w as reverse transcribed using an oligo dT (ι5) primer and Superscript II reverse transcriptase. These samples were used as template for PCR reactions using primers specific to EST accession R62339 or to beta-actin. Primer sequences were as follows:
Novel PlX-kinase adapter Seq ID:79/80 Clone pIE9 (EST accession R62339). Forward Primer 5' GCC CTT A GT TTT TCA CTT CTT CGT 3 ' Reverse Primer 5' CCT TAA GAT CCA TTC TCA TTG CTG AT 3 ' Beta Actin
Forward Primer 5' GCC CTG AGG CAC TCT TCC A 3 Reverse Primer 5' GCG GAT GTC CAC GTC ACA 3'
All RT-PCR reactions were performed using an AB I Prism 7700 Sequence Detector system . For each Q- PCR run, a m aster mix w as prepared with 2x SYBR Green I m aster mix (Applied B iosystem s) and primers at 5μM . Two microlitres of respective diluted cDNA w ere added to PCR m aster mixture, amounting to 25μL. The thermal cycling conditions comprised 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles at 95°C for 15 seconds, and 60°C for 1 minute. PCR reactions were set up in 96 well form at with duplicate amplifications for each data point including 8 serial cDNA dilutions (0.2, 0.1 , 0.05, 0.025, 0.01 , 0,005, 0,001 and 0.0001) of macrophage treated with 18 hours hypoxia to compose a standard curve, a no template control, no amplification control lacking reverse transcriptase, and each cDNA sample at a dilution value of 0.1. The experiment for the novel PI3K adapter was carried out in triplicate for reproducibility which were later determined by linear regression analysis. Data was analysed with necessary adjustm ent of the default baseline and threshold line using ABI Prism 7700 software. The C( value, an important raw data for each sample, was calculated as the cycle number at which the ΔRn crosses the baseline. For each run, a standard curve was constructed by plotting a graph with mean Ct values from 8 data points from standard sample against log input of the corresponding dilution values with a best fit trend line. From the trend line, the formula 'y=mx+c' w as created according to the y- intercept and slope of standard curve which then were used for calculating the log input am ount of the experimental cDNA samples, as related to the calibration sample. Data for the Novel PI-3-kinase adapter was normalized to that of beta-actin to correct for potential differences in efficiency of cDNA synthesis betw een the RNA samples. From the TaqM an data the specificity to m onocytes and m acrophage found from the array data is confirmed and found to be even m ore pronounced (see Figure 9b). The data presented in the Figure are listed below . In'the data listed below , the norm alized expression values are multiplied by 1000 for clarity.
Cell type Oxygen Norm alised expression
(clone pl E9 / SeqID :79/80) adipocyte norm oxia 0.050 adipocyte hypoxia 6hr 0.007 adipocyte hypoxia 18hr 0.015 cardiom yocyte normoxia 0.163 cardiom yocyte hypoxia 6hr 0.037 cardiomyocyte hypoxia 18hr 0.222 endothelial norm oxia 3.093 endothelial hypoxia 6hr 0.059 fibroblast normoxia 0.527 fibroblast hypoxia 6hr 0.043 fibroblast hypoxia 18hr 0.037 m acrophage norm oxia 404.593 macrophage hypoxia 6hr 503.026 m acrophage hypoxia 18hr 1 162.056 m am mary epithelial norm oxia 0.026 mammary epithelial hypoxia 6hr 0.068 m ammary epithelial hypoxia 18hr 0.112 m onocyte normoxia 565.471 m onocyte hypoxia 6hr 657.465 monocyte hypoxia 18hr 979.048 neuroblastoma norm oxia 8.482 neuroblastoma hypoxia 6hr 7.104 neuroblastom a , hypoxia 18hr 4,707 renal epithelial norm oxia 17.898 renal epithelial hypoxia 6hr 9.831 renal epithelial hypoxia 18hr 10.929 skeletal m yocyte normoxia 0.930 skeletal m yocyte hypoxia 6hr 0.638 skeletal myocyte hypoxia 18hr 1.627 There are several technical reasons w hy the results from the array-based data might be m ore pronounced in the Taqman results - the lower sensitivity of the array-based method means that genes which are not expressed will be detected as a background signal. Also the array method is m ore likely to suffer from cross-hybridisation between similar genes. The TaqM an data illustrates dramatically the concept that the hypoxia response is not just a generic response found in all cell types, relating to generic cell processes such as m etabolism ,
Database searches for gene sequences showing identity with IM AGE clone acc:R62339 reveal that there are no m atching hum an sequences of any type other than ESTs. This includes full length cD NAs, truncated cDNAs, gene sequences from chrom osom al data or hypothetical protein gene sequences. Therefore the hum an gene represented by IM A GE clone acc:R62339 is a novel human gene.
Although this hum an EST is unannotated, by comparison w ith m ouse sequence data (ace AF293806), it appears likely to encode a novel human Phosphoinositol 3-kinase (PI3-kinase) adapter m olecule, homologous to the recently described mouse gene, B CAP. This class of molecule, involved in intracellular signalling, have been shown to have utility as a drug target (see Stein RC et al, "PI3-kinase inhibition: a target for drug developm ent" Mol Med Today. 2000 Sep;6(9):347-57). PI3-kinases are key to many cellular processes relevant to human disease, including proliferation, apoptosis and inflam mation. The data presented for the gene encoded by Seq ID :79/80 provides evidence that the encoded protein is a novel drug target in hum ans, specifically targeting m onocyte/ macrophages at hypoxic disease sites.
In the publication relating to murine B CAP, the protein is identified as an adapter molecule connecting the non-receptor protein tyrosine kinase Syk to the p85 subunit of PI3-kinase, and therefore to the pivotal signalling pathw ays centred around PI3-kinase (Okada T et al "B CAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation." Immunity. 2000 13:817-27). Although, in this report, Syk is acting as the intracellular signalling component of the B cell antigen receptor, which is present exclusively on B -cells, Syk has been shown to initiate intracellular signalling from other cell surface receptors which are expressed on macrophages, including the Fc gamm a receptor, the chemokine receptor CCR5 and m acrophage-expressed CD 8 (Darby C et al "Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein" . J Immunol 1994 152:5429-37) (Kedzierska K et al "Fcgamm aR-mediated phagocytosis by hum an m acrophages involves Hck, Syk, and Pyk2 and is augmented by GM -CSF." J Leukoc Biol 2001 Aug;70(2):322-8.), (Ganju RK et al "Beta- chem okine receptor CCR5 signals through SHP1 , SHP2, and Syk." J Biol Chem . 2000 275 : 17263-8.), (Lin TJ et al "Activation of macrophage CD 8 : pharmacological studies of TNF and IL-1 beta production." J Immunol. 2000 164:1783-92.). Indeed, syk has been validated as target in m acrophages to inhibit inflam m atory activities of this cell type (Stenton GR et al "Aerosolized S yk antisense suppresses Syk expression, mediator release from macrophages, and pulmonary inflammation." J Immunol. 2000 Apr l ;164(7):3790-7.).
Additional to the finding that the probable human orthologue of the adapter molecule B CAP is preferentially hypoxia-induced in hum an m onocytes/ m acrophages, we also find from data generated by the custom array, that the protein acting im mediately upstream of B CAP (i.e. Syk) is also regulated by hypoxia in this novel cell type specific m anner, greatly increasing the biological significance of the original finding (see Figure 9c). The data used to generate this Figure are presented below for clarity. Cell type Oxygen Norm alised expression
(of syk) adipocyte normoxia 2,6573591 adipocyte hypoxia 6hr 1.499927 adipocyte hypoxia 18hr 1 ,1 115488 cardiomyocyte normoxia 0,8357341 cardiomyocyte hypoxia 6hr 2.161058 cardiom yocyte hypoxia 18hr 0.908801 14 endothelial normoxia 0.60265505 endothelial hypoxia 6hr 0.56874704 endothelial hypoxia 1 8hr 0.43321633 fibroblast normoxia 0.8542026 fibroblast hypoxia 6hr 0.7657573 fibroblast hypoxia 18hr 0.784982 hepatocyte normoxia 0.5238476 hepatocyte hypoxia 6hr 0,8465495 m acrophage normoxia 4.272981 m acrophage hypoxia 6hr 6.144931 macrophage hypoxia 18hr 10.278416 mammary epithelial normoxia 1.1023632 m am mary epithelial hypoxia 6hr 2.7382789 mammary epithelial hypoxia 18hr 0.7985004 monocyte normoxia 6.052118 m onocyte hypoxia 6hr 8.6809225 m onocyte hypoxia 18hr 1 1.58468 neuroblastoma normoxia 1.0230793 neuroblastoma hypoxia 6hr 1.089154 neuroblastoma hypoxia 18hr 0.7689335 renal epithelial norm oxia 0.88565326 renal epithelial hypoxia 6hr 1.2609364 renal epithelial hypoxia 18hr 0,6242461 skeletal m yocyte normoxia 1 ,3959162 skeletal m yocyte hypoxia 6hr 0,91255134 skeletal myocyte hypoxia 18hr 0.64795935
In summary, we have shown here that a novel hum an gene encoding a predicted signalling protein relevant to human disease is activated by hypoxia, specifically in monocytes and macrophages. This data is validated by non-array based means. Furthermore, we identify the protein immediately upstream of this signalling system as being co-regulated in this manner too. Therefore the human PI3-kinase adapter encoded by IMAGE clone ace: R62339 and the non-receptor tyrosine kinase Syk are both identified here for the first time as therapeutic targets for diseases involving hypoxic macrophages, including Rheumatoid arthritis, chronic occlusive pulmonary disease, atherosclerosis and cancer. Because both genes are preferentially expressed in hypoxic macrophages, toxicity effects of therapeutic products directed at the encoded proteins are likely to be limited.
As discussed in detail above, fragments and functional equivalents of the PI-3-kinase adapter protein represented in Seq ID :79/80 and other equivalent proteins are included within the present invention, in addition to ligands that bind specifically to these proteins. Furthermore, the invention also embraces purified and isolated nucleic acid molecules encoding these proteins, fragments and functional equivalents, vectors containing such nucleic acid molecules and host cells transformed with these vectors.
Regulator of G-protein signalling 1 (Seq 10 :375/376)
Another intracellular signalling protein, Regulator of G-protein signalling 1 (RGS 1 ; Seq ID:375/376), in shown in Figure 10. Here the expression levels in the hypoxic monocyte is 30-fold higher than the median expression level of this gene throughout the other cell types. The function of this protein is to negatively regulate G protein signalling pathways, and inhibit chemokine-induced cell migration of immune cells (M oratz C et al J Immunol 2000 164:1829-38 and Denecke B et al J Biol Chem. 1999 274:26860-8.).
Our data suggests that this gene is preferentially expressed in macrophages, consistent with the findings of Denecke B et al (J Biol Chem. 1999 274:26860-8.), Our novel finding that expression is even further enhanced by hypoxia illuminates a mechanism by which cell migration is inhibited in hypoxia, leading to an accumulation of these cells at pathological sites of hypoxia. This mechanism is novel and distinct to other mechanisms proposed in the art to explain this key aspect of hypoxia and inflammation (for example: Grimshaw MJ et al "Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation--a potential mechanism ." Eur J Immunol. 2001 31 :480-9).
Furthermore, Figure 10 shows that Regulator of G-protein signalling 1 is upregulated during differentiation of monocytes to macrophages, with significance to changes in cell motility, This discovery therefore provides that inhibitors of RGS 1 have utility in increasing the motility of macrophages that are used for cell-based therapies. Accordingly, one embodiment of this aspect of the invention provides for the use of an inhibitor of RGS 1 in therapy, by increasing the motility of macrophage cells.
GM2 ganglioside activator protein
The gene shown in Figure 11, GM2 ganglioside activator protein, was originally characterised as a lysosomal co-factor required for degradation of gangliosides. It has been proposed to have alternative roles as a secreted protein, and can bind and inhibit the actions of the inflammatory mediator, platelet activating factor (Rigat B et al Biochem Biophys Res Commun. 1999 258:256-9.).
Our novel finding, presented in Figure 11 , shows that GM 2 ganglioside activator protein is induced by hypoxia, preferentially in macrophages, suggesting an influence on the inflammatory functions of the macrophage in hypoxia.
In Figures 15-18, genes are shown which are expressed preferentially in the monocyte/ macrophage, but which are decreased in expression in response to hypoxia. Being expressed at highest levels in the monocyte/ macrophage, these genes are more likely to be significant to the biological functions of this cell type. Interleukin 1 receptor antagonist (Seq ID :357/358)
In Figure 15, the gene interleukin 1 receptor antagonist (Seq ID :357/358) is seen to be down-regulated by hypoxia in the macrophage. Since the function of the encoded protein is anti-inflammatory, then down- regulation of this gene would be expected to have a pro-inflammatory effect. Therefore, corrective expression of the gene, would be expected to produce therapeutic effects in inflammatory disorders involving macrophages and hypoxia, such as Rheumatoid Arthritis (Hollander AP et al, Arthritis Rheum. 2001 44:1540-4). This correlates with effects seen from the application the drug Anakrina / Kineret™ developed by Amgen. This supports the applicability of the genes disclosed herein as novel targets for therapeutic products.
The example of gene interleukin 1 receptor antagonist also provides good exemplification of the concept that different cell types respond to hypoxia differently. Here, not only are there quantitative differences, but also qualitative differences in that this gene is -/øwfl-regulated by hypoxia in macrophages, but up- regulated by hypoxia in several other cell types, such as renal epithelial cells (see Figure 15), Such findings are not documented in the art.
The dataset of Table 12 also contains genes which are induced preferentially in monocyte/ macrophages and also in some but not all other cell types tested, Several of these genes are present as multiple clones on the gene array, giving separate data, therefore adding extra confidence to the conclusions. These genes, presented in Figures 19-28 correspond to:
SeqID :313/314 adipophilin
SeqID:163/164 Hypothetical protein FLJ13511 SeqID :267/268 Osteopontin
SeqID :17/18 Hematopoietic Zinc finger protein
SeqID :137/138 CYP 1B 1
SeqID:325/326 CYP1B 1 It will also be seen that in the case of CYP 1B 1 (clones pi FI 6 and plE3) the hypoxia response in monocytes / macrophages is qualitatively different to the other cell types tested, in that the gene is upregulated rather than down-regulated in response to hypoxia.
Genes with a greater response in endothelial cells The dataset of Table 12 also contains genes which are induced preferentially in endothelial cells, a cell type key to the process of angiogenesis, in response to hypoxia. These genes are as follows, and are presented in Figures 29-31 :
SeqID :205/206 Hypothetical protein FLJ22690 SeqID :65/66 cDNA DKFZp586E1624 SeqID:197/198 EST
Genes with a greater response in hepatocytes
The dataset of Table 12 also contains genes which are induced preferentially in hepatocytes, in response to hypoxia. These genes are presented in Figures 32a and 33-38. It is noted that most of these genes, including hqp0376, encode proteins of the metallotheionein family, Furthermore, close inspection of these data reveals that the fold induction in hypoxia compared to normoxia for monocyte/ macrophages are very high, though the absolute levels of expression are below that of hepatocytes.
SeqID:85/86 EGL nine (C.elegans) homolog 3
SeqID:83/84 Novel Metallothionein
SeqID :337/338 Hypothetical protein hqp0376 (a metallotheionein) SeqID :265/266 M etallothionein 2A
SeqID:243/244 M etallothionein 1G
SeqID:141/142 Hepcidin antimicrobial peptide
SeqID:239/240 Metallothionein IH
EGL nine (C.elegans) homolog 3 As described above, it has been discovered that a polypeptide encoded by a gene identified from the EST recited in SEQ ID No 86, having the Protein accession number BAB 15101 (encoded by Homo sapiens cDNA: FLJ21620 fis, clone COL07838 Nucleotide accession AK025273) is regulated by hypoxia. Other public domain sequences corresponding to this gene include Homo sapiens cDNA: FLJ23265 fis, clone COL06456 Nucleotide accession AK026918. Accordingly, when referring in the present specification to the EST recited in SEQ ID No 86, it is intended that these gene and protein sequences are also embraced. This gene was identified using Research Genetics Human GeneFilters arrays, which contain an EST corresponding to the gene (accession number R00332), The gene is now termed EGL nine (C.elegans) homolog 3.
There are no reports that describe the function of this human gene. However, a high degree of amino acid homology is observed between the protein encoded by this gene, and a rat protein called "Growth factor responsive smooth muscle protein" or "SM20" (Nucleotide accession U06713; Protein accession A53770). An alignment of single letter amino acid sequences is shown below. Over the highlighted region there is 97% amino acid similarity and 96% amino acid identity.
A53770 (1 ) MTLRSRRGFLSFLPGLRPPRR RISKRGPPTSHASPALGGRTLHYSCR BAB15101 (1)
51 100
A53770 ( 51 ) SQSGTPFSSEFQATFPAFAAKVARGPWLPQ EPPARLSASPLCVRSGQA BAB15101 (1)
101 150
A53770 (101) LGACTLGVPR GSVSEHPLGHIMRLDl-3KIAI-EYI¥PCLHE?GFCY'LDNFi
Figure imgf000092_0001
The high degree of amino acid similarity suggests that the human protein BAB 15101 has an equivalent biochemical function to the rat protein A53770 ("Growth factor responsive smooth muscle protein" or "SM20"). Recent publications have shown that SM20 functions to promote apoptosis in neurons (Lipscomb et al, J Neurochem 1999; 73(l):429-32; Lipscomb et al, J Biol Chem 2000 Nov 1; [epub ahead of print]). Significantly, SM20 has been shown to be expressed at high levels in the heart (Wax et al, J Biol Chem 1994; 269(17): 13041-7).
It has also been discovered that a polypeptide encoded by a gene identified from the EST recited in SEQ ID No 90, having the Protein accession number CAB81622, is regulated by hypoxia. The encoding human gene has been annotated in the UniGene database as "Similar to rat smooth muscle protein SM- 20" ; the nucleotide sequence is contained within the nucleotide accession AL 1 17352. M ore recently, a longer fragment of this gene has been cloned, named cl orfl 2, or EGLN 1 (Nucleotide accession AA G34568 ; Protein accession AA G34568). Accordingly, when referring in the present specification to the EST recited in SEQ ID No 90, it is intended that these gene and protein sequences are also embraced. This distinct hum an gene, encoding a protein related to SM 20 and EGLN3 (BAB 15101 ), is also induced in response to hypoxia. This gene was identified using Research Genetics Hum an GeneFilters arrays, which contain an EST corresponding to the gene (accession number H56028).
Independently to this, a fragm ent of this gene has been cloned from a cDNA library derived from hypoxic hum an cardiom yoblasts, and it has been shown that the gene is increased in expression in response to hypoxia in this cell type (see Table 1 herein; penultim ate row ). The nucleotide sequence of this cDNA fragment is referred to herein as SEQ ID No 90a.
In the light of this novel discovery reported herein that these hum an equivalents of SM20 are induced by hypoxia, it is herein proposed that in cardiac ischaemia, the resulting apoptosis is due at least in part, to increased expression of these genes. The therapeutic modulation of the activity of EGLN3 (BAB 15101 ), cl orfl 2 (AAG34568), CAB 81622, SM 20 and other equivalent proteins and encoding genes therefore provides a novel means for the treatment of m yocardial ischaemia, through the alteration of the propensity of m yocardial .cells to undergo apoptosis. For example, a suitable treatment may involve altering the susceptibility of ischaemic myocardial tissue to subsequent reperfusion and re-oxygenation, or m ay involve modulating the susceptibility of chronic ischaem ic m yocardial tissue (including form s of angina) to later m ore severe ischaem ia, which would result in m yocardial infarction. It is submitted that, by way of analogy, cerebral ischaem ia may be treated using the same principle.
Although the Applicant does not wish to be bound by this theory, the downstream effects of SM 20 and related genes such as EGLN3 (B AB 15101 ), c l orfl 2 (AAG34568), and CAB 81622, namely, apoptosis and angiogenesis might be explained as follows. The apoptotic effect of N GF withdraw al may be mediated by induction of the hypoxia pathway, but m ay be an aspect of the supposed involvement of the HIF protein in the stress response. FHFlα is induced by reactive oxygen species (see Richard et al. J Biol Chem 2000 Sep 1 ;275 (35):26765-71 ). This could, in turn, be mediated by over-load of the proteosomal pathway for HIFlα degradation and the consequent accumulation of undegraded HOOFlα. Accordingly, it is considered that m odulation of SM 20 and the related genes EGLN3 (BAB 15101 ), cl orfl 2 (AAG34568), and CAB 81622 m ay have applications in the treatment of diseases resulting from disturbances in proteosome function, such as prion diseases and other neuro-degenerative diseases.
These data provide the first connection between these related genes and the physiological response to hypoxia, Recently published research papers have identified that the protein products of these genes can act as proline hydroxylases (see Bruick RK et al Science. 2001 294:1337-40 and Epstein AC et al Cell. 107:43-54), This is consistent with our observations that certain proline hydroxylases are induced in response to hypoxia and the genes EGLN 1 and EGLN3 are part of the hypoxia response. For example, two genes encoding proline hydroxylases have been identified herein as being increased in expression in response to hypoxia (proline 4-hydroxylase, alpha polypeptide 1 ; SeqID : 231/232, proline 4-hydroxylase, alpha polypeptide II; SeqID : 349/ 350). This identified a functional significance of proline hydroxylation as a response to hypoxia,
Proline hydroxylase leads to degradation of HIFlα in normoxia (HDF regulates its own degradation - feedback). Hydroxylated HEFlα + VHL leads to ubquitination and consequent degradation of HFlα by proteosome. The activity of the prolyl hydroxylase is 02-dependent, so under conditions of hypoxia, HIFlα is not hydroxylated efficiently and is stabilised. HIFlα protein thus accumulates to a high level. The hypoxia-induction of the prolyl hydroxylase ensures that when O2 concentration returns to normal, there is sufficient enzyme available to target this high level of HDFlα efficiently for rapid degradation.
Degradation of FHFlα is dependent on HIFl-induced transcription (i.e. is hypoxia inducible). Berra et al (FEBS Lett 2001 Feb 23;491 (l -2):85-90) raises the specific hypothesis of an unknown hypoxia-inducible factor which targets HIFla for proteosomal degradation. It appears reasonable to propose that this factor will clearly be hypoxia-inducible, to ensure that a rapid and effective constraint on the hypoxic response would operate on return to normoxia, It now appears as if the genes EGLN 1 and EGLN3 form part of this mechanism . It is also hypothesised that SM20 and the related genes EGLN3 (BAB 15101), cl orfl2 (AAG34568), and CAB 81622 may act as tetramers, Known prolyl hydroxylases such as prolyl 4-hydroxylase (P4H) are known to act as tetramers of two alpha subunits and two beta subunits. SM20 and the related genes exhibits high similarity to the alpha subunit of P4H and it therefore seems likely that SM20 and the related genes are likely to have a binding partner that is equivalent to the beta subunit of P4H. SM20 has been shown to bind to the transcription factor HIFlα, and shares a low level homology with a p53 binding protein. P53 is a transcription factor that is known to be involved in apoptosis. Accordingly, it is proposed that in addition to binding to HIF1A, SM 20 and the related genes EGLN3 (BAB 15101 ), clorfl2 (AAG34568), and CAB 81622 may also bind and modify other transcription factors that are involved in the hypoxic response such as EPAS and HIF3A, or other transcription factors such as p53 and thereby influencing apoptosis. This aspect of the invention thus provides dimer and tetrameric forms of the EGLN3 (BAB 15101), cl orfl2 (AAG34568), and CAB81622 proteins, preferably complexed with a protein selected from the group consisting of HIFlα, p53 and a protein binding partner that is equivalent to the beta subunit of P4H. Preferably, such dimers and tetramers are heterodimers/heterotetramers. To provide further evidence that these related genes are a significant part of the hypoxia response additional expression data is presented here.
Expression profiles for these two genes will be displayed with pre-chip normalisation to correct for differences in RNA labelling etc, but within each gene no further norm alisation is done (per-gene norm alisation), so the relative absolute expression levels of the tw o genes can be compared and Y-axis units between separate graphs from the same experiment are comparable. These graphs are presented as Figures 32b (cl orfl 2) and 32c (EGLN3).
It can be seen from these Figures that both genes (cl orf 12 and EGLN 3) are inducible in response to hypoxia in m acrophages whether activated by gamm a interferon and lipopolysaccharide or if de-activated by treatment with interleukin-10. In m acrophages the absolute expression level of C l orf 12 appears to be higher than EGLN3.
There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show herein that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. From Figures 32a and 32d and the data presented below, differing expression profiles of the two related genes cl 0RF12 and EGLN3 are apparent throughout the 1 1 tested cell types, though C l orfl 2 is generally expressed at higher levels than EGLN3.
Cell type Oxygen mRNA expression mRNA expression
(clORF12 SeqID :89/90) (EGLN3 SeqID :85/86) adipocyte normoxia 0.0075 0.0033 adipocyte hypoxia 6hr 0.0091 0.0027 adipocyte hypoxia 18hr 0.0182 0.0025 cardiom yocyte norm oxia 0.0067 0.0019 cardiom yocyte hypoxia 6hr 0.0381 0.0023 cardiom yocyte hypoxia 18hr 0.0201 0.0026 endothelial norm oxia 0.0198 0.0019 endothelial hypoxia 6hr 0.0583 0.0033 endothelial hypoxia 18hr 0.0397 0.0026 fibroblast norm oxia 0.01 19 0.0032 fibroblast hypoxia 6hr 0,0260 0.0046 fibroblast hypoxia 18hr 0.0235 0.0040 hepatocyte normoxia 0.0075 0.0080 hepatocyte hypoxia 6hr 0.0074 0.0146 macrophage normoxia 0.0033 0.0008 m acrophage hypoxia 6hr 0.0083 0.0018 m acrophage hypoxia 18hr 0.0058 0.0021 m amm ary epithelial norm oxia 0.0065 0.0014 m ammary epithelial hypoxia 6hr 0.0137 0.0055 m am m ary epithelial hypoxia 18hr 0.0144 0.0065 monocyte norm oxia 0.0027 0.0006 m onocyte hypoxia 6hr 0.0084 0.0014 m onocyte hypoxia 18hr 0.0080 0.0016 neuroblastoma normoxia 0.0344 0.001 1 neuroblastom a hypoxia 6hr 0.1085 0.0013 neuroblastom a hypoxia 18hr 0.0551 0.0020 renal epithelial normoxia 0.0275 0.0046 renal epithelial hypoxia 6hr 0.0560 0.0046 renal epithelial hypoxia 18hr 0.0395 0.0096 skeletal m yocyte normoxia 0.0088 0.0029 skeletal m yocyte hypoxia 6hr 0.0277 0.0035 skeletal myocyte hypoxia 18hr 0.0245 0.0038
For instance, in the hypoxic hepatocyte (6hr) the norm alised expression values of EGLN and clorf 12 are 0.015 and 0.0074 respectively, i.e. EGLN being the dom inant gene. In contrast, in the neuroblastom a cell line SH-SY 5Y, the normalised expression values of EGLN and c l orfl 2 after 6hr hypoxia are 0.0012 and 0.108 respectively, i.e. cl orf 12 being the dominant gene by a large margin. This data dem onstrates that cl ORF12 and EGLN 3 are not constitutively expressed at an equal amount in different tissues indicating specificity of function. Therefore, it is considered that therapeutic products may be developed based on this data, with the goal of modulating proline hydroxylation of target proteins (such as HIFl alpha) in specific tissues, based on the differing expression profile of cl ORF12 and EGLN 3 in those tissues.
In Example l b herein, genes were identified from a custom array, which give a greater induction in macrophages (by a factor of at least 1.5) when hypoxia is augmented by over-expression of HIFl alpha or EPAS from an adenovirus. The data from the HIF/ EPAS over-expression w ork is presented herein in Example l c, but specifically relating to c l ORF12 and EGLN3 is summ arised in Figures 32e and 32f. From this data it is apparent that EGLN 3/ FLJ21620 fis cl.COL07838 but not cl ORF12 is increased in expression by the transcription factor EPAS l but not HIFl alpha, This is apparent by comparing experimental condition 9 (hypoxia with EPAS overexpression; expression value=3.48) to that of 5 (hypoxia without EPAS overexpression; expression value= 1.65). This adds valuable information about the mechanism of regulation of the gene encoding EGLN3.
To confirm this data the RNA samples for experimental conditions 1 ,3,5,7,9 (corresponding to the high dose of adenovirus) were also measured using a different array-based m ethodology- the AffyMetrix GeneChip. The results of this experiment are presented in Figures 32g and 32h.
Functional Characterisation of EGL nine (C.elegans) homolog 3 role in the induction of Cardiomyocyte apoptotic cell death
EGLN3 has been cloned into pONYδ.l and Smart2. IRES. GFP equine infectious anaemia virus (EIAV) vectors, and AdCM V. TRACK. GFP (AdenoQuest) adenoviral genome vectors (see co-owned co-pending
International patent application PCT/GB01/00758). These vectors have been used in "gain-of-function" studies in which EGLN3 has been overexpressed in order to elucidate corresponding protein function.
Human embryo kidney (HEK 293T) and dog osteosarcoma (D 17) cell lines have been used in transient plasmid transfection experiments to confirm EGLN3 expression from viral vector genomes. Rat cardiomyocyte cell line (H9C2) and primary human neonatal cardiomyocytes (PHNC) (BioWhittaker,
CC2582) have been used in viral transduction experiments to determine the biological activity of EGLN3.
In all cell types, expression of EGLN3 has been followed by combinations of immunofluorescence,
Western blotting and TaqMan quantitative PCR. Immunofluorescence and Western blotting employ an antibody specific for the FLAG epitope engineered into the 3' terminus of EGL nine (C.elegans) homolog 3 (Sigma, F3165). TaqMan quantitative PCR utilises the SYBR Green method (Applied Biosystems).
Western blotting has confirmed the transient expression of EGLN3 from an EIAV genome construct in HEK 293T (expected size approx 717 bp, 26 Kda). Immunofluorescence has localised transient expression of EGL nine (C.elegans) homolog 3 from EIAV expression construct in HEK293T to the cytoplasm . Expression of EGL nine (C .elegans) homolog 3 is elevated after 4 hours exposure to hypoxic conditions (0.1 % (v/v) oxygen), when compared to expression observed under normoxia (20% (v/v) oxygen) (see Figure 32i). TaqMan primers have been designed and optimised for the initial measurement of EGL nine (C.elegans) homolog 3 expression in EIAV or Adenovirus transduced H9C2 and PHNC (Forward: TCATCGACAGGCTGGTCCTC ; Reverse: GTTCCATTTCCCGGATAGAA). All findings at the RNA level are corroborated by immunofluorescence and Western blotting analyses at the protein level.
EIAV transduction of H9C2 and PHNC has been optimised with constructs containing green fluorescence protein (GFP) and LacZ reporter genes, using the VSVg envelope and a range of MOI between 10 and 100. GFP results were scored by fluorescence microscopy, while LacZ transductants were identified through the assay of β-galactosidase activity. An MOI of 50 transduced approximately 50% of the cell population.
EGLN3 is predicted to have pro-apoptotic activity in cardiomyocytes. Early, Mid and late phase apoptosis are characterised by translocation of membrane phospholipid phosphatidylserine (PS) from the inner face of the plasma membrane to the cell surface, activation of specific proteases (caspases) and fragmentation of DNA, respectively (Martin, S .J., et al., J. Exp. Med. 1995, 182, 1545-1556; Alnemri, E.S., et al., J. Cell. Biochem . 1997, 64, 33-42; W ylie, A.H., et al„ Int. Rev. Cytol. 1980, 68, 251-306). Translocation of PS has been identified through use of ApoAlert kit (Clontech; K2025-1), which employs FITC-labelled antibodies to detect surface expression of the PS, Annexin V. Caspase activity has been followed using the homogeneous fluorimetric caspase assay (Roche; 3005372) which allows the quantification of caspase activity through the cleavage of a fluorescent substrate. DNA fragmentation has been estimated using the nuclear stain Hoescht 33345 (Sigma, B2261 ; and fluorescence microscopy to locate areas of chromatin condensation. Total viability of cell population has been quantified through measurement of the ability of mitochondrial reductase to metabolise the fluorescent substrate MTT (Sigma, M2128)(Levitz S.M & Diamond, R.D, J. Infect. Dis. 1985 Nov; 152(5):938-45).
Conditions for early, mid and late stage apoptosis in H9C2 and PHNC have been defined using hypoxia and nutrient-depleted growth medium to mimic those ischaemic conditions found in vivo (Brar, B .K., et al., J. Biol. Chem . 2000, 275, 8508-8514). Transduction of PHNC with EIAV vectors containing EGLN3 is sufficient to cause an increase in caspase activity in cells cultured under normoxic conditions, confirming the role of EGLN3 in the induction of cardiomyocyte apoptosis. Using an MOI of 50, a 2-fold increase in caspase activity was seen in EGLN3 transduced cells, when compared to controls 48 hours post transduction (see Figure 32j),
Increased expression of EGL nine (C.elegans) homolog 3 in transduced cells is confirmed by TaqMan, immunofluorescence and Western blotting. Similar experiments are performed to determine whether EGL nine (C.elegans) homolog 3 expression further sensitises H9C2 and PHNC to previously defined ischaemic insults. Staurosporine (Calbiochem ; 569397) and Smart2. IRES. GFP EIAV vectors containing the Bax gene will be applied as chemical and viral pro-apoptotic controls, respectively (Yue, T-L., et al., J. M ol. Cell, Cardiol. 1998, 30, 495-507; Reed, J.C. J Cell Biol, 1994, 124(1 -2):1 -6).
Gene silencing approaches may be undertaken to down-regulate endogenous expression of EGLN3 in PHNC to determine the degree of protection against apoptotic cell death provided by a reduction in EGLN3 activity. RNA interference (RNAi) (Elbashir, SM et al., Nature 2001 , 411 , 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed. Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA , reducing or ablating target protein expression. A Hammerhead ribozyme library, contained in EIAV expression vectors, may also be ' applied. Efficacy of both gene silencing approaches m ay be assessed initially through the measurement of EGLN3 expression, at the RN A level by TaqM an and at the protein level by W estern blotting, Protection against previously described ischaemic insults provided by these methods of EGLN3 gene silencing may be assayed biologically as detailed above. C aspase inhibitors (caspase 3 inhibitor V, 2129002 and caspase inhibitor I, 627610, both Calbiochem) and Sm art2. IRES , GFP EIA V vectors containing the B cl-2 gene may be applied as chemical and viral anti-apoptotic controls, respectively (Kroemer, G, Nat Med. 1997, 3(6):6 l4-20). Similar "gain-of-function" and gene silencing approaches will be applied to the related gene, encoded by SEQ ID 90, named cl ofl 2.
Genes with a greater response in renal epithelial cells
The dataset of Table 12 also contains genes which are induced preferentially in renal epithelial cells, in response to hypoxia. These genes are presented in Figures 39-44. SeqID :1 17/1 18 EST
SeqID :129/130 Hypothetical protein FLJ22622
SeqID :31/32 TRIP-B r2
SeqID :301/302 Tumor protein D 52
SeqID :91/92/92a Semaphorin 4b SeqID:371/372 Dec-1
For Sem aphorin 4b (SeqID :91/92/92a), the clone presented in Figure 43 is p l Pl4, corresponding to IMAGE clone ace B E910319, the sequence of w hich covers a large region of the gene including protein coding sequence, which may cross-hybridise to other members of the semaphorin family. A separate clone (p l D 17) as found in the original filing, was derived from the subtracted library and corresponds to a more unique region of this gene in the untranslated region. From Table 12 it will be appreciated that a significant response is also found in the m acrophage. This is validated by RNase protection assay data (see Figure 57). Further clarification of this gene using complementary experimentation methods will resolve the exact cell-type specific nature of the expression of this gene, though it is clear from this data that it is induced in renal epithelial cells and m acrophages. Genes with a greater response in mammary epithelial cells
The dataset of Table 12 also contains genes which are induced preferentially in m ammary epithelial cells, in response to hypoxia. These genes are presented in Figures 45-52. SeqID :447/448 Calgranulin A SeqID :67/68 ER01 (S, cerevisiae)-like
SeqID:25/26 Hypothetical protein FLJ20500
SeqID :229/230 N-myc downstream regulated SeqID:387/388 Decidual protein induced by progesterone
SeqID:379/380 Integrin, alpha 5
SeqID :225/226 Tissue factor
SeqID:237/238 COX-2
In the case of Cox-2, which encodes a key drug target, it can be seen that in many cell types, especially the mammary epithelial cells, there is a clear induction in response to hypoxia. In contrast, for endothelial cells there is a very significant time-dependent decrease in Cox-2 gene expression in response to hypoxia, Similarly, for Calgranulin A, there is strong positive induction in hypoxic mammary epithelial cells, but in the macrophage, the response to hypoxia is negative. These clearly exemplify the unexpected finding that cell types respond to hypoxia differentially, both quantitatively but also qualitatively. This is not currently known.
Hypoxia regulation of Novel human genes
From Table 12, it will be appreciated that several genes with no prior annotation in public domain gene sequence databases are now identified as being regulated by hypoxia, in at least one cell type. To make this clear, these genes have been copied from Table 12 and presented in Tables 13 and 14), showing the hypoxia/ normoxia induction ratio of the cell type in which the response is most pronounced, These figures are derived by dividing the normalised expression value, as found in Table 5, in hypoxia by that in normoxia for the same cell type. In some cases, where hypoxia causes inhibition of gene expression, the fold change is prefixed by the term "DOWN" . The cell type and time point of maximal response to hypoxia are also noted in Tables 13 and 14. The main purpose of Tables 13 and 14 is to demonstrate that these genes have significant responses to hypoxia per se,
In many cases, significant responses are seen in multiple cell types, though this data is not apparent here. In Table 13, the cDNA clones are currently un-annotated in public domain databases. In Table 14, the cDNA clones are currently annotated, but were not so as at the priority date,
Example 4: Additional disclosure of the effect of macrophage activation on hypoxia regulation of gene expression
In Example 2, it is shown that activated and resting macrophages respond to hypoxia in different ways, showing that the hypoxia response is not a generic phenomenon. To consolidate this data, experiments were performed with the custom array, using additional experimental conditions and with a more in-depth analysis. Significantly, the expression values used are not simple hypoxia/ normoxia ratios, done separately for macrophages of differing activation status, but rather the values used allow comparison of the relative expression levels throughout the entire set of experimental conditions. Hence, for any gene, all values throughout the entire set of experimental conditions are calculated by comparison to the median level of that gene throughout the dataset. This allows a clearer appreciation of the effects of hypoxia in the context of cell activation status. The following data demonstrates that of the newly discovered genes responsive to hypoxia, expression changes are also seen in response to key cytokines of the immune system , implying functions outside of the generic response to hypoxia and metabolism . This especially applies to unannotated genes, including ESTs and hypothetical proteins, showing potential functions in inflammation and angiogenesis on the basis of cytokine-regulation.
M acrophages w ere derived and cultured as described elsewhere in the specification. A total of 6 experimental conditions were analysed, as shown below . Where cells were treated with cytokines or hypoxia (0.1 % oxygen), this was for 6 hr. Lipopolysaccharide (LPS) (from E.coli 026:B6; Sigma), gamma Interferon (IFN) and Interleukin-10 (IL-10) were all used at a final concentration of lOOng/ml. The effect of gamma Interferon and Lipopolysaccharide is to activate macrophages, with a Thl biased phenotype, as found in many inflammatory conditions. Interleukin-10 is a Th2 cytokine and de-activates macrophages, and suppresses their effector functions.
Exp erimental
Con dition
1. No cytokines Normoxia
2. No cytokines Hypoxia
3. IL-10 Normoxia
4. IL-10 Hypoxia
5, LPS+IFN Normoxia
6. LPS+IFN Hypoxia
In Table 15, genes are shown which respond to LPS+IFN in normoxia by producing at least a 2-fold increase in expression, indicating probable pro-inflammatory functions, From this dataset various patterns of hypoxia regulation will be appreciated on top of the effect of LPS+IFN .
For instance, the gene SCYA8 (plI21 ; SeqID : 479/480) is decreased in expression by hypoxia, changing from 0.54 to 0.18 between conditions #1 and #2. In condition #5 (LPS+IFN normoxia), expression is dramatically increased to a value of 19.6. When LPS+IFN is combined with hypoxia, this increase is dampened-down to a value of 12.2. So for this example, hypoxia and cell activation have opposing effects on gene expression. A similar expression profile is found for several other genes in Table 15, In contrast, the gene P8 protein-candidate of metastasis 1 (pl F17; SeqID: 329/330) is increased in expression by hypoxia, changing from 0.26 to 1.78 between conditions #1 and #2. In condition #5 (LPS+IFN normoxia) expression is increased from condition #1 to a value of 1.16. In condition #6, (LPS+IFN normoxia) the expression is further increased to a value of 2.59. So for this example, hypoxia and cell activation have similar effects on expression (i.e. increases) and these are found to be synergistic. A similar expression profile is found for several other genes in Table 15, including for Semaphorin 4b (plP14; SeqID :91/92/92a), which has been independently verified by RNase protection assay (see Figure 57). .
A selection of novel genes taken from Table 15 is also presented as Figure 53-. These novel genes are hence annotated here for the first time as being regulated not only by hypoxia, but also by Thl inflammatory signals, as provided by LPS+IFN.
It will be appreciated that certain IMAGE clones were classed as novel and unannotated when the original patent filing was made (8 Dec 2000), but which can now be assigned to named genes. These are Uridine 5' monophosphate hydrolase 1 (clone pi 17 ; SeqID: 49/50) and Insulin induced protein 2 (clone pID IO; SeqID:75/76).
In Table 16, genes are shown which respond to LPS+IFN in normoxia by producing at least a 2-fold decrease in expression. From this dataset, various patterns of hypoxia regulation will be appreciated on top of the effect of LPS+IFN.
In Figure 54, novel genes from Table 16 which are down-regulated by LPS+IFN and up-regulated by hypoxia are presented. For most of these, the combined effect of LPS+IFN AND hypoxia produces only a minor induction above the level of expression for activated normoxic cells (for example pl F8/ SeqID :10/ Hypothetical Protein KIAA0914). In other cases, this is not the case, and hypoxia is able to over-ride the inhibitory effect of LPS+IFN on gene expression (for example plD 12/ SeqID:30/ Hypothetical Protein KIAA 1376). This clearly demonstrates the finding that different cell types or physiological states of a cell type (as here), respond to hypoxia differently.
In Figure 55, novel genes from Table 16 which are down-regulated both by LPS+IFN and by hypoxia are presented. In many of the genes presented here, these stimuli are synergistic, with minimal expression obtained with a combination of LPS+IFN and hypoxia.
In Figure 56, a selection of named genes from Table 16 which are down-regulated by LPS+IFN, with various responses to hypoxia are presented. For the gene, Max-interacting Protein 1 two separate clones were available on the array corresponding to this gene (plG5 from SeqID:280 and plD22 from SeqID:120). In the original specification, the IMAGE clone corresponding to SeqID:120 (accession AA401496) was classified as an EST, and the IMAGE clone corresponding to SeqlD:280 (accession AA401496) was classified as "M ax-interacting Protein 1 ", as determ ined by the UniGene database at that time, Now it is apparent that both of these clones correspond to Max-interacting Protein 1 , explaining the similarity of their expression profiles in Figure 56. Clearly the response of this gene to hypoxia is inhibited by LPS+IFN . The additional data showing effects of the Thl activation stimulus LPS+IFN extends the finding of these genes as novel hypoxia regulated genes, and provides additional information about the relevance of these genes to disease mechanism s.
It will be appreciated that certain IM AGE clones were classed as novel and unannotated when the original patent filing w as m ade (8 Dec 2000), but w hich can now be assigned to named genes. These are TRIP- B r2 (clone pl D 15 ; SeqID :31/32), M AX -interacting protein 1 (clone p l D22; SeqID : 1 19/120).
In Tables 15 and 16 and Figures 53 -56, showing genes which respond to LPS+IFN , it will be noticed that some of these genes also response to the inhibitory cytokine IL-10 (e.g. Sem aphorin 4b, Hypothetical protein CGI-1 17). Other genes respond only to IL-10, but not to LPS+IFN , Specific responses to IL-10 are significant because this cytokine has been shown to have utility in suppressing inflammatory reactions (Huizinga TW et al., Rheumatology 2000, 39 : 1180-8).
Table 17 show s genes responsive to IL-10 (increased or decreased) but not affected significantly by LPS+IFN . Various patterns of hypoxia regulation will be appreciated.
Example 5: Gene expression in human tum ors
One of the utilities of the genes identified herein relates to the diagnosis and treatment of human tumors, on the basis that hypoxia is frequently found in tumors.
A study has been performed to examine the expression of these genes in a selection of breast and ovary tumors, comparing expression with normal adjacent tissue from the sam e patient. There is expected to be a large degree of variation between different patients, and the study here contains only 5 patients with a range of diagnoses. Therefore although certain genes will be identified from this data, other genes in the current specification not flagged by this study are nevertheless likely to have utility in cancer.
Patients are designated as Letters:
E: 50 year old Caucasian female. Diagnosis: ovarian adenocarcinom a. Norm al ovarian tissue derived from an age-m atched separate individual.
F: 60 year old female. Diagnosis: poorly differentiated adenocarcinoma. Norm al ovarian tissue derived from the same individual. G: 41 year old female. Diagnosis: moderately-differentiated adenocarcinoma. Normal ovarian tissue derived from the same individual.
H: 40 year old female. Diagnosis: invasive ductal carcinoma. Normal breast tissue derived from the same individual. K: 58 year old female. Diagnosis: invasive ductal carcinoma. Normal breast tissue derived from the same individual.
Data normalisation was done per-chip to correct for differences in labelling and hybridisation efficiency. Per-gene normalisation was done such that the expression values of each gene are relative to the median value of that gene throughout the series of samples, By comparing the expression values under normal (nor) and tumor (tum) for a single patient, differences in expression between the normal and malignant tissue of that patient can be inferred.
In Table 18 are genes which are up-regulated at least 3-fold in at least one patient, comparing the tumor tissue to the adjacent normal tissue.
In Table 19 are genes which are down-regulated at least 3-fold in at least one patient, comparing the tumor tissue to the adjacent normal tissue.
Example 6: Effects of inflammatory cytokines on hypoxia-regulated genes
Tumor necrosis factor alpha (TNF ) is a key pro-inflammatory cytokine both produced by and acting on the macrophage. The significance of TNFα to human disease is well established in the art. This is particularly the case in Rheumatoid arthritis and neutralising antibodies to TNFα have been reported to offer clinical utility. Because hypoxia is another pathological condition exerted on macrophages in the synovia of RA patients, synergistic effects of these two stimuli are highly relevant to the discovery of novel inflammatory targets expressed by the macrophage. To investigate this, primary human macrophages we re exposed to either hypoxia (0.1% oxygen) or 100 ng/ml TNFα or to both for 6hr. The data shown below provides further credence to the utility of the encoded proteins as inflammatory targets in macrophages and applies to any disease where hypoxia and TNFαare co-in cident.
Gene expression levels were measured and compared using the custom gene array. In data analysis per- gene normalisation was set up such that expression values represent the fold-change compared with the expression in untreated normoxic cells. Genes which are increased in expression in response to TNFαby at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 20. Genes which are decreased in expression in response to TNFαby at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 21. Another inflammatory cytokine implicated in diseases where hypoxia is frequently found is In terleu kin - 17 (IL-17). For example, this cytokine has been shown to mediate inflammation and joint destruction in arthritis (Lubberts et al J.Immunol 2001 167:1004-1013). IL-17 has also been shown to stimulate macrophages to release other key pro-inflammatory cytokines (Jovanovic et a 1 J Immunol 1998 160:3513-21). Therefore genes which respond to both hypoxia and IL-17 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products. Genes which are increased in expression in response to IL-17 by at least 2- fold, in either normoxic or hypoxic cells, are shown in Table 22. Genes which are decreased in expression in response to IL-17 by at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 23.
The cytokine IL-15 is implicated in several disease in which macrophages and hypoxia both feature as elements of the inflammatory state, such as in atherosclerosis (Wuttge DM et al Am J Pathol. 2001 159:417-23) and rheumatoid arthritis (Mclnnes IB et al Immunol Today. 1998 19:75-9). Although the main target of IL-15 is T-cells effects have also been shown on monocytes (Badolato R et al Blood, 1997 90:2804-9). Therefore genes which respond to both hypoxia and IL-15 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products. Genes which are increased in expression in response to IL-15 by at least 2- fold, in either normoxic or hypoxic cells, are shown in Table 24. Genes which are decreased in expression in response to IL-15 by at least 2-fold, in either normoxic or hypoxic cells, are shown in Table 25. Example 7: Rat foetal cardiomyocytes
Primary rat foetal cardiomyocytes provide an attractive experimental model for studying the responses of cardiac cells to ischaemia. Cells are obtained which are non-immortalised and which are seen to contract or beat in culture. It is of interest to examine how the responses of these cells to hypoxia (or related experimental conditions) compared and contrasts to other cell types. These other cell types might include those that are similarly sensitive to the effects of hypoxia (such as neurones) or might be cells that show a higher tolerance to hypoxia (such as macrophages). Experiments are performed in parallel for cardiomyocytes and other cell type(s). The responses of these specific cell types is then determined by hybridising labelled mRNA to microarrays. Alternative methods will include the construction of subtracted cDNA libraries for the individual treated cell types and assessing which genes are contained therein by sequencing.
Methods
Cardiomyocytes are harvested from heart ventricles of embryos aged E18 days, using a cell isolation kit (Neonatal cardiomyocyte isolation system; Worthington Biochemical Corporation, Lakewood, New Jersey, 08701). They are seeded at 5xl06 cells/lOOcm diameter petri dish in DMEM/M 199, 10% horse serum , 5% FCS, 1 % penicillin, streptomycin, glutamine for 5 days at 37C . Media is changed during the 5 days.
Other cell types used for comparison with cardiomyocytes, are cultured according to their optimum conditions and/ or the standard routine. These cell types may include cardiomyocytes in a different physiological setting, such as in an intact beating heart, or a different developmental state of the cardiomyocyte, such as cardiomyoblast.
Identical seeded petri dishes are placed either in a standard tissue culture incubator (95% air/ 5% C02) or in a hypoxia incubator (0.1 % oxygen / 5% C02 / 0.1 % oxygen for 6 hours. This is done separately for both cardiomyocytes and the other cell type(s) to be compared. Other experimental conditions might more closely approximate ishemia, by incorporating components additional to hypoxia.
At the end of the exposure to hypoxia, cells are placed on a chilled platform, washed in cold PB S and total RNA is extracted using RNazol B (Tel-Test, Inc; distributed by Biogenesis Ltd) following the manufacturers instructions. W here appropriate, polyadenylated mRNA is extracted from the total RNA using a commercial kit following the manufacturers instructions (Promega; PolyATract mRNA isolation System IV),
Array hybridisations and construction/analysis of subtracted cDNA libraries are performed according to standard methods or as described elsewhere in this specification.
Example 8: Comparison of the hypoxic-responses between populations of rat primary cultured neurons by a subtraction cloning / array screening approach.
Different regions of the central nervous system display different sensitivities to hypoxia and to ischaemia. Susceptibility to tissue damage in this manner may occur as a result of intrinsic differences in gene expression between cells. To evaluate this hypothesis, primary cultures of rat neurons from different regions of the brain are established. Cultures are exposed to various experimental conditions which are pertinent to pathologies of the hypoxic/ischemic brain. These would include hypoxic insults as have been described, or to hypoxia/ischaemia where the conditions more closely approximate pathological ischemia. Either condition may be preceded by prior hypoxic-preconditioning, where transient exposure to hypoxia renders cells less sensitive to subsequent acute treatment. For all possible experimental treatments, a similar routine is performed for distinct neuron subtypes, in order to compare their responses. Such comparisons may be m ade by hybridizing labelled mRNA to microarrays or derivatives thereof, Alternatively subtracted libraries might be constructed individually for each treated neuron subtype, and clones which are confirmed to be changed in expression to be sequenced, The collection of genes arising from the different neuron subtypes will be compared. Methods
Primary cultures are established according to standard procedures from embryonic rats aged from E14 to E18 (Dunnett SB , Bjorkland A (Eds.) 1992. Neural Transplantation, A Practical Approach. IRL Press). Isolated neurons include but are not limited to those from ventral mesencephalon, striatum, hippocampus, cerebellum , cerebral cortex, dorsal root ganglia and superior cervical ganglia.
Cells are maintained in culture for 3-14 days in humidified culture incubators at 37°C, 5% C02, 95% air (Normoxia) in Neurobasal Medium (Brewer GJ, 1995, Journal of N euro science Research 42:674-83) supplemented with B27 (both Life Technologies). For the hypoxia-preconditioning, cells are transferred to a second incubator at 37°C, 5% C02, 94.9% Nitrogen, 0.1 % Oxygen (Hypoxia) for 30-180 minutes and returned to the normoxic incubator for 24 hours (Pringle et al, 1997, Neuropathology and Applied Neurobiology 23:289-298). For the hypoxic stimulus, either independent from or subsequent to hypoxia- preconditioning, cells are transferred to the hypoxic incubator for 2-6 hours as determined in time course experiments. Additionally, as appropriate, the medium in which the cells are grown is replaced with glucose-free media for establishment of experimental ischaemia (Ray AM , Owen DE, Evans ML, Davis JB Benham , 2000. Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA 1 death in rat organotypic hippocampal slices). At the end of the exposure to hypoxia (or hypoxia/ischaemia), cells are, placed on a chilled platform, washed in cold PB S and total RNA is extracted using RNazol B (Tel-Test, Inc; distributed by Biogenesis Ltd) following the manufacturers instructions. W here appropriate, polyadenylated mRNA is extracted from the total RNA using a commercial kit following the manufacturers instructions (Promega; PolyATract mRNA isolation System IV).
Array hybridisations and construction/analysis of subtracted cDNA libraries are performed according to standard methods or as described elsewhere in this specification.
Example 9: Semaphorin 4b W e have screened cDNA libraries derived from the human brain and leukocytes, to obtain an unequivocal and accurate full length cDNA sequence (SEQ ID No 92a) and the accurate presumptive amino acid sequence (SEQ ID No 91 ).
The amino acid sequence above was derived by taking the first ATG. W e have various independent lines of evidence that this is the bona fide translation initiation codon, Basic analysis of this sequence, reveals the following motifs: signal peptide (pSORT) Start: 1 End: 37; Transmembrane (pSORT) Start: 718 End: 734; cleavage site (pSORT) Start: 38 End: 38; Proline rich region Start: 758 End: 824; Sema dom ain (pfam ) Start: 70 End: 503; Plexin repeat (pfam ) Start: 525 End: 548 ; integrin, beta domain (pfam ) Start: 532 End: 546 ; cytoplasm ic tail Start: 735 End: 837.
To confirm the hypoxic regulation of Sem a4b, w e used RN ase protection assay (see Figure 57). Hypoxia is a feature of several inflamm atory conditions often accompanied by superoxide radicals and the immune regulator gam m a interferon. In this experim ent we have m ade the following findings:
• Expression is activated by hypoxia (3.3 fold) • Expression is activated by gamm a interferon and LPS (3.9 fold)
• Expression is activated synergistically by hypoxia plus gamm a interferon/ LPS (7.3 fold)
• Expression is activated by superoxide radicals (5.0 fold)
To investigate the size of the mRNA and the tissue distribution, N orthern blotting was done (see Figure 58). This show s that the gene is expressed as a single transcript at relatively low levels in unstimulated human tissues.
W e have also found that a m olecule that is probably associated with Semaphorin 4B , called psd-95 is another m acrophage hypoxia-induced protein (see SEQ ID N o 299). This is based on the fact that psd-95 binds the cytoplasmic tail of Sem a4c (Inagaki et al., J B iol Chem . 2001 ; 276(12): 9174-81 ), w hich like Sema4b, contains proline rich sequence. Therefore, both Sem aphorin 4B , and a probable partner are co- ordinately regulated by hypoxia.
Example 10: Discussion of relevance of individual clones
The O xford BioM edica clone pl F12 represents Hypothetical protein FLJ13611. The protein sequence encoded by Hypothetical protein FLJ13611 is represented in the public databases by the accession NP_079217 and is described in this patent by Seq ID 1. The nucleotide sequence is represented in the public sequence databases by the accession NM_024941 and is described in this patent by Seq ID 2. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford BioM edica clone p l F2 represents Hypothetical protein FLJ20037. The protein sequence encoded by Hypothetical protein FLJ20037 is represented in the public databases by the accession CAB65981 and is described in this patent by Seq ID 3. The nucleotide sequence is represented in the public sequence databases by the accession NM, 017633 and is described in this patent by Seq ID 4. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein FLJ20037 is downregulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. W e expect increased activity of the gene product to have an anti-tum our effect.
The O xford BioMedica clone pl Fl O represents Hypothetical protein D KFZp434P0116. The protein sequence encoded by Hypothetical protein DKFZp434P0116 is represented in the public databases by the accession T46364 and is described in this patent by Seq ID 5. The nucleotide sequence is represented in the public sequence databases by the accession NM_017593 and is described in this patent by Seq ID 6, Hypothetical protein DKFZρ434P0116 is predicted to be a kinase due to high structural similarity with other known kinases, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypothetical protein DKFZp434P01 16 is repressed in m acrophages activated by LPS and gamma interferon. W e expect it to have an anti-inflammatory role. The Oxford BioM edica clone p 1 FI 9 represents Hypothetical protein KIAA0212. The protein sequence encoded by Hypothetical protein KIAA0212 is represented in the public databases by the accession B AA 13203 and is described in this patent by Seq ID 7 , The nucleotide sequence is represented in the public sequence databases by the accession NM_014674 and is described in this patent by Seq ID 8. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioMedica clone p lF8 represents Hypothetical protein KIAA0914. The protein sequence encoded by Hypothetical protein KIAA0914 is represented in the public databases by the accession NP_055698 and is described in this patent by Seq ID 9. The nucleotide sequence is represented in the public sequence databases by the accession NM_014883 and is described in this patent by Seq ID 10. Hypothetical protein KIAA0914 show s high structural similarity to Human Class I alpha 1 ,2- M annosidase and conservation of active site and binding site residues, therefore we predict that Hypothetical protein KIAA0914 will act as a mannosidase. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein KIAA0914 is repressed in m acrophages activated by LPS and gamma interferon. W e expect the gene product to have an anti-inflamm atory role.
The O xford BioM edica clone p l F5 represents Hypothetical protein FLJ20281. The protein sequence encoded by Hypothetical protein FLJ20281 is represented in the public databases by the accession XP_008736 and is described in this patent by Seq ID 11. The nucleotide sequence is represented in the public sequence databases by the accession NM_017742 and is described in this patent by Seq ID 12. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. TNFalpha is an inflam m atory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatm ent of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Hypothetical protein FLJ20281 is induced in .m acrophages activated by TNFalpha.
The O xford B ioM edica clone plFl 8 represents Hypothetical protein KIAA0876. The protein sequence encoded by Hypothetical protein KIAA0876 is represented in the public databases by the accession BAA74899 and is described in this patent by Seq ID 13. The nucleotide sequence is represented in the public sequence databases by the accession XM_035625 and is described in this patent by Seq ID 14. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford BioMedica clone pl F7 represents Spectrin, beta, non-erythrocytic 1 . The protein sequence encoded by Spectrin, beta, non-erythrocytic 1 is represented in the public databases by the accession NP_0031 19 and is described in this patent by Seq ID 15. The nucleotide sequence is represented in the public sequence databases by the accession NM_003128 and is described in this patent by Seq ID 16. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tum ours w here m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Spectrin, beta, non-erythrocytic 1 is downregulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. W e expect increased activity of the gene product to have an anti-tum our effect,
The Oxford BioM edica clone p l F21 represents Hem atopoietic Zinc finger protein. The protein sequence encoded by Hem atopoietic Zinc finger protein is represented in the public databases by the accession AAL08625 and is described in this patent by Seq ID 17. The nucleotide sequence is represented in the public sequence databases by the accession AK024404 and is described in this patent by Seq ID 18. Hematopoietic Zinc finger protein is a transcriptional regulator that contains a Cys2-His2 zinc finger motif. It is predicted to bind to metal response elements (MRE) and therefore activate the transcription of genes that contain a MRE sequence within their promoter region such as metallothioneins. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Hematopoietic Zinc finger protein is preferentially induced by hypoxia in monocytes or macrophages and a restricted number of other cell types. It is therefore a candidate for specific intervention for treatment or diagnosis of the above diseases.
The Oxford BioMedica clone plF9 represents Hypothetical protein KIAA0742. The protein sequence encoded by Hypothetical protein KIAA0742 is represented in the public databases by the accession NP_060903 and is described in this patent by Seq ID 19. The nucleotide sequence is represented in the public sequence databases by the accession AB018285 and is described in this patent by Seq ID 20. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein KIAA0742 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. Hypothetical protein KIAA0742 shows significant homolgy to the transcription factor hairless. W e therefore propose that Hypothetical protein KIAA0742 may play a crucial role in the regulation of hair growth. Accordingly, this aspect of the invention includes the use of this protein, fragments and functional equivalents of this protein, encoding nucleic acid molecules, in addition to ligands that bind specifically to this protein, in the diagnosis and treatment of hair loss. The Oxford BioMedica clone plEl 3 represents Hypothetical protein PRO0823. The protein sequence encoded by Hypothetical protein PRO0823 is represented in the public databases by the accession AAF71073 and is described in this patent by Seq ID 21. The nucleotide sequence is represented in the public sequence databases by the accession AF116653 and is described in this patent by Seq ID 22. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein PRO0823 is repressed in m acrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein PRO0823 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect increased activity of the gene product to have an anti-tumour effect.
The Oxford BioMedica clones plD l and plD2 represent the Hypothetical protein FLJ10134. The protein sequence encoded by Hypothetical protein FLJ10134 is represented in the public databases by the accession NP_060474 and is described in this patent by Seq ID 23. The nucleotide sequence is represented in the public sequence databases by the accession NM_018004 and is described in this patent by Seq ID 24. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPAS l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. By adenoviral over- expression of EPAS l we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Hypothetical protein FLJ10134 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPASl . M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Hypothetical protein FLJ10134 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein FLJ10134 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect increased activity of the gene product to have an anti-tumour effect. The Oxford BioMedica clone plD4 represents Hypothetical protein FLJ20500. The protein sequence encoded by Hypothetical protein FLJ20500 is represented in the public databases by the accession NP_061931 and is described in this patent by Seq ID 25. The nucleotide sequence is represented in the public sequence databases by the accession NM_019058 and is described in this patent by Seq ID 26. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypothetical protein FLJ20500 is preferentially induced by hypoxia in mammary epithelial cells.
The Oxford BioMedica clone plD9 represents Hypothetical protein DKFZP564D 116. The protein sequence encoded by Hypothetical protein DKFZP564D 116 is represented in the public databases by the accession T08708 and is described in this patent by Seq ID 27, The nucleotide sequence is represented in the public sequence databases by the accession AL050022 and is described in this patent by Seq ID 28. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein DKFZP564D 116 is repressed in macrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Hypothetical protein DKFZP564D 116 is induced in macrophages activated by TNFalpha.
The Oxford BioMedica clone plD 12 represents Hypothetical protein KIAA 1376. The protein sequence encoded by Hypothetical protein KIAA 1376 is represented in the public databases by the accession BAA92614 and is described in this patent by Seq ID 29, The nucleotide sequence is represented in the public sequence databases by the accession AB037797 and is described in this patent by Seq ID 30, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Hypothetical protein KIAA 1376 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role, The Oxford BioMedica clone plD 15 represents TRIP-Br2, The protein sequence encoded by TRIP-Br2 is represented in the public databases by the accession NP_055570 and is described in this patent by Seq ID 31. The nucleotide sequence is represented in the public sequence databases by the accession NM_014755 and is described in this patent by Seq ID 32,. TRIP-BR2 is a PHD zinc finger and bromodomain interacting protein transcriptional regulator and is involved in the regulation of cell cycle progression. Its hypoxia-regulation is likely to have important disease-relevant effects. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue. TRIP-B r2 is preferentially induced by hypoxia in renal epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TRIP-Br2 is repressed in macrophages activated by LPS and gamma interferon. The O xford BioM edica clone pl D 16 represents Hypothetical protein FLJ20308. The protein sequence encoded by Hypothetical protein FLJ20308 is represented in the public databases by the accession XP_039852 and is described in this patent by Seq ID 33. The nucleotide sequence is represented in the public sequence databases by the accession AK000315 and is described in this patent by Seq ID 34. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein FLJ20308 is repressed in macrophages activated by LPS and gamm a interferon. W e expect it to have an anti-inflamm atory role.
The Oxford B ioM edica clone p 1 J 13 represents Hypothetical nuclear factor SBB I22. The protein sequence encoded by Hypothetical nuclear factor SB B I22 is represented in the public databases by the accession NP_065128 and is described in this patent by Seq ID 35. The nucleotide sequence is represented in the public sequence databases by the accession NM_020395 and is described in this patent by Seq ID 36. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone pi 122 represents Hypothetical protein KIAA 1429. The protein sequence encoded by Hypothetical protein KIAA 1429 is represented in the public databases by the accession B AA92667 and is described in this patent by Seq ID 37. The nucleotide sequence is represented in the public sequence databases by the accession AB 037850 and is described in this patent by Seq ID 38, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The O xford BioM edica clone pl J6 represents Hypothetical protein FLJ10206. The protein sequence encoded by Hypothetical protein FLJ10206 is represented in the public databases by the accession AAH06108 and is described in this patent by Seq ID 39. The nucleotide sequence is represented in the public sequence databases by the accession NM_018025 and is described in this patent by Seq ID 40. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein FLJ10206 is repressed in macrophages activated by IL-17 and is also repressed in m acrophages activated by IL-15. These are pro-inflamm atory cytokines, and we expect the hypothetical protein FLJ10206 to have an anti-inflam matory role.
The O xford BioM edica clone p 115 represents Hypothetical protein FLJ10815. The protein sequence encoded by Hypothetical protein FLJ10815 is represented in the public databases by the accession B AA91830 and is described in this patent by Seq ID 41. The nucleotide sequence is represented in the public sequence databases by the accession NM_018231 and is described in this patent by Seq ID 42, Hypothetical protein FLJ10815 is structurally sim ilar to an alpha / beta barrel structure. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein FLJ10815 is repressed in m acrophages activated by LPS and gamm a interferon. W e expect it to have an anti-inflammatory role. The O xford B ioMedica clone p 1 II 3 represents Hypothetical protein FLJl l l OO. The protein sequence encoded by Hypothetical protein FLJl l lOO is represented in the public databases by the accession NP_060701 and is described in this patent by Seq ID 43. The nucleotide sequence is represented in the public sequence databases by the accession NM_018321 and is described in this patent by Seq ID 44. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone pi 117 represents Hypothetical protein FLJ20644. The protein sequence encoded by Hypothetical protein FLJ20644 is represented in the public databases by the accession NP_060387 and is described in this patent by Seq ID 45. Hypothetical protein FLJ20644 is a putative Serine/threonine phosphotase. Region 250 - 450 show s high structural similarity to other Serine/threonine phosphotases. The nucleotide sequence is represented in the public sequence databases by the accession NM_017917 and is described in this patent by Seq ID 46, Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford B ioM edica clone pi II 5 represents Hypothetical protein CGI-1 17. The protein sequence encoded by Hypothetical protein CGI-1 17 is represented in the public databases by the accession Q9Y3C 1 and is described in this patent by Seq ID 47 , The nucleotide sequence is represented in the public sequence databases by the accession NM_016391 and is described in this patent by Seq ID 48 , Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore im plicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPA S l are transcription factors that m ediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. B y adenoviral over-expression of HIFl alpha or EPAS l we show augmentation of the hypoxic induction of certain genes, further confirm ing their status as responsive to hypoxia. Hypothetical protein C GI-1 17 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of either HIF l alpha or EPA S l . Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein CGI-117 is repressed in m acrophages activated by LPS and gamma interferon. W e expect it to have an anti-inflammatory role.
The O xford BioMedica clone p 117 represents Uridine 5' monophosphate hydrolase 1. The protein sequence encoded by Uridine 5' monophosphate hydrolase 1 is represented in the public databases by the accession NP_057573 and is described in this patent by Seq ID 49. The nucleotide sequence is represented in the public sequence databases by the accession NM_016489 and is described in this patent by Seq ID 50. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Uridine 5' monophosphate hydrolase 1 is induced in m acrophages activated by LPS and gamma interferon and is also is induced in m acrophages activated by IL-15. W e expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflam m atory effect. The protein sequence encoded by Hypothetical protein KIAA0014 is represented in the public databases by the accession NP_055480 and is described in this patent by Seq ID 51. The nucleotide sequence is represented in the public sequence databases by the accession NM_014665 and is described in this patent by Seq ID 52, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone p 114 represents Hypothetical protein HSPC 196. The protein sequence encoded by Hypothetical protein HSPC 196 is represented in the public databases by the accession NP_057548 and is described in this patent by Seq ID 53. The nucleotide sequence is represented in the public sequence databases by the accession NM_016464 and is described in this patent by Seq ID 54. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein HSPC 196 is repressed in m acrophages activated by LPS and gam ma interferon. W e expect it to have an anti-inflamm atory role.
The O xford B ioMedica clone p l I8 represents Hypothetical protein FLJ1 1296. The protein sequence encoded by Hypothetical protein FLJ1 1296 is represented in the public databases by the accession XP_004747 and is described in this patent by Seq ID 55. The nucleotide sequence is represented in the public sequence databases by the accession NM_018384 and is described in this patent by Seq ID 56. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioM edica clone p 1 II 6 represents Hypothetical protein KIAA 1668. The protein sequence encoded by Hypothetical protein KIAA 1668 is represented in the public databases by the accession B AB 33338 and is described in this patent by Seq ID 57. The nucleotide sequence is represented in the public sequence databases by the accession AB051455 and is described in this patent by Seq ID 58. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone pl ll l represents SECIS binding protein 2. The protein sequence encoded by SECIS binding protein 2 is represented in the public databases by the accession AAK57518 and is described in this patent by Seq ID 59. The nucleotide sequence is represented in the public sequence databases by the accession AF380995 and is described in this patent by Seq ID 60. SECIS binding protein 2 is a crucial component in the complex required for the translation of mammalian selenoprotein mRNAs. Selenoproteins are important responders to redox conditions and many selenoproteins are known to protect from cell death. Our demonstration of the hypoxia induction of SECIS binding protein 2 opens new avenues for diagnosis and therapeutic intervention. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SECIS binding protein 2 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect increased activity of the gene product to have an anti-tumour effect.
The Oxford BioMedica clone plE8 represents cDNA: FLJ22249 fis, clone HRC02674. The sequence cDNA : FLJ22249 fis, clone HRC02674 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AK025902 and is described in this patent by Seq ID 62. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone p IE 18 represents Plexin C l . The protein sequence encoded by Plexin C l is represented in the public databases by the accession NP_005752 and is described in this patent by Seq ID
63. The nucleotide sequence is represented in the public sequence databases by the accession
NM_005761 and is described in this patent by Seq ID 64. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates and play a significant role in signal transduction [Tamagnone et al 1999, Cell 99:71 -80]. Elsewhere in this patent we disclose hypoxic regulation of a new semaphorin 4b, and we propose co-regulation of these molecules by hypoxia and their relevance to inflammatory disease, its diagnosis and therapy. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Plexin C l is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone plE16 represents cDNA DKFZp586E1624. The sequence cDNA DKFZp586E1624 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AL1 10152 and is described in this patent by Seq ID 66. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPAS l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. By adenoviral over-expression of EPAS l we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Its preferential regulation by EPAS l provides a route to preferential intervention, to avoid toxicity to other tissues. The cDNA DKFZp586El 624 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPAS l . Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheumatoid arthritis. The cDNA DKFZp586E1624 is preferentially induced by hypoxia in endothelial cells. We expect this gene product to have a pro-angiogenic effect, and its inhibition to have an anti-angiogenic effect.
The Oxford BioMedica clones plD5 and plD6 represent ERO l (S . cerevisiae)-like. The protein sequence encoded by ERO l (S . cerevisiae)-like is represented in the public databases by the accession NP_055399 and is described in this patent by Seq ID 67. The nucleotide sequence is represented in the public sequence databases by the accession NM_014584 and is described in this patent by Seq ID 68. ERO l (S. cerevisiae)-like has been shown to be a flavin adenine dinucleotide (FAD) binding protein, Binding of FAD enables ERO l (S. cerevisiae)-like to oxidise protein disulfide isomerase (PDI). We propose that the oxidisation of PDI by ERO l (S. cerevisiae)-like stops PDI autodegradation, therefore increasing levels of the protein. Increased levels of PDI have been shown to be neuroprotective by inhibiting apoptotic cell death. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFlalpha and EPAS l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. By adenoviral over- expression of EPAS l we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. ERO l (S. cerevisiae)-like has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPAS l . Its preferential regulation by EPASl provides a route to preferential intervention, to avoid toxicity to other tissues. EROl (S. cerevisiae)-like is preferentially induced by hypoxia in mammary epithelial cells. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, ERO l (S, cerevisiae)-like is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, ERO l (S . cerevisiae)-like is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The O xford B ioM edica clone pl E12 represents Hypothetical protein DKFZP434E1723. The protein sequence encoded by Hypothetical protein DKFZP434E1723 is represented in the public databases by the accession XP_05338 and is described in this patent by Seq ID 69. The nucleotide sequence is represented in the public sequence databases by the accession B C010005 and is described in this patent by Seq ID 70. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone pl El O represents cDNA FLJ1 1041 fis clone PLACE 1004405. The sequence encoded by cDNA FLJ1 1041 fis, clone PLACE 1004405 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AK001903 and is described in this patent by Seq ID 72. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The cDNA FLJ11041 fis clone PLACE 1004405 is induced in macrophages activated by LPS and gamma interferon. We expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflam m atory effect.
The Oxford B ioMedica clone p l C21 represents Tubulin, beta, 4. The protein sequence encoded by Tubulin, beta, 4 is represented in the public databases by the accession NP_006077 and is described in this patent by Seq ID 73. The nucleotide sequence is represented in the public sequence databases by the accession NM_006086 and is described in this patent by Seq ID 74. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford BioMedica clone p i D 10 represents Insulin induced protein 2. The protein sequence encoded by Insulin induced protein 2 is represented in the public databases by the accession AAD43048 and is described in this patent by Seq ID 75. The nucleotide sequence is represented in the public sequence databases by the accession AF125392 and is described in this patent by Seq ID 76. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Insulin induced protein 2 is induced in m acrophages activated by LPS and gam m a interferon. W e expect it to have a pro- inflamm atory role,-and its inhibition may have an anti-inflammatory effect.
The Oxford B ioM edica clones p lD 13 and p i A22 represent Adenylate kinase 3. The protein sequence encoded by Adenylate kinase 3 is represented in the public databases by the accession NP_037542 and is described in this patent by Seq ID 77 and 263. The nucleotide sequence is represented in the public sequence databases by the accession NM_013410 and is described in this patent by Seq ID 78 and 264. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Adenylate kinase 3 is induced in m acrophages activated by LPS and gam ma interferon. TNFalpha is an inflamm atory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis, Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions. Adenylate kinase 3 is induced in m acrophages activated by TNFalpha.
The Oxford BioM edica clone pl E9 represents a novel PI-3-kinase adapter. The protein sequence encoded by the novel PI-3-kinase adapter is not represented in the public databases by a protein accession but is described in this patent by Seq ID 79. The nucleotide sequence of an unannotated EST corresponding to the novel PI-3-kinase adapter is represented in the public sequence databases by the accession R62339 and is described in this patent by Seq ID 80. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types, M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD and peripheral arterial disease. The novel PI-3-kinase adapter is preferentially induced by hypoxia in monocytes or macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving macrophages and hypoxia. In a gene array analysis it is expressed in hypoxic m onocytes and macrophages at levels 6-fold higher than the median expression level of this gene throughout 9 other cell types in either norm oxia or hypoxia. In more sensitive TaqM an analysis the novel PI-3-kinase adapter it is found to be expressed at approximately 1000 times the levels of 9 other cell types, all exposed to hypoxia for 18hr. The relevance of the novel PI-3-kinase adapter to hum an disease is also appreciated from comparison with a related murine gene, B CAP. It is known that this gene is phosphorylated by the tyrosine kinase, Syk. W e also show novel data regarding Syk, in that it is also induced in response to hypoxia in a tissue specific manner identical to that of the novel PI-3-kinase adapter. Therefore the biological relevance and utility of our discovery of hypoxic induction of the novel PI-3-kinase adapter gene is further highlighted.
The Oxford B ioMedica clone plFl represents an unannotated EST . The protein sequence encoded by this EST is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession AA489477 and is described in this patent by Seq ID 82, Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford B ioM edica clone p l E7 represents a novel M etallothionein. The protein sequence encoded by Novel M etallothionein is not represented in the public databases by a protein accession but is described in this patent by Seq ID 83. The nucleotide sequence is represented in the public sequence databases by the accession R06601 and is described in this patent by Seq ID 84. M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPA S l are transcription factors that mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. The novel Metallothionein represented by Seq ID 84 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFl alpha. Hepatocytes are the m ain cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to developm ent of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. The novel Metallothionein represented by Seq ID 84 is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The novel Metallothionein represented by Seq ID 84 is induced in macrophages activated by LPS and gamma interferon.
The O xford B ioM edica clone pl E6 represents EGL nine (C .elegans) hom olog 3. The protein sequence encoded by EGL nine (C.elegans) hom olog 3 is represented in the public databases by the accession NP_071356 and is described in this patent by Seq ID 85. The nucleotide sequence is represented in the public sequence databases by the accession NM_022073 and is described in this patent by Seq ID 86. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPA S l are transcription factors that m ediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. B y adenoviral over-expression of EPAS l we show augm entation of the hypoxic induction of certain genes, further confirm ing their status as responsive to hypoxia. EGL nine (C .elegans) hom olog 3 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPA S l . Its preferential regulation by EPAS l provides a route to preferential intervention, to avoid toxicity to other tissues. Hepatocytes are the m ain cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. EGL nine (C .elegans) hom olog 3 is preferentially induced by hypoxia in hepatocytes. We find that EGLN3 and a related hum an gene C l orf 12 (seq ID 89/90) both of which are predicted to be proline hydroxylases, are expressed at differing absolute expression levels in different tissues. For instance, in the hypoxic hepatocyte (6hr) the normalised expression values of EGLN and cl orfl 2 are 0.015 and 0.0074 respectively, i.e. EGLN being the dominant gene. In contrast, in the neuroblastoma cell line SH-SY5Y , the normalised expression values of EGLN and cl orfl 2 after 6hr hypoxia are 0.0012 and 0.108 respectively, i.e. cl orfl 2 being the dominant gene by a large m argin. This data demonstrates that cl ORF12 and EGLN3 are not constitutively expressed at an equal am ount in different tissues indicating specificity of function. Therefore therapeutic products m ay be developed based on this data, with the goal of m odulating proline hydroxylation of target proteins (such as HIFl alpha) in specific tissues, based on the differing expression profile of cl ORF12 and EGLN 3 in those tissues.
The Oxford BioM edica clone p l D 14 represents C l orf 12. The protein sequence encoded by C l orfl 2 is represented in the public databases by the accession NP_071334 and is described in this patent by Seq ID 89. The nucleotide sequence is represented in the public sequence databases by the accession NM_022051 and is described in this patent by Seq ID 90. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. W e find that C l orf 12 and a related hum an gene EGLN3 (seq ID 85/86) both of which are predicted to be proline hydroxylases, are expressed at differing absolute expression levels in different tissues. For instance, in the hypoxic hepatocyte (6hr) the norm alised expression values of EGLN and cl orf 12 are 0.015 and 0.0074 respectively, i.e. EGLN being the dominant gene. In contrast, in the neuroblastoma cell line SH-SY5Y, the normalised expression values of EGLN and c 1 o rf 12 after 6hr hypoxia are 0,0012 and 0.108 respectively, i.e. cl orfl 2 being the dominant gene by a large m argin. This data dem onstrates that cl ORF12 and EGLN3 are not constitutively expressed at an equal am ount in different tissues indicating specificity of function. Therefore therapeutic products m ay be developed based on this data, with the goal of m odulating proline hydroxylation of target proteins (such as HIFl alpha) in specific tissues, based on the differing expression profile of cl ORF12 and EGLN3 in those tissues.
The Oxford BioM edica clone p2B l represents PRAME. The protein sequence encoded by PRAM E is represented in the public databases by the accession NP_006106 and is described in this patent by Seq ID 87. The nucleotide sequence is represented in the public sequence databases by the accession NM_0061 15 and is described in this patent by Seq ID 88. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tum ours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, PRAM E is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. PRAME is a w ell-known tumour-associated antigen. Our surprising dem onstration of its hypoxia-regulation provides for an important diagnostic test to distinguish false-positive results. In addition, we show the relevance of PRAM E to hypoxia-related functions of tumours such as angiogenesis.
The Oxford BioM edica clones p 1 D 17 and plP 14 represent Semaphorin 4b. The protein sequence encoded by Semaphorin 4b is represented in the public databases by the accession BAB21836 and is described in this patent by Seq ID 91. The nucleotide sequence is represented in the public sequence databases by the accession AB 051532 and is described in this patent by Seq ID 92. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue. Sem aphorin 4b is preferentially induced by hypoxia in renal epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Semaphorin 4b is induced in m acrophages activated by LPS and gamm a interferon.. Semaphorin 4b is also induced by the the presence of reactive oxygen species. W e expect it to have a pro-inflammatory role, and its inhibition may have an anti-inflammatory effect. We have cited elsewhere in this specification that a plexin is hypoxia-regulated, and we propose a functional relationship between these two molecules. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Semaphorin 4b is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. Semaphorin 4b is also induced in response to superoxide radicals, as found in various disease states, implying utility. Semaphorin 4b is predicted to function in modulating several cellular processes key to human disease, including angiogenesis, inflammation, immune cell migration and tissue remodelling. Other Semaphorins including Semaphorin E, which are induced in response to hypoxia will also be implicated in these disease processes and have utility as described for Semaphorin 4b.
The Oxford BioMedica clone plC24 represents SLC25A 19, The protein sequence encoded by SLC25A 19 is represented in the public databases by the accession NP_068380 and is described in this patent by Seq ID 93. The nucleotide sequence is represented in the public sequence databases by the accession NM_021734 and is described in this patent by Seq ID 94, SLC25A 19 transports deoxynucleotides into mitochondria and is therefore essential for mtDNA synthesis, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plD3 represents Serine carboxypeptidase 1. The protein sequence encoded by Serine carboxypeptidase 1 is represented in the public databases by the accession NP_067639 and is described in this patent by Seq ID 95. The nucleotide sequence is represented in the public sequence databases by the accession NM_021626 and is described in this patent by Seq ID 96. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Serine carboxypeptidase 1 is repressed in macrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions, Serine carboxypeptidase 1 is induced in macrophages activated by TNFalpha. Increased serine carboxypeptidase activity in glial cells has been shown to result in neurological abnormalities, due to the degradation of essential neuro-active factors. Similarly, peripheral neurological disease could result from such activity in macrophages. Our demonstration of hypoxia regulation of serine carboxypeptidase activity opens a route for diagnosis and treatment of these diseases. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Serine carboxypeptidase 1 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plE14 represents an unknown mRNA (schizophrenia-linked). The protein sequence encoded by the unknown mRNA (schizophrenia-linked) is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AY0101 12 and is described in this patent by Seq ID 98. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Unknown mRNA (schizophrenia-linked) is induced in macrophages activated by TNFalpha. There are many enzymic activities that can give rise to neurological abnormalities, and their hypoxia regulation is pertinent to the diagnosis and treatment of such diseases, including schizophrenia.
The Oxford BioMedica clone plE20 represents Myo-inositol monophosphatase A3, The protein sequence encoded by M yo-inositol monophosphatase A3 is represented in the public databases by the accession AAK52336 and is described in this patent by Seq ID 99, The nucleotide sequence is represented in the public sequence databases by the accession NM_017813 and is described in this patent by Seq ID 100, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. As refered to elsewhere in this specification, we have found several components of the phosphatidylinisotol second messenger system to be hypoxia-regulated, This system has profound effects which are relevant to many diseases with known associations with hypoxia and ischaemia. Local and transient ischaemia is relevant to such diseases as rheumatoid arthritis and atherosclerosis, and also potentially to such diseases as schizophrenia and bi-polar disorder. It is instructive that lithium , which is a well-recognised treatment for affective disorders, appears to operate via the phosphatidylinisotol system [Pettegrew et al 2001 , Bipolar Disord 3:189-201]. Macrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. M yo-inositol monophosphatase A3 is repressed in macrophages activated by LPS and gamm a interferon. The Oxford B ioMedica clone p2A24 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA521314 and is described in this patent by Seq ID 102. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone pl E 17 represents Hypothetical protein FLJ31668. The protein sequence encoded by Hypothetical protein FLJ31668 is represented in the public databases by the accession B AB71 124 and is described in this patent by Seq ID 103. The nucleotide sequence is represented in the public sequence databases by the accession AK056230 and is described in this patent by Seq ID 104. Hypoxia is an im portant feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioMedica clone p l E 19 represents an unannotated EST . The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession R51835 and is described in this patent by Seq ID 106. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 106 is up-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford B ioM edica clone pl E 15 represents cDNA YI27F12. The protein sequence encoded by cDNA YI27F12 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AF075018 and is described in this patent by Seq ID 108. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, The cDNA YI27F12 is induced in macrophages treated with the inhibitory cytokine IL-10. The cDNA YI27F12 is repressed in macrophages activated by IL-17. W e expect the product of cDNA YI27F12 to have an anti-inflam m atory role, The Oxford BioMedica clone plEl l represents an unannotated EST.* The protein sequence encoded by this EST is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession R69248 and is described in this patent by Seq ID 110, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford BioMedica clone plE23 represents cDNA FLJ14041 fis, clone HEMBA1005780. The protein sequence encoded by cDNA FLJ14041 fis, clone HEMBA1005780 is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession AK024103 and is described in this patent by Seq ID 112, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plE21 represents Glutamate-cysteine ligase, modifier subunit. The protein sequence encoded by Glutamate-cysteine ligase, modifier subunit is represented in the public databases by the accession NP_002052 and is described in this patent by Seq ID 1 13. The nucleotide sequence is represented in the public sequence databases by the accession NM_002061 and is described in this patent by Seq ID 114. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Glutamate-cysteine ligase is the rate-limiting enzyme of glutathione synthesis, and this enzyme is relevant to cell survival under stress, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Glutamate-cysteine ligase, modifier subunit is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plD23 represents PTEN . The protein sequence encoded by PTEN is represented in the public databases by the accession NP_000305 and is described in this patent by Seq ID 115. The nucleotide sequence is represented in the public sequence databases by the accession NM_000314 and is described in this patent by Seq ID 116. PTEN is a member of the mixed function, serine/threonine/tyrosine phosphatase subfamily of protein phosphatases. Its physiological substrates, however, are primarily 3-phosphorylated inositol phospholipids, which are products of phosphoinositide 3-kinases [Downes et al 2001 , Biochem Soc Trans 29:846-51]. Hypoxia-regulation of this gene is a further element in the hypoxic regulation of this important second messenger system . Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clone plD24 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession T73780 and is described in this patent by Seq ID 118. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic-, prognostic and diagnostic products. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue. The EST represented by Seq ID 118 is preferentially induced by hypoxia in renal epithelial cells. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 118 is induced in macrophages activated by LPS and gamma interferon,
The Oxford BioMedica clones plD22 and plG5 represent MAX-interacting protein 1. The protein sequence encoded by MAX-interacting protein 1 is represented in the public databases by the accession NP_005953 and is described in this patent by Seq ID 119 and 279. The nucleotide sequence is . represented in the public sequence databases by the accession NM_005962 and is described in this patent by Seq ID 120 and 280. M AX-interacting protein 1 is a negative regulator of myc oncoprotein with tumor suppressor properties. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, MAX-interacting protein 1 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone plE2 represents Mannosidase, alpha, class 1A, member 1. The protein sequence encoded by Mannosidase, alpha, class 1 A, member 1 is represented in the public databases by the accession NP_005898 and is described in this patent by Seq ID 121. The nucleotide sequence is represented in the public sequence databases by the accession NM_005907 and is described in this patent by Seq ID 122. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Mannosidase, alpha, class 1A, member 1 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone plEl represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA446361 and is described in this patent by Seq ID 124. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 124 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone plE4 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA931411 and is described in this patent by Seq ID 126. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in. the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 126 is repressed in macrophages activated by LPS and gamma interferon, We expect this gene product to have an anti-inflammatory role. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 126 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clone plD 18 represents cDNA FLJ13443 fis, clone PLACE1002853. The protein sequence encoded by cDNA FLJ13443 fis, clone PLACE1002853 is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession AK023505 and is described in this patent by Seq ID 128. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The cDNA FLJ13443 fis, clone PLACE1002853 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. The Oxford BioM edica clone pl D21 represents Hypothetical protein FLJ22622. The protein sequence encoded by Hypothetical protein FLJ22622 is represented in the public databases by the accession B AB 15424 and is described in this patent by Seq ID 129. The nucleotide sequence is represented in the public sequence databases by the accession NM_025151 and is described in this patent by Seq ID 130. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue. Hypothetical protein FLJ22622 is preferentially induced by hypoxia in renal epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein FLJ22622 is repressed in m acrophages activated by LPS and gamm a interferon. W e expect it to have an anti-inflammatory role. Hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein FLJ22622 is up-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford B ioM edica clone p l C22 represents CD 84-H 1 . The protein sequence encoded by CD84-H 1 is represented in the public databases by the accession AAK69052 and is described in this patent by Seq ID 131. The nucleotide sequence is represented in the public sequence databases by the accession AF275725 and is described in this patent by Seq ID 132. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone p l C23 represents Hypothetical protein FLJ12832, The protein sequence encoded by Hypothetical protein FLJ12832 is represented in the public databases by the accession XP_043394 and is described in this patent by Seq ID 133. The nucleotide sequence is represented in the public sequence databases by the accession AK022894 and is described in this patent by Seq ID 134. Hypothetical protien FLJ12832 is a putative ubiquitin as it shows high structural similarity to ubiquitin C and contains a ubiquitin dom ain, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone p l D l l represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA251748 and is described in this patent by Seq ID 136. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have, utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clones plE3 and plFlδ represent CYPIB I. The protein sequence encoded by CYP1B 1 is represented in the public databases by the accession NP_000095 and is described in this patent by Seq ID 137 and 325. The nucleotide sequence is represented in the public sequence databases by the accession NM_000104 and is described in this patent by Seq ID 138 and 326. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD. CYPIB I is preferentially induced by hypoxia in monocytes or macrophages and a restricted number of other cell types. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. CYPIB I is repressed in m acrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. CYPIB I is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, CYPl B l is up-regulated and also down regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plD20 represents Hypothetical protein KIAA 1125. The protein sequence encoded by Hypothetical protein KIAA 1125 is represented in the public databases by the accession XP_012932 and is described in this patent by Seq ID 139. The nucleotide sequence is represented in the public sequence databases by the accession AB032951 and is described in this patent by Seq ID 140. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plE5 represents Hepcidin antimicrobial peptide. The protein sequence encoded by Hepcidin antimicrobial peptide is represented in the public databases by the accession NP_066998 and is described in this patent by Seq ID 141. The nucleotide sequence is represented in the public sequence databases by the accession NM_021175 and is described in this patent by Seq ID 142. Hypoxia is an important feature. of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hepatocytes are the main cell type of the liver and genes that are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. Hepcidin antimicrobial peptide is preferentially induced by hypoxia in hepatocytes. Hepcidin antimicrobial peptide is induced in macrophages treated with the inhibitory cytokine IL-10. TNFalpha is an inflam m atory cytokine, w hich acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam m atory conditions. Hepcidin antimicrobial peptide is repressed in m acrophages activated by TNFalpha.
The O xford B ioMedica clone plD 19 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession R68736 and is described in this patent by
Seq ID 144. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown, to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 144 is induced in macrophages activated by LPS and gamma interferon and. is also induced in m acrophages activated by IL-15. W e expect the gene product relevant to the EST represented by Seq ID 144 to have a pro-inflam matory role, and its inhibition may have an anti-inflammatory effect.
The O xford B ioM edica clone p2A 15 represents Sialyltransferase. The protein, sequence encoded by Sialyltransferase is represented in the public databases by the accession NP_006447 and is described in this patent by Seq ID 145. The nucleotide sequence-is represented in the public sequence databases by the accession NM_006456 and is described in this patent by Seq ID 146. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone pi II 4 represents cDNA DKFZp564D 016. The protein sequence encoded by cDNA DKFZp564D016 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AL050021 and is described in this patent by Seq ID 148. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone p 112 represents cDNA FLJ11302 fis, clone PLACE1009971. The protein sequence encoded by cDNA FLJ11302 fis, clone PLACE1009971 is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession AK002164 and is described in this patent by Seq ID 150. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease
" sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The cDNA
FLJ11302 fis, clone PLACE1009971 is repressed in macrophages activated by LPS and gamma interferon. We expect it to have an anti-inflammatory role. The Oxford BioMedica clone p 1112 represents Hypothetical protein MGC4549, The protein sequence encoded by Hypothetical protein MGC4549 is represented in the public databases by the accession XP_032794 and is described in this patent by Seq ID 151. The nucleotide sequence is represented in the public sequence databases by the accession NM_032377 and is described in this patent by Seq ID 152. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypothetical protein M GC4549 is induced in macrophages treated with the inhibitory cytokine IL-10. Hypothetical protein M GC4549 is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. We expect it to have an anti-inflammatory role.
The Oxford BioMedica clone p 113 represents ELM02. The protein sequence encoded by ELM 02 is represented in the public databases by the accession AAL14467 and is described in this patent by Seq ID 153. The nucleotide sequence is represented in the public sequence databases by the accession XM_012933 and is described in this patent by Seq ID 154, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. This gene has been shown recently to promote phagocytosis and cell shape changes [Gumienny et al 2001 , Cell 107:27-41]. These functions are typical of the macrophage, and are likely to play a role in macrophage-associated diseases.
The Oxford BioMedica clone pill 0 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA420992 and is described in this patent by Seq ID 156. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford B ioMedica clone p l H 18 represents Ubiquitin specific protease 7. The protein sequence encoded by Ubiquitin specific protease 7 is represented in the public databases by the accession NP_003461 and is described in this patent by Seq ID 157. The nucleotide sequence is represented in the public sequence databases by the accession NM_003470 and is described in this patent by Seq ID 158. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Ubiquitin specific protease 7 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. We expect decreased activity of the gene product to have an anti-tumour effect. The Oxford B ioMedica clone p l H24 represents Nucleolar phosphoprotein Nopp34. The protein sequence encoded by Nucleolar phosphoprotein Nopp34 is represented in the public databases by the accession NP_1 15766 and is described in this patent by Seq ID 159. The nucleotide sequence is represented in the public sequence databases by the accession NM_032390 and is described in this patent by Seq ID 160. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioMedica clone p l E22 represents cDNA FLJ13618 fis, clone PLACE 1010925. The protein sequence encoded by cDNA FLJ13618 fis, clone PLACE1010925 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AK023680 and is described in this patent by Seq ID 162. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The cDNA FLJ13618 fis, clone PLACE1010925 is induced in macrophages activated by LPS and gamma interferon.
The Oxford B ioM edica clone p l H21 represents Hypothetical protein FLJ1351 1. The protein sequence encoded by Hypothetical protein FLJ13511 is represented in the public databases by the accession NP_149014 and is described in this patent by Seq ID 163. The nucleotide sequence is represented in the public sequence databases by the accession NM_033025 and is described in this patent by Seq ID 164.
Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD . Hypothetical protein FLJ13511 is preferentially induced by hypoxia in m onocytes or macrophages and a restricted number of other cell types. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein FLJ13511 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clone pi ll represents Ribosomal RNA intergenic spacer. The protein sequence encoded by Ribosom al RNA intergenic spacer is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession AA664228 and is described in this patent by Seq ID 166, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, The O xford B ioM edica clone plH 14 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession R44397 and is described in this patent by Seq ID 168 , Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford B ioMedica clone pl H l l represents Carboxypeptidase M . The protein sequence encoded by Carboxypeptidase M is represented in the public databases by the accession NP_001865 and is described in this patent by Seq ID 169. The nucleotide sequence is represented in the public sequence databases by the accession NM_001874 and is described in this patent by Seq ID 170. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioMedica clone pl H 17 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession W 87747 and is described in this patent by Seq ID 172. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 172 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pi H 12 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA973568 and is described in this patent by Seq ID 174. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford BioMedica clone plH7 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession T98529 and is described in this patent by Seq ID 176, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clone plH 15 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA022679 and is described in this patent by Seq ID 178. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 178 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plH20 represents an unannotated EST. The protein sequence encoded by EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession H17921 and is described in this patent by Seq ID 180. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 180 is up-regulated in the malignant tissue as . compared to adjacent normal tissue in at least one patient. We expect decreased activity of the gene product to have an anti-tumour effect-. The Oxford BioMedica clone plH8 represents ABL. The protein sequence encoded by ABL is represented in the public databases by the accession NP_009297 and is described in this patent by Seq ID 181. The nucleotide sequence is represented in the public sequence databases by the accession NM_007313 and is described in this patent by Seq ID 182. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. ABL is induced in macrophages treated with the inhibitory cytokine IL-10. ABL is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. We expect it to have an anti-inflammatory role Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, ABL is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The O xford BioMedica clone p lH 16 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession W91958 and is described in this patent by Seq ID 184. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 184 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plH9 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession R63694 and is described in this patent by Seq ID 186. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioM edica clone plH23 represents Hypothetical protein FLJ21094. The protein sequence encoded by Hypothetical protein FLJ21094 is represented in the public databases by the accession AAH14003 and is described in this patent by Seq ID 187. The nucleotide sequence is represented in the public sequence databases by the accession AK024747 and is described in this patent by Seq ID 188. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone p i H 10 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA909912 and is described in this patent by Seq ID 190. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioM edica clone plH6 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession T99032 and is described in this patent by Seq ID 192. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The EST represented by Seq ID 192 is induced in m acrophages treated with the inhibitory cytokine IL-10. The EST represented by Seq ID 192 is repressed in m acrophages activated by IL-15. W e expect it to have an anti-inflammatory role.
The Oxford B ioMedica clone p l H 13 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession H52503 and is described in this patent by Seq ID 194. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 194 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford B ioMedica clone p I H 19 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession A A 127017 and is described in this patent by Seq ID 196. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by the Seq ID 196 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plG22 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession R38647 and is described in this patent by Seq ID 198 , Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheum atoid arthritis. The EST represented by Seq ID 198 is preferentially induced by hypoxia in endothelial cells. W e expect this gene product to have a pro- angiogenic effect, and its inhibition to have an anti-angiogenic effect.
The Oxford B ioM edica clone pi G21 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession, The nucleotide sequence is represented in the public sequence databases by the accession T87233 and is described in this patent by Seq ID 200. Hypoxia is an important-feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone pl H l represents Hypothetical protein FLJ10826. The protein sequence encoded by Hypothetical protein FLJ10826 is represented in the public databases by the accession BAB 14226 and is described in this patent by Seq ID 201. The nucleotide sequence is represented in the public sequence databases by the accession NM_018233 and is described in this patent by Seq ID 202. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility, in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone p l G20 represents cDNA YO23H03. The protein sequence encoded by cDNA YO 23H03 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AF075053 and is described in this patent by Seq ID 204. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The cDNA YO23H03 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone plH5 represents Hypothetical protein FLJ22690. The protein sequence encoded by Hypothetical protein FLJ22690 is represented in the public databases by the accession NP_078987 and is described in* this patent by Seq ID 205. The nucleotide sequence is represented in the public sequence databases by the accession NM_02471 1 and is described in this patent by Seq ID 206. Hypoxia is an important feature of several diseases-, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Endothelial cells are key to angiogenesis, a process implicated in several diseases associated with hypoxia, including cancer and rheumatoid arthritis. Hypothetical protein FLJ22690 is preferentially induced by hypoxia in endothelial cells. We expect this gene product to have a pro-angiogenic effect, and its inhibition to have an anti-angiogenic effect. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Hypothetical protein FLJ22690 is induced in macrophages activated by IL-15,
The Oxford BioMedica clone pi G 19 represents Mitochondrion sequence. The protein sequence encoded by Mitochondrion sequence is represented in the public databases by the accession AAH05845 and is described in this patent by Seq ID 207. The nucleotide sequence is represented in the public sequence databases by the accession BC005845 and is described in this patent by Seq ID 208. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates. are also found. In a series of 5 patients with either ovarian or breast cancer, the Mitochondrion sequence represented by Seq ID 208 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plH2 represents Fatty acid binding protein 5. The protein sequence encoded by Fatty acid binding protein 5 is represented in the public databases by the accession NP_001435 and is described in this patent by Seq ID 209. The nucleotide sequence is represented in the public sequence databases by the accession NM_001444 and is described in this patent by Seq ID 210. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Fatty acid binding protein 5 is preferentially induced by hypoxia in monocytes or macrophages. Crucially and very recently, Fatty acid binding protein 5 expressed in macrophages has been shown to play a very important role in the development of atherosclerotic plaques [Layne et al 2001 , FASEB J 15:2733-5], Our demonstration of hypoxic-regulation of this gene not only makes clear how this gene can participate in disease initiation and progression, but provides for a potential route to diagnosis and therapy of atherosclerosis. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Fatty acid binding protein 5 is repressed in macrophages activated by TNFalpha.
The Oxford BioMedica clone p 1 G 18 represents Mitochondrion sequence. The protein sequence encoded by Mitochondrion sequence is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession BC001612 and is described in this patent by Seq ID 212. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The Mitochondrion sequence represented by Seq ID 212 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioM edica clone plH4 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA679939 and is described in this patent by Seq ID 214. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 214 is repressed in macrophages activated by IL-17. W e expect it to have an anti-inflammatory role. Hypoxia is frequently found in human tum ours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by the Seq ID 214 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford B ioMedica clone p l H3 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA630167 and is described in this patent by Seq ID 216. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, the EST represented by Seq ID 216 is up-regulated and also dow n-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The protein sequence encoded by B CL2/adenovirus E 1 B 19kD-interacting protein 3-like is represented in the public databases by the accession NP_004322 and is described in this patent by Seq ID 217. The nucleotide sequence is represented in the public sequence databases by the accession NM _004331 and is described in this patent by Seq ID 218. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The protein sequence encoded by SLC2A 1 is represented in the public databases by the accession NP_006507 and is described in this patent by Seq ID 219. The nucleotide sequence is represented in the public sequence databases by the accession NM_006516 and is described in this patent by Seq ID 220. SLC2A 1 is a glucose transporter gene and is also known as GLUT 1. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plP3 represents PDGFB . The protein sequence encoded by PDGFB is represented in the public databases by the accession NP_148937 and is described in this patent by Seq ID 221. The nucleotide sequence is represented in the public sequence databases by the accession NM_033016 and is described in this patent by Seq ID 222. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. PDGFB is induced in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clones pl A8 and plA9 represent Lactate dehydrogenase A . The protein sequence encoded by Lactate dehydrogenase A is represented in the public databases by the accession NP_005557 and is described in this patent by Seq ID 223. The nucleotide sequence is represented in the public sequence databases by the accession NM_005566 and is described in this patent by Seq ID 224. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Lactate dehydrogenase A is repressed in macrophages activated by LPS and gamma interferon and is also repressed in macrophages activated by IL-15. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Lactate dehydrogenase A is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Lactate dehydrogenase A is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone p 1 B 17 represents Tissue factor. The protein sequence encoded by Tissue factor is represented in the public databases by the accession NP_001984 and is described in this patent by Seq ID 225. The nucleotide sequence is represented in the public sequence databases by the accession NM_001993 and is described in this patent by Seq ID 226. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Tissue factor is preferentially induced by hypoxia in mammary epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Tissue factor is induced in macrophages activated by TNFalpha. Tissue factor is the primary initiator of blood coagulation with structural homology to the cytokine receptor family, and has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Our demonstration of hypoxic regulation leads to a clear undertanding of the possibility of intervention in disease by modulation of Tissue factor activity.
The Oxford BioMedica clone plO20 represents VEGF. The protein sequence encoded by VEGF is represented in the public databases by the accession NP_003367 and is described in this patent by Seq ID 227. The nucleotide sequence is represented in the public sequence databases by the accession NM_003376 and is described in this patent by Seq ID 228. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, VEGF is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plB2 represents N-myc downstream regulated. The protein sequence encoded by N-myc downstream regulated is represented in the public databases by the accession NP_006087 and is described in this patent by Seq ID 229. The nucleotide sequence is represented in the public sequence databases by the accession NM_006096 and is described in this patent by Seq ID 230. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. N-myc downstream regulated is preferentially induced by hypoxia in mammary epithelial cells.
The Oxford BioMedica clone plB3 represents Proline 4-hydroxylase, alpha polypeptide I. The protein sequence encoded by Proline 4-hydroxylase, alpha polypeptide I is represented in the public databases by the accession NP_000908 and is described in this patent by Seq ID 231. The nucleotide sequence is represented in the public sequence databases by the accession NM_000917 and is described in this patent by Seq ID 232. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Proline 4-hydroxylase, alpha polypeptide I is repressed in macrophages activated by LPS and gamma interferon, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Proline 4-hydroxylase, alpha polypeptide I is down-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
The protein sequence encoded by B CL2/adenovirus E l B -interacting protein 3 is represented in the public databases by the accession NP_004043 and is described in this patent by Seq ID 233. The nucleotide sequence is represented in the public sequence databases by the accession NM_004052 and is described in this patent by Seq ID 234. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clones p I B 18 and p l B 19 represent Plasminogen activator inhibitor, type 1. The protein sequence encoded by Plasminogen activator inhibitor, type 1 is represented in the public databases by the accession NP_000593 and is described in this patent by Seq ID 235. The nucleotide sequence is represented in the public sequence databases by the accession NM_000602 and is described in this patent by Seq ID 236. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Plasm inogen activator inhibitor, type 1 is induced in macrophages activated by LPS and gamma interferon. Plasminogen activator inhibitor, type 1 is repressed in macrophages activated by IL-17. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Plasminogen activator inhibitor, type 1 is induced in m acrophages activated by TNFalpha. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Plasminogen activator inhibitor, type 1 is down-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford BioM edica clone p l N 17 represents COX-2. The protein sequence encoded by COX-2 is represented in the public databases by the accession NP_000954 and is described in this patent by Seq ID 237. The nucleotide sequence is represented in the public sequence databases by the accession NM_000963 and is described in this patent by Seq ID 238. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. COX-2 is preferentially induced by hypoxia in m amm ary epithelial cells. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. COX-2 is induced in macrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. COX-2 is induced in macrophages activated by TNFalpha, In view of the known role of COX-2 in prostaglandin synthesis and tumour progression, its induction by hypoxia has profound clinical implications, and clear utility in diagnosis and therapy. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found.
The Oxford BioMedica clone plA24 represents Metallothionein I H . The protein sequence encoded by Metallothionein I H is represented in the public databases by the accession NP_005942 and is described in this patent by Seq ID 239. The nucleotide sequence is represented in the public sequence databases by the accession NM_005951 and is described in this patent by Seq ID 240. M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. Metallothionein IH is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, M etallothionein IH is induced in macrophages activated by LPS and gamma interferon. The protein sequence encoded by M etallothionein IL is represented in the public databases by the accession NP_002441 and is described in this patent by Seq ID 241. The nucleotide sequence is represented in the public sequence databases by the accession NM_002450 and is described in this patent by Seq ID 242. Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plB l represents Metallothionein 1 G. The protein sequence encoded by Metallothionein 1 G is represented in the public databases by the accession NP_005941 and is described in this patent by Seq ID 243. The nucleotide sequence is represented in the public sequence databases by the accession NM_005950 and is described in this patent by Seq ID 244. Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFlalpha and EPASl are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Metallothionein 1G has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFl alpha. Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. Metallothionein 1 G is preferentially induced by hypoxia in hepatocytes. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Metallothionein 1 G is induced in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, M etallothionein 1 G is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The protein sequence encoded by Metallothionein IE (functional) is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA872383 and is described in this patent by Seq ID 246. Metallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clones pi A l , plA2, pi A3 and pl A4 represent SLC2A3. The protein sequence encoded by SLC2A3 .is represented in the public databases by the accession NP_008862 and is described in this patent by Seq ID 247. The nucleotide sequence is represented in the public sequence databases by the accession NM_006931 and is described in this patent by Seq ID 248. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. SLC2A3 is induced in macrophages treated with the inhibitory cytokine IL-10. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. SLC2A3 is induced in macrophages activated by TNFalpha.
The Oxford BioMedica clones pi A 15, pi A 16, pi A 17 and pi A 18 represent Hexokinase-2. The protein sequence encoded by Hexokinase-2 is represented in the public databases by the accession NP_000180 and is described in this patent by Seq ID 249. The nucleotide sequence is represented in the public sequence databases by the accession NM_000189 and is described in this patent by Seq ID 250. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hexokinase-2 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clones plB 14, plB 15 and pi B 16 represent Interleukin 8. The protein sequence encoded by Interleukin 8 is represented in the public databases by the accession NP_000575 and is described in this patent by Seq ID 251. The nucleotide sequence is represented in the public sequence databases by the accession NM_000584 and is described in this patent by Seq ID 252. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Interleukin 8 is induced in macrophages activated by LPS and gamma interferon and is also induced in macrophages activated by IL-17, TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Interleukin 8 is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Interleukin 8 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clones plA l l and pi A 12 represent GAPDH. The protein sequence encoded by GAPDH is represented in the public databases by the accession NP_002037 and is described in this patent by Seq ID 253. The nucleotide sequence is represented in the public sequence databases by the accession NM_002046 and is described in this patent by Seq ID 254. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. GAPDH is repressed in macrophages activated by LPS and gamma interferon and is also induced in m acrophages activated by IL- 17 or IL-15. TNFalpha is an inflam m atory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions, GAPDH is induced in m acrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, GAPDH is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clone pi A 13 represents Phosphoglycerate kinase 1. The protein sequence encoded by Phosphoglycerate kinase 1 is represented in the public databases by the accession NP_000282 and is described in this patent by Seq ID 255, The nucleotide sequence is represented in the public sequence databases by the accession NM_000291 and is described in this patent by Seq ID 256, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Phosphoglycerate kinase 1 is repressed in macrophages activated by LPS and gam ma interferon. TNFalpha is an inflamm atory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Phosphoglycerate kinase 1 is induced in macrophages activated by TNFalpha.
The Oxford B ioM edica clone p i A 14 represents Enolase 1. The protein sequence encoded by Enolase 1 is represented in the public databases by the accession NP_001419 and is described in this patent by Seq ID 257. The nucleotide sequence is represented in the public sequence databases by the accession NM_001428 and is described in this patent by Seq ID 258. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Enolase 1 is repressed in macrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions, Enolase 1 is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Enolase 1 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pi A 19 represents Aldolase C, The protein sequence encoded by Aldolase C is represented in the public databases by the accession NP_005156 and is described in this patent by Seq ID 259. The nucleotide sequence is represented in the public sequence databases by the accession NM_005165 and is described in this patent by Seq ID 260. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Aldolase C is induced in macrophages activated by IL-15. Aldolase C is repressed in macrophages activated by IL-15. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Aldolase C is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Aldolase is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pi A20 represents Triosephosphate isomerase 1. The protein sequence encoded by Triosephosphate isomerase 1 is represented in the public databases by the accession NP_000356 and is described in this patent by Seq ID 261. The nucleotide sequence is represented in the public sequence databases by the accession NM_000365 and is described in this patent by Seq ID 262. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Triosephosphate isomerase 1 is repressed in macrophages activated by LPS and gamm a interferon and is also repressed in macrophages activated by IL-15. TNFalpha is an , inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions, Triosephosphate isomerase 1 is induced in macrophages activated by TNFalpha, The Oxford BioMedica clone pi A23 represents Metallothionein 2A , The protein sequence encoded by Metallothionein 2A is represented in the public databases by the accession NP_005944 and is described in this patent by Seq ID 265. The nucleotide sequence is represented in the public sequence databases by the accession NM_005953 and is described in this patent by Seq ID 266. M etallothioneins can act as an antioxidant and free-radical scavenger and are therefore protective against cell death in hypoxia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFlalpha and EPAS l are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. B y adenoviral over-expression of HIFl alpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Metallothionein 2A has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFlalpha. Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis, Metallothionein 2A is preferentially induced by hypoxia in hepatocytes. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Metallothionein 2A is induced in macrophages activated by LPS and gamma interferon and also induced in macrophages activated by IL-15. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Metallothionein 2A is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clones plB20 and p 1 B 21 represent Osteopontin. The protein sequence encoded by Osteopontin is represented in the public databases by the accession NP_000573 and is described in this patent by Seq ID 267. The nucleotide sequence is represented in the public sequence databases by the accession NM_000582 and is described in this patent by Seq ID 268. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types, M onocytes and m acrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD , Osteopontin is preferentially induced by hypoxia in monocytes or macrophages and a restricted num ber of other cell types. Osteopontin has been shown recently to play a role in autoimmune disease [Chabas et al, 2001 , Science 294: 1731 -5]. W e present a new association between the hypoxic response and autoimmune disease. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. O steopontin is repressed in m acrophages activated by LPS and gamm a interferon. Hypoxia is frequently found in hum an tum ours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Osteopontin is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clones p l C 17 and p 1 C 18 represent Granulin. The protein sequence encoded by Granulin is represented in the public databases by the accession NP_002078 and is described in this patent by Seq ID 269. The nucleotide sequence is represented in the public sequence databases by the accession NM_002087 and is described in this patent by Seq ID 270. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Granulin is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients w ith either ovarian or breast cancer, Granulin is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. The up-regulation of Granulin, which is a known growth factor, is a clinically significant feature of the hypoxic response with clear diagnostic and therapeutic utility.
The Oxford B ioM edica clone pl D 8 represents Hypoxia-inducible protein 2. The protein sequence encoded by Hypoxia-inducible protein 2 is represented in the public databases by the accession NP_037464 and is described in this patent by Seq ID 271. The nucleotide sequence is represented in the public sequence databases by the accession NM_013332 and is described in this patent by Seq ID 272. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia-inducible protein 2 is induced in m acrophages treated with the inhibitory cytokine IL- 10. Hypoxia-inducible protein 2 is repressed in m acrophages activated by IL-17 and is also repressed in m acrophages activated by IL-15.
The O xford B ioM edica clone pi A 10 represents Enolase 2. The protein sequence encoded by Enolase 2 is represented in the public databases by the accession NP_001966 and is described in this patent by Seq ID 273 , The nucleotide sequence is represented in the public sequence databases by the accession NM_001975 and is described in this patent by Seq ID 274. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Enolase 2 is repressed in macrophages activated by LPS and gam m a interferon. Hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Enolase 2 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. W e expect it to have an anti-inflamm atory role. The O xford B ioMedica clone pi G24 represents Glycogen synthase 1. The protein sequence encoded by Glycogen synthase 1 is represented in the public databases by the accession NP_002094 and is described in this patent by Seq ID 275. The nucleotide sequence is represented in the public sequence databases by the accession NM_002103 and is described in this patent by Seq ID 276. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Glycogen synthase 1 is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. The O xford BioM edica clone pl G23 represents ALCAM . The protein sequence encoded by ALCAM is represented in the public databases by the accession NP_001618 and is described in this patent by Seq ID 277. The nucleotide sequence is represented in the public sequence databases by the accession NM_001627 and is described in this patent by Seq ID 278, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. In view of the recently-discovered role of ALCAM in angiogenesis [Ohneda et al, 2001 , Blood 2001 Oct 1 ;98(7):2134-42], our demonstration of hypoxic regulation of ALCAM has great clinical significance in the treatment and diagnosis of vascular disease and cancer. The Oxford BioM edica clone plG7 represents an unannotated EST, The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession BC008022 and is described in this patent by Seq ID 282. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design- of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. The EST represented by Seq ID 282 is repressed in macrophages activated by LPS and gamma interferon. W e expect the product of EST represented by Seq ID 282 to have an anti-inflammatory role,
The Oxford BioMedica clone p2A23 represents Chitinase 3-like 2, The protein sequence encoded by Chitinase 3-like 2 is represented in the public databases by the accession NP_003991 and is described in this patent by Seq ID 283, The nucleotide sequence is represented in the public sequence databases by the accession NM_004000 and is described in this patent by Seq ID 284, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Chitinase 3-like 2 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone plGl represents BACH l . The protein sequence encoded by BACHl is represented in the public databases by the accession NP_001 177 and is described in this patent by Seq ID 285. The nucleotide sequence is represented in the public sequence databases by the accession NM_001 186 and is described in this patent by Seq ID 286. BACHl , a novel helicase-Iike protein, interacts directly with BRCA 1 and contributes to its DNA repair function. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The induction by hypoxia of this known transcriptional repressor and potential oncogene [Cantor et al 2001, Cell 105:149-60] is a very significant finding with profound implications for the diagnosis and treatment of cancer. The Oxford B ioM edica clone pi G 15 represents Phosphoglucomutase 1. The protein sequence encoded by Phosphoglucomutase 1 is represented in the public databases by the accession NP_002624 and is described in this patent by Seq ID 287. The nucleotide sequence is represented in the public sequence databases by the accession NM_002633 and is described in this patent by Seq ID 288. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Phosphoglucomutase 1 is induced in m acrophages treated with the inhibitory cytokine IL-10.
The Oxford BioM edica clone plF23 represents Hypothetical protein LO C51014. The protein sequence encoded by Hypothetical protein LOC51014 is represented in the public databases by the accession Q9Y3B 3 and is described in this patent by Seq ID 289 , The nucleotide sequence is represented in the public sequence databases by the accession AF151867 and is described in this patent by Seq ID 290. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein LOC51014 is downregulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford BioM edica clone p l G8 represents Sin3-associated polypeptide. The protein sequence encoded by Sin3-associated polypeptide is represented in the public databases by the accession NP_003855 and is described in this patent by Seq ID 291. The nucleotide sequence is represented in the public sequence databases by the accession NM_003864 and is described in this patent by Seq ID 292. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone pi G 13 represents AB CA 1. The protein sequence encoded by AB CA 1 is represented in the public databases by the accession NP_005493 and is described in this patent by Seq ID 293. The nucleotide sequence is represented in the public sequence databases by the accession NM_005502 and is described in this patent by Seq ID 294. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. AB CA 1 is repressed in m acrophages activated by LPS and gamma* interferon. The hypoxia induction of ABCA 1, which is known to be relevant to atherosclerosis [Kielar et al 2001 , Clin Chem 47:2089-97], has profound implications for the diagnosis and treatment of this disease.
The Oxford BioM edica clone pl G l O represents SEC24 member A . The protein sequence encoded by SEC24 mem ber A is represented in the public databases by the accession CAA 10334 and is described in this patent by Seq ID 295. The nucleotide sequence is represented in the public sequence databases by the accession AJ131244 and is described in this patent by Seq ID 296. Hypoxia is an important feature of several. diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford B ioM edica clone p l F24 represents Glia-derived nexin. The protein sequence encoded by Glia-derived nexin is represented in the public databases by the accession AAA 35883 and is described in this patent by Seq ID 297. The nucleotide sequence is represented in the public sequence databases by the accession M 17783 and is described in this patent by Seq ID 298. Glia-derived nexin is a glycoprotein that functions as a serine protease inhibitor with activity towards thrombin, trypsin and urokinase. It is known to play a role in neuro-degeneration [Seidel et al 1998, B rain Res M ol B rain Res 60:296-300]. Thus the hypoxia induction of this gene is highly significant for the diagnosis and treatment of neuro-degenerative disease. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Glia-derived nexin is induced in macrophages activated by LPS and gamm a interferon. Hypoxia is frequently found in hum an tumours w here m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Glia-derived nexin is down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pl G2 represents Postsynaptic density-95. The protein sequence encoded by Postsynaptic density-95 is represented in the public databases by the accession NP_001356 and is described in this patent by Seq ID 299. The nucleotide sequence is represented in the public sequence databases by the accession NM_001365 and is described in this patent by Seq ID 300. Postsynaptic density-95 belongs to the MAGUK family of cell junction proteins. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The recent demonstration for a possible role for Postsynaptic density-95 in ischaemic pre-conditioning [Tauskela et al 2001 , Neuroscience 107 :571 -584] underlines the m edical significance of our determ ination of the hypoxic regulation of this gene, and its utility in the diagnosis and treatment of ischaemic disease.
The Oxford B ioM edica clone p l G l l represents Tumour protein D52. The protein sequence encoded by Tum our protein D 52 is represented in the public databases by the accession NP_005070 and is described in this patent by Seq ID 301. The nucleotide sequence is represented in the public sequence databases by the accession NM_005079 and is described in this patent by Seq ID 302. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the m edullary, tissue. Tum our protein D52 is preferentially induced by hypoxia in renal epithelial cells. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Tum our protein D52 is up-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient. Our observation of hypoxia-regulation of this tumour-associated protein is highly significant for the diagnosis and treatment of cancer. The Oxford B ioM edica clone p i G 16 represents p27, Kip l . The protein sequence encoded by p27, Kip l is represented in the public databases by the accession NP_004055 and is described in this patent by Seq ID 303. The nucleotide sequence is represented in the public sequence databases by the accession NM_004064 and is described in this patent by Seq ID 304. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The hypoxia regulation of this anti-mitogen has important utility in oncology and angiogenesis [Fouty et al 2001 , Am J Respir Cell M ol Biol 25 :652-658],
The Oxford BioM edica clone p l G9 represents PI-3-kinase, catalytic, beta polypeptide. The protein sequence encoded by PI-3-kinase, catalytic, beta polypeptide is represented in the public databases by the accession NP_006210 and is described in this patent by Seq ID 305. The nucleotide sequence is represented in the public sequence databases by the accession NM_006219 and is described in this patent by Seq ID 306. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. PI-3-kinase, catalytic, beta polypeptide is repressed in m acrophages activated by LPS and gamπra interferon. The very recent publication of a role for PI3 kinase in angiogenesis induced by hypoxic pre-conditioning [Zhu et al 2001 , FEB S Lett 508:369-74] re-enforces the clinical utility which we claim for this gene as a result of its hypoxia-induction.
The Oxford BioMedica clone plG4 represents SLC5A3. The protein sequence encoded by SLC5A3 is represented in the public databases by the accession AAC39548 and is described in this patent by Seq ID 307. The nucleotide sequence is represented in the public sequence databases by the accession AF027153 and is described in this patent by Seq ID 308. Hypoxia is an important feature of several diseases, and- genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. SLC5A3 is over-expressed in the brains of children with Downs Syndrome, and may play a role in brain pathology [Berry et al 1999, J Pediatr 135:94-7]. Thus our claims of clinical utility following from hypoxia induction have great medical significance for the diagnosis and treatment of ischaemic and degenerative disease. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SLC5A3 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone pi G 14 represents Cytohesin binding protein. The protein sequence encoded by Cytohesin binding protein is represented in the public databases by the accession NP_004279 and is described in this patent by Seq ID 309. The nucleotide sequence is represented in the public sequence databases by the accession NM_004288 and is described in this patent by Seq ID 310. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Cytohesin has been shown to modulate PI3-kinase activity [Dierks et al 2001 , J Biol Chem 276:37472- 81], re-enforcing our claim here and elsewhere in this filing of the relevance to the hypoxic response of pathways controlled by the critical second-messenger PI3. The Oxford BioMedica clones plA5 and plA6 represent SLC2A5. The protein sequence encoded by SLC2A5 is represented in the public databases by the accession NP_003030 and is described in this patent by Seq ID 311. The nucleotide sequence is represented in the public sequence databases by the accession NM_003039 and is described in this patent by Seq ID 312. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SLC2A5 is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SLC2A5 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clones plB6, plB7, plB 8 and plB9 represent Adipophilin. The protein sequence encoded by Adipophilin is represented in the public databases by the accession NP_001113 and is described in this patent by Seq ID 313. The nucleotide sequence is represented in the public sequence databases by the accession NM_001122 and is described in this patent by Seq ID 314. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD , The hypoxia induction of adipophilin has profound implications for the causation, diagnosis and treatment of atherosclerosis, because this protein plays a key role in the uptake of lipid and foam cell formation [Buechler et al 2001 , Biochim Biophys Acta 1532:97-104], Adipophilin is preferentially induced by hypoxia in monocytes or m acrophages and a restricted number of other cell types. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Adipophilin is repressed in macrophages activated by LPS and gamma' interferon and is also repressed in m acrophages activated by IL-15. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Adipophilin is induced in macrophages activated by TNFalpha, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Adipophilin is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone plG 17 represents Early development regulator 2. The protein sequence encoded by Early development regulator 2 is represented in the public databases by the accession NP_004418 and is described in this patent by Seq ID 315. The nucleotide sequence is represented in the public sequence databases by the accession NM_004427 and is described in this patent by Seq ID 316. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown- to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Early development regulator 2 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford B ioM edica clone pl G3 represents B -cell translocation gene 1. The protein sequence encoded by B -cell translocation gene 1 is represented in the public databases by the accession NP_001722 and is described in this patent by Seq ID 317. The nucleotide sequence is represented in the public sequence databases by the accession NM_001731 and is described in this patent by Seq ID 318. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. B -cell translocation gene 1 is induced in macrophages activated by LPS and gam m a interferon. Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, B -cell translocation gene 1 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioM edica clone p lF22 represents Sorting nexin 9. The protein sequence encoded by Sorting nexin 9 is represented in the public databases by the accession NP_057308 and is described in this patent by Seq ID 319. The nucleotide sequence is represented in the public sequence databases by the accession NM_016224 and is described in this patent by Seq ID 320. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions. Sorting nexin 9 is induced in m acrophages activated by TNFalpha.
The Oxford B ioM edica clone p l G 12 represents Cyclin G2. The protein sequence encoded by Cyclin G2 is represented in the public. databases by the accession NP_004345 and is described in this patent by Seq ID 321. The nucleotide sequence is represented in the public sequence databases by the accession NM_004354 and is described in this patent by Seq ID 322. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Cyclin G2 is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone pi FI 1 represents Hypothetical protein LOC51754. The protein sequence encoded by Hypothetical protein LOC51754 is represented in the public databases by the accession
XP_049657 and is described in this patent by Seq ID 323. The nucleotide sequence is represented in the public sequence databases by the accession AL137430 and is described in this patent by Seq ID 324.
Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein LOC51754 is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein LOC51754 is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone p 1 FI 4 represents Butyrate response' factor 1. The protein sequence encoded by Butyrate response factor 1 is represented in the public databases by the accession NP_004917 and is described in this patent by Seq ID 327. The nucleotide sequence is represented in the public sequence databases by the accession NM_004926 and is described in this patent by Seq ID 328. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFl alpha and EPAS l are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. By adenoviral over-expression of EPAS l we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Butyrate response factor 1 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of EPAS l . Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Butyrate response factor 1 is down-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient.
The O xford BioM edica clone p l F17 represents P8 protein (candidate of m etastasis 1 ). The protein sequence encoded by P8 protein (candidate of m etastasis 1 ) is represented in the public databases by the 5 accession NP_036517 and is described in this patent by Seq ID 329. The nucleotide sequence is represented in the public sequence databases by the accession NM_012385 and is described in this patent by Seq ID 330. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and
10 contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and - 'cytokines are especially relevant. P8 protein (candidate of metastasis 1 ) is induced in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tum ours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, P8
15 protein (candidate of m etastasis 1 ) is up-regulated and also down-regulated in- the malignant tissue as compared to adjacent norm al tissue in at least one patient.
The O xford B ioM edica clones p l C l and pl C2 represent CXCR4. The protein sequence encoded by CXCR4 is represented in the public databases by the accession NP_003458 and is described in this patent
■ • by Seq ID 331. The nucleotide sequence is represented in the public sequence databases by the accession 0 NM_003467 and is described in this patent by Seq ID 332. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several- diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene 5 expression responses to both hypoxia and cytokines are especially relevant. CXCR4 is repressed in macrophages activated by LPS and gamm a interferon. TNFalpha is an inflam matory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
30 CXCR4 is induced in m acrophages activated by TNFalpha. CXCR4 may act through the PI3-K pathway. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, CXCR4 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. The Oxford BioMedica clone plF3 represents Hypothetical protein XP_017131. The protein sequence encoded by Hypothetical protein XP_017131 is represented in the public databases by the accession XP_017131 and is described in this patent by Seq ID 333. The nucleotide sequence is represented in the public sequence databases by the accession XM_017131 and is described in this patent by Seq ID 334. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein XP_017131 is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Hypothetical protein XP_017131 is downregulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pi F20 represents Proline-rich protein with nuclear targeting signal. The protein sequence encoded by Proline-rich protein with nuclear targeting signal is represented in the public databases by the accession NP_006804 and is described in this patent by Seq ID 335. The nucleotide sequence is represented in the public sequence databases by the accession NM_006813 and is described in this patent by Seq ID 336. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Proline-rich protein with nuclear targeting signal is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Proline-rich protein with nuclear targeting signal is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plF6 represents Hypothetical protein hqp0376. The protein sequence encoded by Hypothetical protein hqp0376 is represented in the public databases by the accession T08745 and is described in this patent by Seq ID 337. The nucleotide sequence is represented in the public sequence databases by the accession AF078844 and is described in this patent by Seq ID 338. Hypothetical protein hqp0376 is a putative dead box protein as it shows high structural similarity to dead box proteins and yeast initiation factor 4A. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. HIFlalpha and EPAS l are transcription factors which mediate the response to hypoxia of several genes, and have them selves been implicated in specific diseases. By adenoviral over-expression of HIFlalpha we show augmentation of the hypoxic induction of certain genes, further confirming their status as responsive to hypoxia. Hypothetical protein hqp0376 has been shown to be induced by hypoxia to a greater degree following adenoviral over-expression of HIFl alpha. Hepatocytes are the main cell type of the liver and genes which are induced in response to hypoxia in this cell type are relevant to development of diagnostics and therapeutics towards liver diseases involving hypoxia, including cirrhosis. Hypothetical protein hqp0376 is preferentially induced by hypoxia in hepatocytes. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Hypothetical protein hqp0376 is induced in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone plF4 represents CYPl . The protein sequence encoded by CYPl is represented in the public databases by the accession NP_000776 and is described in this patent by Seq ID 339. The nucleotide sequence is represented in the public sequence databases by the accession NM_000785 and is described in this patent by Seq ID 340. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . CYPl is preferentially induced by hypoxia in monocytes or macrophages. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. CYPl is induced in macrophages activated by LPS and gamma interferon. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflamm atory conditions. CYP l is induced in m acrophages activated by TNFalpha.
The O xford B ioM edica clone p 1 FI 5 represents SHB adaptor protein. The protein sequence encoded by SHB adaptor protein is represented in the public databases by the accession NP_003019 and is described in this patent by Seq ID 341. The nucleotide sequence is represented in the public sequence databases by the accession NM_003028 and is described in this patent by Seq ID 342. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. SHB adaptor protein participates in tyrosine kinase-mediated signalling and the regulation of angiogenesis and apotosis [Dixelius J. 2000, Blood 95:3403-1 1]. Our surprising observation of the hypoxia regulation of this protein has clear medical utility in the diagnosis and treatm ent of vascular disease and cancer. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SHB adaptor protein is repressed in macrophages activated by LPS and gamma interferon.
The Oxford BioM edica clone p 1 FI 3 represents Papillom avirus regulatory factor PRF-1 , The protein sequence encoded by Papillom avirus regulatory factor PRF-1 is represented in the public databases by the accession NP_061 130 and is described in this patent by Seq ID 343. The nucleotide sequence is represented in the public sequence databases by the accession AK023418 and is described in this patent by Seq ID 344. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Papillomavirus regulatory factor PRF-1 is repressed in macrophages activated by LPS and gam ma interferon.
The O xford B ioM edica clone p l A7 represents SLC31A2. The protein sequence encoded by SLC31 A2 is represented in the public databases by the accession NP_001851 and is described in this patent by Seq ID 345. The nucleotide sequence is represented in the public sequence databases by the accession NM_001860 and is described in this patent by Seq ID 346. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SLC31A2 is induced in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone pi A21 represents UDP-glucose pyrophosphorylase 2. The protein sequence encoded by UDP-glucose pyrophosphorylase 2 is represented in the public databases by the accession NP_006750 and is described in this patent by Seq ID 347. The nucleotide sequence is represented in the public sequence databases by the accession NM_006759 and is described in this patent by Seq ID 348. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clones plB4 and plB5 represent Proline 4-hydroxylase, alpha polypeptide II. The protein sequence encoded by Proline 4-hydroxylase, alpha polypeptide II is represented in the public databases by the accession NP_004190 and is described in this patent by Seq ID 349. The nucleotide sequence is represented in the public sequence databases by the accession NM_004199 and is described in this patent by Seq ID 350. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Proline 4-hydroxylase, alpha polypeptide II is repressed in macrophages activated by LPS and gamma interferon and is also repressed in macrophages activated by IL-15. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Proline 4-hydroxylase, alpha polypeptide II is induced in macrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Proline 4-hydroxylase, alpha polypeptide II is up-regulated in the malignant tissue as compared to adjacent nor al tissue in at least one patient.
The Oxford BioMedica clones plB 10, plB l l and plB 12 represent Stearoyl-CoA desaturase. The protein sequence encoded by Stearoyl-CoA desaturase is represented in the public databases by the accession NP_005054 and is described in this patent by Seq ID 351. The nucleotide sequence is represented in the public sequence databases by the accession NM_005063 and is described in this patent by Seq ID 352, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TNFalpha is an inflammatory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatm ent of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam m atory conditions. Stearoyl-CoA desaturase is induced in macrophages activated by TNFalpha.
The Oxford B ioM edica clone pi B 13 represents Diacylglycerol kinase, zeta. The protein sequence encoded by Diacylglycerol kinase, zeta is represented in the public databases by the accession NP_003637 and is described in this patent by Seq ID 353. The nucleotide sequence is represented in the public sequence databases by the accession NM_003646 and is described in this patent by Seq ID 354. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone p l B 22 represents Protease, serine, 1 1. The protein sequence encoded by Protease, serine, 1 1 is represented in the public databases by the accession NP_002766 and is described in this patent by Seq ID 355. The nucleotide sequence is represented in the public sequence databases by the accession NM_002775 and is described in this patent by Seq ID 356. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Protease, serine, 1 1 is repressed in m acrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Protease, serine, 1 1 is down-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford BioMedica clone plB23 represents Interleukin 1 receptor antagonist. The protein sequence encoded by Interleukin 1 receptor antagonist is represented in the public databases by the accession NP_000568 and is described in this patent by Seq ID 357. The nucleotide sequence is represented in the public sequence databases by the accession NM_000577 and is described in this patent by Seq ID 358. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and m acrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Interleukin 1 receptor antagonist is preferentially induced by hypoxia in m onocytes or macrophages. TNFalpha is an inflam matory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatm ent of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflamm atory conditions. Interleukin 1 receptor antagonist is induced in m acrophages activated by TNFalpha.
The Oxford BioM edica clone p l B 24 represents NS l -binding protein. The protein sequence encoded by NS 1 -binding protein is represented in the public databases by the accession NP_006460 and is described in this patent by Seq ID 359. The nucleotide sequence is represented in the public sequence databases by the accession NM_006469 and is described in this patent by Seq ID 360. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford BioM edica clone pl C3 represents Activin A receptor, type I. The protein sequence encoded by Activin A receptor, type I is represented in the public databases by the accession NP_001096 and is described in this patent by Seq ID 361. The nucleotide sequence is represented in the public sequence databases by the accession NM_001 105 and is described in this patent by Seq ID 362. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Activin A is known to induce apoptosis [Hughes et al 1999, Prog Neurobiol 57:421 -50], and so the regulation of its receptor by hypoxia has clear clinical significance. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Activin A receptor, type I is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pl C4 represents FGF receptor activating protein 1. The protein sequence encoded by FGF receptor activating protein 1 is represented in the public databases by the accession NP_055304 and is described in this patent by Seq ID 363. The nucleotide sequence is represented in the public sequence databases by the accession NM.014489 and is described in this patent by Seq ID 364. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. FGF has been shown to enhance survival of cardiac cells after ischaemic insult [Sheikh et al 2001 , Am J Physiol Heart Circ Physiol 280:H 1039-50], and so our observation of the hypoxia-regulation of the FGF receptor activating protein 1 is highly significant for the diagnosis and treatment of ischaemic disease. FGF receptor activating protein 1 is induced in m acrophages treated with the inhibitory cytokine IL-10. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, FGF receptor activating protein 1 is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford B ioM edica clone p l C5 represents Galectin 8, The protein sequence encoded by Galectin 8 is represented in the public databases by the accession NP_006490 and is described in this patent by Seq ID 365. The nucleotide sequence is represented in the public sequence databases by the accession NM_006499 and is described in this patent by Seq ID 366. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Galectin 8 is an important tum our marker [for review see B idon et al 2001 , Int J M ol M ed 8 :245-50] , and so its hypoxia-regulation is highly significant clinically.
The O xford B ioM edica clone p l C6 represents Glucose phosphate isom erase. The protein sequence encoded by Glucose phosphate isomerase is represented in the public databases by the accession NP_000166 and is described in this patent by Seq ID 367. The nucleotide sequence is represented in the public sequence databases by the accession NM_000175 and is described in this patent by Seq ID 368. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Glucose phosphate isomerase is induced in m acrophages activated by IL-17 and also induced in macrophages activated by IL-15. TNFalpha is an inflam m atory cytokine, w hich acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam matory conditions. Glucose phosphate isomerase is induced in m acrophages activated by TNFalpha. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Glucose phosphate isomerase is up-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. The O xford B ioM edica clone p l C7 represents D 123. The protein sequence encoded by D 123 is represented in the public databases by the accession NP_006014 and is described in this patent by Seq ID 369. The nucleotide sequence is represented in the public sequence databases by the accession NM_006023 and is described in this patent by Seq ID 370. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. D 123 is repressed in macrophages activated by LPS and gamm a interferon and is also repressed in m acrophages activated by IL-15. D 123 protein is an important regulator of the cell cycle [Onisto et al 1998, Exp Cell Res 242:451 - .9]. Recently it has been shown to be regulated by modification and turnover [Okuda et al 2001 , Cell Struct Fund 26:205-14], W e have shown the hypoxia-regulation of this protein, and also of several prolyl hydroxylases which are know n to target proteins for ubiquitination and proteasomal degradation. W e believe that concerted hypoxic control of D 123 and its regulating prolyl hydroxylase is part of the means of hypoxic regulation of cell growth and tissue re-modelling.
The O xford B ioMedica clone pl C8 represents DEC-1 , The protein sequence encoded by DEC-1 is represented in the public databases by the accession NP_003661 and is described in this patent by Seq ID 371 , The nucleotide sequence is represented in the public sequence databases by the accession NM_003670 and is described in this patent by Seq ID 372. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. DEC-1 is a helix-loop-helix transcription factor, and its hypoxia-regulation is highly significant. The response of renal epithelial cells to hypoxia is pertinent to kidney failure, especially regarding the medullary tissue. DEC-1 is preferentially induced by hypoxia in renal epithelial cells. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, DEC-1 is up-regulated and also down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford B ioM edica clone p l C9 represents RAB -8b protein. The protein sequence encoded by RAB - 8b protein is represented in the public databases by the accession NP_057614 and is described in this patent by Seq ID 373. The nucleotide sequence is represented in the public sequence databases by the accession NM_016530 and is described in this patent by Seq ID 374, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The hypoxia regulation of this sm all GTP-ase, w hich is involved in intracellular membrane trafficking, is highly significant. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. RAB -8b protein is induced in m acrophages activated by LPS and gam m a interferon.
The Oxford B ioM edica clone pI C I O represents Regulator of G-protein signalling 1. The protein sequence encoded by Regulator of G-protein signalling 1 is represented in the public databases by the accession NP_002913 and is described in this patent by Seq ID 375. The nucleotide sequence is represented in the public sequence databases by the accession NM_002922 and is described in this patent by Seq ID 376. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and m acrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Regulator of G-protein signalling 1 is preferentially induced by hypoxia in m onocytes or macrophages. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Regulator of G-protein signalling 1 is repressed in macrophages activated by LPS and gamma interferon, Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found. In a series of 5 patients w ith either ovarian or breast cancer, Regulator of G-protein signalling 1 is down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford B ioM edica clone p l C l l represents Polyubiquitin. The protein sequence encoded by Polyubiquitin is represented in the public databases by the accession BAA 23632 and is described in this patent by Seq ID 377. The nucleotide sequence is represented in the public sequence databases by the accession AB 009010 and is described in this patent by Seq ID 378. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Polyubiquitin is repressed in macrophages activated by LPS and gamm a interferon. TNFalpha is an inflammatory cytokine, w hich acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflamm atory conditions. Polyubiquitin is induced in m acrophages activated by TNFalpha, Hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Polyubiquitin is up-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient,
The Oxford BioM edica clone pi C 12 represents Integrin, alpha 5. The protein sequence encoded by Integrin, alpha 5 is represented in the pubiic databases by the accession NP_002 I96 and is described in this patent by Seq ID 379, The nucleotide sequence is represented in the public sequence databases by the accession NM _002205 and is described in this patent by Seq ID 380. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Integrin, alpha 5 may play a role in the response to neuronal injury [King et al 2001 , J Neurocytol 30:243-52]. Our observation of hypoxia regulation of both COX-2 and integrin, alpha 5 supports the very recent suggestion that they may both function in recovery from cardiovascular injury [Hein et al 2001 , Am J Physiol Heart Circ Physiol 281 :H2378-84], which is pre-figured by our claim s, Integrin, alpha 5 is induced by hypoxia in mamm ary epithelial cells, and may play an important role in cancer progression in that tissue through its function of regulating interaction w ith the extracellular matrix. The Oxford BioM edica clone pl C 13 represents Jk-recombination signal binding protein. The protein sequence encoded by Jk-recombination signal binding protein is represented in the public databases by the accession AAA60258 and is described in this patent by Seq ID 381. The nucleotide sequence is represented in the public sequence databases by the accession L07872 and is described in this patent by Seq ID 382. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Jk-recombination signal binding protein is repressed in m acrophages activated by LPS and gamm a interferon. TNFalpha is an inflam matory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Jk-recombination signal binding protein is induced in m acrophages activated by TNFalpha, The important role of Jk- recombination signal binding protein in the regulation of the immune response is thus m odulated by hypoxia, and there are potentially m any w ays of exploiting that m odulation in the design of diagnostics and therapeutics. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Jk-recombination signal binding protein is down-regulated in the m alignant tissue as compared to adjacent norm al tissue in at least one patient. It is of particular interest and significance, in view of the escape from immunological surveillance of many tumours, that Jk-recombination signal binding protein is down-regulated.
The Oxford BioMedica clone pl C 14 represents Abstrakt. The protein sequence encoded by Abstrakt is represented in the public databases by the accession NP_057-306 and is described in this patent by Seq ID 383. The nucleotide sequence is represented in the public sequence databases by the accession NM_016222 and is described in this patent by Seq ID 384. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have' utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam m atory processes, In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Abstrakt is repressed in macrophages activated by IL-15 , TNFalpha is an inflamm atory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam m atory conditions. Abstrakt is induced in m acrophages activated by TNFalpha. The general role of Abstrakt in the regulation of gene expression [Schmucker et al 2000, Mech Dev 91 :189-96] implies particular significance to the recovery of cells from hypoxic insult.
The Oxford B ioM edica clone p l C 15 represents High-m obility group protein 2. The protein sequence encoded by High-mobility group protein 2 is represented in the public databases by the accession NP_002120 and is described in this patent by Seq ID 385. The nucleotide sequence is represented in the public sequence databases by the accession NM_002129 and is described in this patent by Seq ID 386. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plC 16 represents Decidual protein induced by progesterone. The protein sequence encoded by Decidual protein induced by progesterone is represented in the public databases by the accession NP_008952 and is described in this patent by Seq ID 387. The nucleotide sequence is represented in the public sequence databases by the accession NM_007021 and is described in this patent by Seq ID 388. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Decidual protein induced by progesterone is preferentially induced by hypoxia in mammary epithelial cells. Human decidual cells have not been tested, but we predict that Decidual protein induced by progesterone is hypoxia-regulated in those cells. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes, In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Decidual protein induced by progesterone is repressed in macrophages activated by IL-17. The Oxford BioMedica clone p 1 C 19 represents GM2 ganglioside activator protein. The protein sequence encoded by GM 2 ganglioside activator protein is represented in the public databases by the accession NP_000396 and is described in this patent by Seq ID 389. The nucleotide sequence is represented in the public sequence databases by the accession NM_000405 and is described in this patent by Seq ID 390. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . GM2 ganglioside activator protein is preferentially induced by hypoxia in monocytes or macrophages, The hypoxia-inducibility of this protein in macrophages is likely to be clinically very significant. It is likely to play a role in the control of inflammation in asthma and inflammatory bowel disease, and in lipid metabolism and phosphatidylinositol-mediated signalling. The Oxford BioMedica clone plC20 represents CN0T8. The protein sequence encoded by CN0T8 is represented in the public databases by the accession NP_004770 and is described in this patent by Seq ID 391. The nucleotide sequence is represented in the public sequence databases by the accession NM_004779 and is described in this patent by Seq ID 392. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The protein sequence encoded by Similar to Nucleoside phosphorylase is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA430382 and is described in this patent by Seq ID 394. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone pl P5 represents SCYA2. The protein sequence encoded by SCYA2 is represented in the public databases by the accession NP_002973 and is described in this patent by Seq ID 395. The nucleotide sequence is represented in the public sequence databases by the accession NM_002982 and is described in this patent by Seq ID 396. Hypoxia is an important feature of several diseases, and genes that respond to this stim ulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SCYA2 is induced in m acrophages activated by LPS and gam ma interferon and is also induced in macrophages activated by IL- 17 or IL-15. Thus the role of SCYA2 in monocyte recruitment [Lu et al 1998, J Exp M ed 187:601 -8], which has clear relevance to the diagnosis and treatment of cardiovascular disease, cancer, rheum atoid arthritis, atherosclerosis and COPD , is enhanced by hypoxia, TNFalpha is an inflammatory cytokine, which acts on m acrophages, and has been show n to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis, Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. SCYA2 is repressed in m acrophages activated by TNFalpha. Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SYCA2 is down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The O xford B ioMedica clone p2L23 represents Endothelin 1 . The protein sequence encoded by Endothelin 1 is represented in the public databases by the accession NP_001946 and is described in this patent by Seq ID 397. The nucleotide sequence is represented in the public sequence databases by the accession NM_001955 and is described in this patent by Seq ID 398. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes'. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Endothelin 1 is induced in macrophages activated by LPS and gamm a interferon, TNFalpha is an inflammatory cytokine, which acts on m acrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis, Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Endothelin 1 is induced in macrophages activated by TNFalpha. Endothelin 1 plays an important role in inducing proliferation of vascular smooth muscle cells. Its hypoxia-inducibility and thus its modulation to ameliorate the consequences of ischaemic insult, is of considerable clinical significance to the recovery from injury, and angiogenesis.
The protein sequence encoded by Similar to Heat shock 70kD protein 4 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA633656 and is described in this patent by Seq ID 400, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products,
The Oxford BioMedica clone plK9 represents Lipocortin I. The protein sequence encoded by Lipocortin I is represented in the public databases by the accession NP_000691 and is described in this patent by Seq ID 401 , The nucleotide sequence is represented in the public sequence databases by the accession NM_000700 and is described in this patent by Seq ID 402, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Lipocortin I (also called annexin I) is an important anti-inflammatory mediator, and its hypoxia-inducibility has important implications for the diagnosis and treatment of ischaemic disease, cancer, atherosclerosis, and inflammatory diseases such as rheumatoid arthritis, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of 5 patients with either ovarian or breast cancer, Lipocortin I is up-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Lipocortin I is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone pl K23 represents M YC. The protein sequence encoded by MYC is represented in the public databases by the accession NP_002458 and is described in this patent by Seq ID 403. The nucleotide sequence is represented in the public sequence databases by the accession NM_002467 and is described in this patent by Seq ID 404. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. MYC is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, MYC is up-regulated and also down-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient.
The Oxford BioMedica clone pi K 15 represents Alpha-2-macroglobulin. The protein sequence encoded by Alpha-2-macroglobulin is represented in the public databases by the accession NP_000005 and is described in this patent by Seq ID 405. The nucleotide sequence is represented in the public sequence databases by the accession NM_000014 and is described in this patent by Seq ID 406. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic" products for diseases involving those cell types. Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Alpha-2-macroglobulin is preferentially induced by hypoxia in monocytes or macrophages. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Alpha-2-macroglobulin is downregulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plK8 represents SCYA4. The protein sequence encoded by SCYA4 is represented in the public databases by the accession XP_008449 and is described in this patent by Seq ID 407. The nucleotide sequence is represented in the public sequence databases by the accession XM_008449 and is described in this patent by Seq ID 408. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SCYA4 is induced in macrophages activated by LPS and gamma interferon and is also induced in macrophages activated by IL- 17. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory condition's. SCYA4 is induced in macrophages activated by TNFalpha. SCYA4 is a chemokine which is likely to be significant in inflammatory disease as a direct result of its hypoxic regulation. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SCYA4 is downregulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plM24 represents Sex hormone-binding globulin. The protein sequence encoded by Sex hormone-binding globulin is represented in the public databases by the accession NP_001031 and is described in this patent by Seq ID 409. The nucleotide sequence is represented in the public sequence databases by the accession NM_001040 and is described in this patent by Seq ID 410. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clone plK7 represents ATP-binding cassette El . The protein sequence encoded by ATP-binding cassette El is represented in the public databases by the accession NP_002931 and is described in this patent by Seq ID 411. The nucleotide sequence is represented in the public sequence databases by the accession NM_002940 and is described in this patent by Seq ID 412. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. ATP-binding cassette El is repressed in macrophages activated by LPS and gamma interferon. The Oxford BioM edica clone pl K 16 represents CCT6A . The protein sequence encoded by CCT6A is represented in the public databases by the accession NP_001753 and is described in this patent by Seq ID 413. The nucleotide sequence is represented in the public sequence databases by the accession NM_001762 and is described in this patent by Seq ID 414. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone pl K 18 represents Colony-stimulating factorl . The protein sequence encoded by Colony-stimulating factorl is represented in the public databases by the accession AAA52117 and is described in this patent by Seq ID 415. The nucleotide sequence is represented in the public sequence databases by the accession M37435 and is described in this patent by Seq ID 416. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, Colony- stimulating factorl is repressed in m acrophages activated by LPS and gamm a interferon.
The Oxford BioM edica clone plN l represents GA 17. The protein sequence encoded by GA 17 is represented in the public databases by the accession NP_006351 and is described in this patent by S eq ID 417. The nucleotide sequence is represented in the public sequence databases by the accession NM_006360 and is described in this patent by Seq ID 418. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioM edica clone pl K22 represents GPR44. The protein sequence encoded by GPR44 is represented in the public databases by the accession NP_004769 and is described in this patent by Seq ID
419. The nucleotide sequence is represented in the public sequence databases by the accession
NM_004778 and is described in this patent by Seq ID 420. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. GPR44 is repressed in macrophages activated by LPS and gamma interferon. GPR44 is most similar to the chemoattractant
GPCR ' s [M archese et al 1999, Genom ics 1999 Feb 15 ;56(1 ): 12-21 ]. Our demonstration of its hypoxic regulation enables prediction of roles in diseases associated with transient hypoxia and macrophages.
GPCR' s are a druggable class of molecules, and represent an ideal route for pharm acological intervention.
The Oxford BioM edica clone pi K 14 represents Keratin 6B . The protein sequence encoded by Keratin 6B is represented in the public databases by the accession NP_005546 and is described in this patent by Seq ID 421. The nucleotide sequence is represented in the public sequence databases by the accession NM_005555 and is described in this patent by Seq ID 422. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Keratin 6B is induced in macrophages treated with the inhibitory cytokine IL-10. Keratin 6B is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15.
The O xford B ioMedica clone p 1 K 13 represents Lymphocyte adaptor protein. The protein sequence encoded by Lymphocyte adaptor protein is represented in the public databases by the accession NP_005466 and is described in this patent by Seq ID 423, The nucleotide sequence is represented in the public sequence databases by the accession NM_005475 and is described in this patent by Seq ID 424. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clone plJ20 represents Neuro-oncological ventral antigen 1. The protein sequence encoded by Neuro-oncological ventral antigen 1 is represented in the public databases by the accession NP_002506 and is described in this patent by Seq ID 425. The nucleotide sequence is represented in the public sequence databases by the accession NM_002515 and is described in this patent by Seq ID 426. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Neuro-oncological ventral antigen 1 is downregulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone pi J22 represents Neutral sphingomyelinase (N-SM ase) activation associated factor. The protein sequence encoded by Neutral sphingomyelinase (N-SM ase) activation associated factor is represented in the public databases by the accession NP_003571 and is described in this patent by Seq ID 427. The nucleotide sequence is represented in the public sequence databases by the accession NM_00358O and is described in this patent by Seq ID 428. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Neutral sphingomyelinase (N-SMase) activation associated factor is induced in macrophages treated with the inhibitory cytokine IL- 10. Neutral sphingomyelinase (N-SMase) activation associated factor is repressed in macrophages activated by IL-17 and is also repressed in macrophages activated by IL-15. We expect activation of of Neutral sphingomyelinase (N-SMase) to have an anti-inflammatory effect. This enzyme is known to modulate the sphingomyelin second messenger cycle, potentially interacting with the oxidative system . Our demonstration of hypoxic regulation provides a crucial indication of the benefit of therapeutic intervention via sphingomyelinase (N-SMase) for the treatment of inflammatory diseases and diseases related to the hypoxic macrophage.
The Oxford BioMedica clone pl Kl represents Cyclophilin F. The protein sequence encoded by Cyclophilin F is represented in the public databases by the accession NP_005720 and is described in this patent by Seq ID 429. The nucleotide sequence is represented in the public sequence databases by the accession NM_005729 and is described in this patent by Seq ID 430. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in hum an tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Cyclophilin F is up-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clone pl K3 represents Pleckstrin. The protein sequence encoded by Pleckstrin is represented in the public databases by the accession NP_002655 and is described in this patent by Seq ID 431. The nucleotide sequence is represented in the public sequence databases by the accession NM_002664 and is described in this patent by Seq ID 432, Hypoxia is an important feature of several diseases, and genes .that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, w e show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . Pleckstrin is preferentially induced by hypoxia in m onocytes or m acrophages. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Pleckstrin is induced in m acrophages activated by LPS and gamma interferon. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found. In a series of 5 patients w ith either ovarian or breast cancer, Pleckstrin is down-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
The O xford B ioM edica clones p l J19 and p l K2 represent CFFM 4. The protein sequence encoded by CFFM 4 is represented in the public databases by the accession NP_067024 and is described in this patent by Seq ID 433. The nucleotide sequence is represented in the public sequence databases by the accession NM_021201 and is described in this patent by Seq ID 434. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and m acrophages have been implicated in the following diseases involving hypoxia: rheum atoid arthritis, atherosclerosis, cancer, COPD . CFFM 4 is preferentially induced by hypoxia in m onocytes or m acrophages. CFFM 4 is induced in m acrophages treated with the inhibitory cytokine IL-10, It has been suggested recently that CFFM 4 is associated w ith m ature cellular function in the m onocytic lineage and that it may be a component of a receptor complex involved in signal transduction [Gingras et al 2001 , Immunogenetics 53:468-76], Our demonstration of hypoxic-regulation opens possible routes of intervention in macrophage-related disease via this potentially important cell surface receptor, Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, CFFM4 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioM edica clone pl K5 represents Ribosomal protein L36a. The protein sequence encoded by Ribosomal protein L36a is represented in the public databases by the accession NP_000992 and is described in this patent by Seq ID 435, The nucleotide sequence is represented in the public sequence databases by the accession NM_001001 and is described in this patent by Seq ID 436, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plJ17 represents SLC6A 1. The protein sequence encoded by SLC6A 1 is represented in the public databases by the accession NP_003033 and is described in this patent by Seq ID 437. The nucleotide sequence is represented in the public sequence databases by the accession NM_003042 and is described in this patent by Seq ID 438, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, SLC6A 1 is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone plJ18 represents Synaptopodin. The protein sequence encoded by Synaptopodin is represented in the public databases by the accession NP_009217 and is described in this patent by Seq ID 439. The nucleotide sequence is represented in the public sequence databases by the accession NM_007286 and is described in this patent by Seq ID 440. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Synaptopodin is a component of the cytoskeleton which has particular importance in neurons, where it is involved in synaptic plasticity. Its hypoxia-regulation is clearly potentially significant in the context of neurological disease. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Synaptopodin is up-regulated and also down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioM edica clone p 1 J 15 represents TERA protein. The protein sequence encoded by TERA protein is represented in the public databases by the accession NP_067061 and is described in this patent by Seq ID 441. The nucleotide sequence is represented in the public sequence databases by the accession NM_021238 and is described in this patent by Seq ID 442. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tumours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, TERA protein is up-regulated and also dow n-regulated in the malignant tissue as compared to adjacent norm al tissue in at least one patient. The Oxford B ioMedica clone pl K4 represents TSC-22. The protein sequence encoded by TSC-22 is represented in the public databases by the accession NP_006013 and is described in this patent by Seq ID
" 443. The nucleotide sequence is represented in the public sequence databases by the accession
NM_006022 and is described in this patent by Seq ID 444. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. TSC-22 is a transcriptional regulator of the leucine zipper class, and its hypoxic regulation is likely to have significant downstream effects which m ay be related to ischaemic disease. Thus it may provide important points of intervention in such diseases. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. TSC-22 is repressed in macrophages activated by LPS and gamm a interferon. Hypoxia is frequently found in hum an tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, TSC-22 is dow n-regulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford B ioM edica clone p2A 14 represents an unannotated EST. The protein sequence encoded by this EST is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AA9881 10 and is described in this patent by Seq ID 446, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, The EST represented by Seq ID 446 is induced in m acrophages treated with the inhibitory cytokine IL-10. The EST represented by Seq ID 446 is repressed in m acrophages activated by IL-17 and is also repressed in m acrophages activated by IL-15.
The Oxford B ioM edica clone p i J23 represents Calgranulin A . The protein sequence encoded by Calgranulin A is represented in the public databases by the accession NP_002955 and is described in this patent by Seq ID 447. The nucleotide sequence is represented in the public sequence databases by the accession NM_002964 and is described in this patent by Seq ID 448. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Calgranulin A, called by its synonym S 100A8, has been cited recently as "wound-regulated" [Thorey et al 2001 , J Biol Chem
276:35818-25] which provides less precise support for our prior determination of its hypoxia-regulation.
In its potential role, as a.chemoattractant, it would be an important point of intervention for the modulation of inflammatory processes. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Calgranulin A is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of
5 patients with either ovarian or breast cancer, Calgranulin A is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone plJ21 represents Replication factor C large subunit. The protein sequence encoded by Replication factor C large subunit is represented in the public databases by the accession NP_002904 and is described in this patent by Seq ID 449. The nucleotide sequence is represented in the public sequence databases by the accession NM_002913 and is described in this patent by Seq ID 450. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plJ24 represents Signal recognition particle 19kD . The protein sequence encoded by Signal recognition particle 19kD is represented in the public databases by the accession NP_003126 and is described in this patent by Seq ID 451 , The nucleotide sequence is represented in the public sequence databases by the accession NM_003135 and is described in this patent by Seq ID 452. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone plJ16 represents cDNA : FLJ23019 fis, clone LNG00916. The protein sequence encoded by cDNA : FLJ23019 fis, clone LNG00916 is not represented in the public databases by a protein accession. The nucleotide sequence is represented in the public sequence databases by the accession AK026672 and is described in this patent by Seq ID 454. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant, The cDNA : FLJ23019 fis, clone LNG00916 is induced in m acrophages activated by LPS and gamm a interferon and is also induced in m acrophages activated by IL-15 ,
The Oxford BioM edica clone p lJ2 represents Proteasome subunit, alpha type, 4. The protein sequence encoded by Proteasome subunit, alpha type, 4 is represented in the public databases by the accession NP_002780 and is described in this patent by Seq ID 455. The nucleotide sequence is represented in the public sequence databases by the accession NM_002789 and is described in this patent by Seq ID 456. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford B ioM edica clone p l J9 represents M AFB , The protein sequence encoded by M AFB is represented in the public databases by the accession NP_005452 and is described in this patent by Seq ID 457. The nucleotide sequence is represented in the public sequence databases by the accession NM_005461 and is described in this patent by Seq ID 458. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products, M AFB is a transcriptional regulator of the leucine zipper type, and is likely to play an important role in the mediation of the hypoxic response, with attendant relevance to associated diseases.
The Oxford B ioM edica clone pl Jl O represents DN CLI2. The protein sequence encoded by DNCLI2 is represented in the public databases by the accession NP_006132 and is described in this patent by Seq ID 459, The nucleotide sequence is represented in the public sequence databases by the accession NM_006141 and is described in this patent by Seq ID 460, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Hypoxia is frequently found in human tum ours where m acrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, gene X is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioM edica clone plJl represents Chrom obox homolog 3. The protein sequence encoded by Chromobox hom olog 3 is represented in the public databases by the accession NP_057671 and is described in this patent by Seq ID 461. The nucleotide sequence is represented in the public sequence databases by the accession NM_016587 and is described in this patent by Seq ID 462. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The O xford BioM edica clone p l J5 represents SCYA7. The protein sequence encoded' by SCYA7 is represented in the public databases by the accession NP_006264 and is described in this patent by Seq ID 463. The nucleotide sequence is represented in the public sequence databases by the accession NM_006273 and is described in this patent by Seq ID 464. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, m acrophages are frequently activated by cytokines, w hich have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SCYA7 is induced in macrophages activated by IL-15. SCYA7 is a chemoattractant protein which, considering its hypoxia- regulation, is likely to play an important role in inflamm atory and ischaemic disease. TNFalpha is an inflam m atory cytokine, w hich acts on m acrophages, and has been shown to be central to the pathophysiology and treatm ent of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflam m atory conditions. SCYA7 is repressed in m acrophages activated by TNFalpha.
The Oxford B ioM edica clone p l Jl l represents Fatty-acid-Coenzyme A ligase, long-chain 2. The protein sequence encoded by Fatty-acid-Coenzyme A ligase, long-chain 2 is represented in the public databases by the accession NP_066945 and is described in this patent by Seq ID 465. The nucleotide sequence is represented in the public sequence databases by the accession NM_021122 and is described in this patent by Seq ID 466. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflamm atory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Fatty-acid-Coenzym e A ligase, long-chain 2 is induced in macrophages activated by LPS and gamm a interferon and also induced in macrophages activated by IL-17 or IL-15. Hypoxia is frequently found in hum an tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Fatty-acid-Coenzyme A ligase, long-chain 2 is downregulated in the m alignant tissue as compared to adjacent normal tissue in at least one patient.
- The O xford B ioM edica clone p l J8 represents Program med cell death 5. The protein sequence encoded by Programmed cell death 5 is represented in the public databases by the accession NP_004699 and is described in this patent by Seq ID 467. The nucleotide sequence is represented in the public sequence databases by the accession NM_004708 and is described in this patent by Seq ID 468. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford BioMedica clone pl I20 represents SCY A3L. The protein sequence encoded by SCYA3L is represented in the public databases by the accession CAA36397 and is described in this patent by Seq ID 469. The nucleotide sequence is represented in the public sequence databases by the accession X52149 and is described in this patent by Seq ID 470. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. M onocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD . SCYA3L is preferentially induced by hypoxia in monocytes or m acrophages. M acrophages are key to several diseases involving hypoxia, and contribute to inflam matory processes. In these, m acrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SCYA3L is induced in m acrophages activated by LPS and gam m a interferon. TNFalpha is an inflamm atory cytokine, w hich acts on macrophages, and has been show n to be central to the pathophysiology and treatment of diseases including rheum atoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflamm atory conditions. SCYA3L is induced in macrophages activated by TNFalpha.
The O xford B ioM edica clone p l J3 represents Furin. The protein sequence encoded by Furin is represented in the public databases by the accession NP_002560 and is described in this patent by Seq ID 471. The nucleotide sequence is represented in the public sequence databases by the accession NM_002569 and is described in this patent by Seq ID 472. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. The Oxford B ioM edica clone p 1 Jl 2 represents Nuclear autoantigenic sperm protein. The protein sequence encoded by Nuclear autoantigenic sperm protein is represented in the public databases by the accession NP_002473 and is described in this patent by Seq ID 473. The nucleotide sequence is represented in the public sequence databases by the accession NM_002482 and is described in this patent by Seq ID 474. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone pi 123 represents Ecotropic viral integration site 2A. The protein sequence encoded by Ecotropic viral integration site 2A is represented in the public databases by the accession NP_055025 and is described in this patent by Seq ID 475. The nucleotide sequence is represented in the public sequence databases by the accession NM_014210 and is described in this patent by Seq ID 476. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. There is a prejudice in the art that the response to hypoxia is generic to all cell types. Contrary to this, we show that genes are regulated by hypoxia to a greater degree in certain cell types, substantiating their utility in designing specific therapeutic products for diseases involving those cell types. Monocytes and macrophages have been implicated in the following diseases involving hypoxia: rheumatoid arthritis, atherosclerosis, cancer, COPD. Ecotropic viral integration site 2A is preferentially induced by hypoxia in monocytes or macrophages. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Ecotropic viral integration site 2A is repressed in macrophages activated by LPS and gamma interferon. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, Ecotropic viral integration site 2A is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone p 1 J7 represents Sjogren syndrome antigen B , The protein sequence encoded by Sjogren syndrome antigen B is represented in the public databases by the accession NP_003133 and is described in this patent by Seq ID 477. The nucleotide sequence is represented in the public sequence databases by the accession NM_003142 and is described in this patent by Seq ID 478. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Sjogren syndrome antigen B is preferentially induced by hypoxia in mammary epithelial cells. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. Sjogren syndrome antigen B is induced in macrophages activated by LPS and gamma interferon.
The Oxford BioMedica clone pi 121 represents SCYA8. The protein sequence encoded by SCYA8 is represented in the public databases by the accession NP_005614 and is described in this patent by Seq ID 479. The nucleotide sequence is represented in the public sequence databases by the accession NM_005623 and is described in this patent by Seq ID 480, Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. SCYA8 is induced in macrophages activated by LPS and gamma interferon and is also induced in macrophages activated by IL- 15. The Oxford BioMedica clone p 1 II 9 represents GR02, The protein sequence encoded by GR02 is represented in the public databases by the accession NP_002080 and is described in this patent by Seq ID
" 481. The nucleotide sequence is represented in the public sequence databases by the accession
NM_002089 and is described in this patent by Seq ID 482. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Macrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. GR02 is induced in macrophages activated by LPS and gamma interferon and is also induced in macrophages activated by IL- 17. GR02 encodes a chemokine which is likely to be involved in the inflammatory response. Its induction by hypoxia provides a potential route for intervention in diseases related to inflammation and ischaemia. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, GR02 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient. The Oxford BioMedica clone plJ4 represents Small nuclear ribonucleoprotein D I . The protein sequence encoded by Small nuclear ribonucleoprotein D I is represented in the public databases by the accession NP_008869 and is described in this patent by Seq ID 483. The nucleotide sequence is represented in the public sequence databases by the accession NM_006938 and is described in this patent by Seq ID 484. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products.
The Oxford BioMedica clone pi 124 represents GR01. The protein sequence encoded by GR01 is . represented in the public databases by the accession NP_001502 and is described in this patent by Seq ID 485. The nucleotide sequence is represented in the public sequence databases by the accession NM_001511 and is described in this patent by Seq ID 486, GR01 has known chemotactic activity for neutrophils, GR01 belongs to the intercrine alpha family of small CXC cytokines, GR01 encodes a chemokine which is likely to be involved in the inflammatory response, Its induction by hypoxia provides a potential route for intervention in diseases related to inflammation and ischaemia. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. M acrophages are key to several diseases involving hypoxia, and contribute to inflammatory processes. In these, macrophages are frequently activated by cytokines, which have been shown to be present at disease sites, so gene expression responses to both hypoxia and cytokines are especially relevant. GR01 is induced in macrophages activated by LPS and gamma interferon and is also induced in macrophages activated by IL-17. Hypoxia is frequently found in human tumours where macrophage infiltrates are also found. In a series of 5 patients with either ovarian or breast cancer, GR01 is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient.
The Oxford BioMedica clone p 1 II 8 represents Selectin L. The protein sequence encoded by Selectin L is represented in the public databases by the accession NP_000646 and is described in this patent by Seq ID
487, The nucleotide sequence is represented in the public sequence databases by the accession
NM_000655 and is described in this patent by Seq ID 488. Hypoxia is an important feature of several diseases, and genes that respond to this stimulus are therefore implicated in the pathogenesis and have utility in the design of therapeutic, prognostic and diagnostic products. Selectin L shedding by leucocytes is one aspect of the induction of the inflammatory response. Hypoxic-regulation of Selectin L is clearly a significant factor in the induction of inflammation following ischaemic insult or in diseases in which transient ischaemic conditions occur, M odulation of this induction is one aspect of the present invention,
Hypoxia is frequently found in human tumours where macrophage infiltrates are also found, In a series of
5 patients with either ovarian or breast cancer, Selectin L is down-regulated in the malignant tissue as compared to adjacent normal tissue in at least one patient,
TABLES
TABLE 1: Hypoxia-inducible genes identified from clones only derived from the cardiomyoblast library
Figure imgf000192_0001
TABLE 2: Hypoxia-inducible genes identified from clones only derived from the macrophage libraries
Figure imgf000193_0001
Figure imgf000194_0001
The gene entitled "Jk-recombination signal binding protein" was found to be hypoxia-inducible using subtracted cDNA probes for hybridization, but with non-subtracted probes, where the hybridisation is quantitative, no signal was detected. This indicates that the gene is probably hypoxra-regulated but the absolute expression levels are very low .
TABLE 3: Hypoxia-inducible genes identified from clones derived from both m acrophage and m yoblast libraries.
Figure imgf000195_0001
TABLE 4: Hypoxia responses amplified by HIFl alpha overexpression
Figure imgf000195_0002
Legend: Data shown in the average of 4 repeat experiments. Experimental condition is as shown in the text. Values represent fold change as compared to untreated cells (condition 1 ). TABLE 5: Hypoxia responses amplified by EPAS l overexpression
Figure imgf000196_0001
Legend: Data shown is the average of 4 repeat experiments. Experimental condition is as shown in the text. Values represent fold change as compared to untreated cells (condition 1 ).
TABLE 6, Negative hypoxia responses amplified by HIFl alpha / EPAS l overexpression
Figure imgf000196_0002
Table 7: Genes induced by hypoxia (similar response +/- cell activation)
l
Figure imgf000197_0001
I-1
Figure imgf000198_0001
S o
Figure imgf000199_0001
CO c
00 CΛ
m
CO
I SO m Ω m
c m r n
Figure imgf000200_0001
Legend
The last 3 columns show mRNA expression as a ratio between the conditions being compared. Of these three columns the first two show expression in hypoxia 5 relative to normoxia, done separately in resting macrophages or activated macrophages. The final column shows expression in activated m acrophages relative to resting m acrophages (both in normoxia) as a ratio, n/d = not determ ined due to low signal intensities. IMAGE ID and accession descride the exact identity of the arrayed clones and do not describe full length cDNA sequence database entries.
CO c
CO CΛ
m
CO
I m m
73 c m r n
Figure imgf000201_0001
Legend to Table 8
The last 3 columns show mRNA expression as a ratio between the conditions being compared. Of these three columns the first two show expression in hypoxia relative to normoxia, done separately in resting macrophages or activated macrophages. The final column shows expression in activated macrophages relative to resting macrophages' (both in normoxia) as a ratio, n/d = not determined due to low signal intensities. IMAGE ID and accession describe the exact identity of the arrayed clones and do not describe full length cDNA sequence database entries.
TABLE 9:.Genes induced by hypoxia (greater response in activated cells)
CO c
00 CO
Figure imgf000202_0001
Legend m
CO The last 3 columns show mRNA expression as a ratio between the conditions being compared. Of these three columns the first two show expression in hypoxia O
I m relative to normoxia, done separately in resting macrophages or activated macrophages. The final column shows expression in activated m acrophages relative to m resting macrophages (both in normoxia) as a ratio, n/d = not determined due to low signal intensities. IMAGE ID and accession describe the exact identity of the
73 arrayed clones and do not describe full length cDNA sequence database entries. c m r n
TABLE 10:_Genes repressed by hypoxia (greater response in activated cells)
Figure imgf000203_0001
Figure imgf000203_0002
CO c
00 CO
Figure imgf000204_0001
m Legend to Table 10
CO
I m m The last 3 columns show mRNA expression as a ratio between the conditions being com pared. Of these three columns the first two show expression in hypoxia
^ 5 relative to norm oxia, done separately in resting m acrophages or activated macrophages. The final column shows expression in activated m acrophages relative to
TJ c resting macrophages (both in normoxia) as a ratio, n/d = not determined due to low signal intensities. IM AGE ID and accession descride the exact identity of the m arrayed clones and do not describe full length cDNA sequence database entries. r en
TABLE 11: Other genes repressed by hypoxia in macrophages
Figure imgf000205_0001
Figure imgf000205_0002
t
Figure imgf000206_0001
t
Figure imgf000207_0001
Figure imgf000208_0001
Legend
The last 3 columns show mRNA expression as a ratio between the conditions being compared. Of these three columns the first two show expression in hypoxia relative to normoxia, done separately in resting macrophages or activated macrophages. The final column shows expression in activated m acrophages relative to resting macrophages (both in normoxia) as a ratio, n/d = not determined due to low signal intensities. IM AGE ID and accession descride the exact identity of the arrayed clones and do not describe full length cDNA sequence database entries.
CO
C 00 CO
m
CO
I m m
c m r en
CM w
XI PQ rf! En
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
30_ MD14 b.67 b.82 .64 b.60 B.42 (.78 B.24 B.57 .076.33 6.11 b.68 b.67 b.29 b.74 b.52 b.58 (.23 (.29 b.24 b.75 b.72
Figure imgf000212_0001
32 MD17 B.32 6.30 b.77 b-46 B.08 (.47 b.41 b.60 b.43 .05 b.92 P.91 .17 (.13 B.73 .77 b.58 ,01 b.76 b.98 .26 .31
32_ blP14 b-43 b.66 b.74 .22 .60 (.14 (.00 .53 .32 b.49 b.73 (.15 b.43 b.69 b.21 b.45 b.68 .63 1.8 B.90 P.14 .71 b.84 34 blC24 b.92 (0.88 b.53 (.76 (.65 .37 .08 .09 b.89 .23 .07 b.85 b.68 .28 b.60 b-77 B.67 .02 6.70 .61 (.06 (.66 b.88
36_ blD3 b.62 (.56 .13 .83 b.85 b.73 B.09 14.01 B.43 b.29 b.52 b.71 b.15 P.2Θ B.72 δ.67 5.80 B.79 b.49 B.80 B.32 B.26 B.79 38 blE14 (.09 .92 b.89 .93 (.46 b.96 (.23 .58 b.96 b.88 b-71 .26 b.87 .68 b.67 b.89 6.54 (.20 b.33 6.55 b.38 b.74 .03 blE20 b.63 b.61 (.12 .47 (.34 b.99 (.45 .94 .49 b.68 b.88 b.98 b.19 b.34 b.36 b.43 b.37 .33 (.44 b.65 b.23 b.43 b.33
102 b2A24 .21 b.65 b.67 6.42 6.21 2.48 6.35 B.05 6.59 .10 b.76 b.68 b.68 P.91 b.28 b.22 b.38 b.37 b.40 P.20 b.18 b.26 b.17
IM WE17 0.94 0.56 P.99 b.95 (.55 b.96 .93 6.41 6.37 b.89 b.88 b.53 b.73 b.84 (.15 b.29 b.39 P.24 .96 2.03 6.06 106 WE19 b.79 b.65 b.62 6.64 6.37 6.996.10 .61 .77 b.61 b.40 b.64 b.42 b.89 b.68 b.76 (.08 b.41 b.50 b.32 b.38 b.90 b.47 ( b1E15 6.82 .46 6.04 (.42 6.65 ( b.92 .10 b.78 (.83 (.73 b.82 b.72 .21 .35 (.27 (.12 (.01 b.85 b.52 b.65 .11
110_ blE11 .36 (.12 b.87 2.09 6.86 B.03 b.74 P.91 b.88 b.89 b.59 b.79 0.776.09 6.76 6.97 6.90 b.63 b.84 b.34 b.64 (.47 (.35 ( 112 blE23 .19 b.65 (.55 .24 6.11 .42 b.75 .15 h.02 b-86 (.09 b.35 b.40 b.31 b.36 b.48 b.88 .02 b.73 b.30 b.55 b.66 B
(14 J1E21 3.82 3.52 3.85 2,08 2.28 2.04 6.14 6.04 6.27 b.74 b.49 b.79 b.51 .04 b.48 b.67 b.67 b.35 b.34 b.21 b.56 .14 b.89
(16 b1D23 b-95 p.47 (3.68 (.21 .62 .30 b.99 .17 ,10 .39 .20 (.05 .35 P.49 P.28 P.2710.3 P.8Q b.85 b.66 ι.39 b.49 b.536
Figure imgf000213_0001
(48 D1I14 P 1.9966 P P..54 b.67 .30 b.68 (.11 6.36 6.45 .69 .10 b.90 b.47 b.20 b.24 b.38 b.26 b.26 6.20 (.28 b.15 b.27 b.1
50 bl!2 .89 .15 .70 6.50 0.12 6.26 .57 .92 (.47 b.73 b.60 b.85 b.46 b.66 b.95 b.63 b.93 .17 .93 b.88 P.16 b.30 b-
(52 bll12 2.00 (.52 (.68 M (.02 (.40 b.66 b.88 b.62 (.81 (.36 .48 (.96 6.49 6.132376.71 b.54 b.27 b-32 6.90 B.25 6.
54 bl!3 (.26 b.94 b.55 .53 (.29 (.14 .13 .40 .20 b.85 b.50 b.42 b.70 b.89 .04 b.70 b.76 b.94 (.64 b.59 b.45 b.72 b.5
56 mo (.82 (.30 b.97 (.15 (.65 (.18 b.59 b.72 b.53 (.64 .05 b.75 107 b.76 b.71 b.85 .50 (.17 b.73 b.92 .1
58 blH18 b.52 b.65 .16 b.83 b.67 b.23 .49 .33 .35 (.34 .21 b.97 (.51 6.07 b.70 b.67 b.22 .07 b.49 P.15 b.65 b.80 .0
(60 blH24 .02 B.55 B.73 b.83 0.66 (.22 (.04 (.32 b.77 (.27 .71 .53 b.89 b.92 B.02 μ.58 k.74 b.93 b.84 b.50 b.76 b.89 .0
62 blE22 b.48 b.30 b.53 .93 6.28 6.13 (.68 .65 b.41 b.35 b.49 b.35 b.46 (.26 (.00 .62 (.04 .05 b.62 b.85 (.66 (.1
(64 blH21 b.82 b.56 b.66 B.63 6.47 B.49 b.83 b.96 b.82 b.64 b.67 b.76 6.64 (0.2 B.34 6.3 (2.1 b.34 b.94 b.49 b.32 b.82 6.1
(66 bill .64 (.61 (.02 .71 b.85 .13 .33 b.97 b.88 b.85 b.77 b.78 b.84 .43 6.04 (.37 b.52 b.45 b.30 .22 .28 .7
68 blH14 b.86 b.45 b.71 .62 .10 b.78 (.65 (.91 .77 b.87 b.87 (.00 b.32 b.46 b.39 b.37 b.35 .14 .18 .02 b.30 b.42 b.3
(70 WH11 b.96 b.63 0.72 6.19 2.53 6.46 6.53 .11 B.04 b.74 b.67 b.79 b.46 b.87 b.78 b.74 b.24 b.41 b.22 b.42 b.68 b.9
72 b!H17 b.58 b.69 .17 b.65 b.64 b.17 .67 .53 .54 .36 .39 .11 .30 .73 b.63 b.71 b.24 .28 b.58 P.15 b.77 b.80 b.8
74 blH12 6.06 .50 .29 .79 6.33 6.36 b.84 .09 b.87 b.80 b.63 b.69 b.82 2.34 b.96 b.78 .03 .02 (.56 b.71 b.58 b.95 b.6
76 blH7 b.70 b.64 (.12 .21 .38 b.75 .66 (.47 .38 (.10 .04 .79 p.27 .86 P.52 (3.55 -31 |θ.35 P-20 P.11 b.54 b.71 b.7
78 b1H15 6.34 .79 (.89 0.91 .77 b.73 b.92 b.85 b.57 .17 b.80 b.76 (.10 (.14 (.43 6.36 2.35 b.61 b.32 b.18 (.05 (.30
I80_ blH20 b.42 b.53 b.98 P.91 b.81 b.24 1.47 (.33 (.26 (.07 b.88 (.04 (.83 b.73 b.76 b.25 (.42 b.56 b.18 b.72 P.91 b
18fL blH8 b.86 b.87 (.87 (.02 (.13 b.22 6.17 6.37 .65 6.56 2.34 (.63 (.93 6.30 (.00 b.97 b.42 b.15 b.06 b.03 b.94 b.98 ( 184_ 1H16 b.68 b.42 b.54 .59 (.56 (.68 (.28 (.01 b.97 b.25 b.14 b.29 (.47 6.48 b.62 b-81 b.76 b.85 b.58 b.93 .24 b.
186 blH9 (.31 b.64 b.55 b.94 b.74 b.46 6.01 (.52 (.05 b.97 (.02 b.25 b.40 b.45 b.35 I.47 (.26 (.82 (.00 b.38 b.46 b.
188_ blH23 .10 b.60 b.60 .28 b.97 b.67 (.96 6.81 6.33 .20 b.93 b.86 b.40 b.52 b.39 b.34 b.38 (.16 (.05 b.99 b.38 b.46 b.
190 b1H10 P.36 4.02 (.57 P.80 6.18 b.85 (.11 b.73 b.97 b.82 b.98 (.07 (.42 6.62 B.20 B.68 b.65 b.65 b.43 b.69 b-81 (.
192_ blH6 B.14 B.12 B.46 b.48 R.02 .26 b.41 b.47 b.29 (.51 (.62 (.06 (.84 (.16 K.77 B.40 B.08 b.16 b.13 P.10 (.87 J 6. 194 b1H13 0.59 6.10 (.03 b.83 b.58 b.21 6.87 (.67 .71 b.49 b.64 (.22 B.85 B.85 (.99 (.55 b.72 H.92 B.05 b.37 6.06 .40 (. m_ MH19 b.47 b.46 b.54 (.12 b.54 b.16 6-12 6.58 (.50 (.53 (.40 (.04 (.65 (.82 (.03 b.80 b.80 6.90 6.66 b.49 b.59 b.89 ,
198_ b1G22 (.14 b.78 b.72 6.75 6.67 .41 B.35 2.7 B.79 (.35 .21 .01 b.59 b.70 b.77 b.63 .77 b.58 b.60 b.24 b.33 b.47 b. 200 blG21 b.99 (.01 b.55 2.02 (.48 .10 (.54 1.13 b.80 b.78 b.65 b.60 b.72 .35 (.28 b.69 b.74 .03 (.34 b.49 b.38 b.57 b.
2_L blHI (.33 b.82 b.82 6.50 6-70 .59 b.94 (.26 .95 .22 .06 b.98 b-81 b.87 b.65 b.82 (.08 b.46 b.38 b.25 b.65 b.94 . 204 blG20 b.74 b.48 b.50 (.54 b.66 b.36 (.64 .29 (.03 b.99 b.84 b.84 (.34 (.19 (.29 b.98 .09 (.85 (.50 b.64 .27 ,46
206 WH5 6.46 .52 (.40 B.58 (.14 B.93 (6.5 (1.3 b.97 b-81 b.87 b.80 (.19 b.92 .18 .14 b.49 b.58 b.40 b.69 b.78 b.
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
1312 b!A6 O.30 E.57 b.31 h.10 tt.88 .02 h.31 h.44 b.56 .502.81 b.16 P24 P.23 b.eo .29 b.55 2.17 2.92 b.15 b.91 h.99 b.99
B12 blA5 B.61J2.87 ,15 H.OO 2.95 b.87 b.47 .77 .64 .79 b.56 b.55 .70 b.19 b.23 b.22 b.98 .78 B.76 b.25
B14 blB9 ,14 9.9 B.20 b.86 2.05 .01 .01 fl.35 h.08 P.63 B.53 fe.52 b.75 2.19 .86 2.87 H.45 .17 b.47 b.17 B.52 9.0 b.16
B14 D1B6 b.69 8.7 h-14 b.59 b.72 b.92 b.70 b.54 b.61 b.59 b.89 .01 .54 m 2.13 3.09 B.12 tt.22 2.38 h.81 0.0 25.1 hβ.o b.60
B14 blB8 05.1 b.81 b.74 .23 .02 h-15 .35 b.91 b.57 .27 B.41 b.85 B.57 2.53 b.7i P.34 b.64 .60 .29 B.86 21.3 21.4 b.55
014 blB7 P.60 04.9 .17 b.59 b.74 0.80 b.90 b.80 b.72 b.48 P.84 h.76 4.62 W.60 i 2.00 .15 2.78 .89 bι.ι m b.46
B16 -1G17 b.85 .53 b.92 .10 b.83 .05 2.04 .86 .78 h.40 2.19 2.22 b.81 b.87 P.46 b.74 P.93 .06 .46 b.76 b.24 b.44 b.99 .10
018 31G3 P.38 P.39 .02 0.76 .16 b.87 .38 .71 P.81 P.73 .00 P.81 2.03 b.24 b.48 b.30 .65 .68 .50 P.58 b.86 .02 b.95
020 lF22 b.94 b.56 b.75 .15 .24 .60 2.56 .11 B.46 .10 .70 .67 b.45 b.47 b.29 b.31 b.35 b.74 b.85 b.83 P.16 b.27 b.31 .51
022 b1G12 129 P.41 .95 .56 .75 h.22 b.54 b.87 h.24 .12 b.31 0.16 h.53 2.64 2.85 P.33 b.51 b.84 .69
024 blFII 1.49 b.94 .01 .16 .64 h-56 b.64 b.91 .71 b.84 b.69 h.oo b.77 .16 P.53 .01 P.89 b.64 P.85 P.57 b.98 .77 .64 2.48
B26 falF16 2.63 P.62 b.65 B.26 .77 h.43 0.39 P.16 b.13 h.07 b.39 P.30 b.29 P.30 2.73 B.22 .02 b.52 b.21 M B.39 .11 b.31
028 blF14 P.75 JP P.97 b.92 b.84 h.29 h.35 .36 P.93 b.90 .03 b.54 b.98 b.16 b.22 b.30 h.52 B.98 B.61 .00 h.72 .66 b.oδ
030 blF17 .52 b.95 .82 B.53 B.68 B.49 b.24 b.32 b.33 2.14 2.44 2.18 b.86 tt.66 b.22 b.92 h.32 1.7 h6.0 B.79 b.04 b.27 .01 b-06
B32 b1C2 b.26 P.31 P.31 h.oo h.28 .53 B.09 3.6 6.1 .17 b.21 P.31 b.19 b.37 J0B7 .53 J2Λ0 b.60 2.84 h.53 P.05 B.91 B.48 b.95
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000226_0002
Figure imgf000226_0003
TABLE 13 Response of Novel genes to Hypoxia
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
TABLE 14 Response of Novel genes to Hypoxia
CO c
CD CO t
C m s co m m
7. c m t n
Figure imgf000230_0002
Figure imgf000231_0001
CO
C CD CO to o m co m m
c m t n
TABLE 15 Genes with increased expression by m acrophage activation
Figure imgf000232_0001
Figure imgf000233_0001
Legend mRNA expression values in the 6 experimental conditions (# 1 no cytokines/ norm oxia, #2 no cytokines/ hypoxia, #3 IL-10/ norm oxia, #4 IL-10/ hypoxia, #5 LPS/IFN/ normoxia, #6 LPS/IFN/ hypoxia) are show n as values referenced to the median value of that gene throughout all 6 experimental conditions.
TABLE 16. Genes down-regulated by m acrophage activation
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
TABLE 17: Genes responsive to IL-10 (increased or decreased) but not affected significantly by LPS+IFN
Figure imgf000235_0002
TABLE 18. Genes up-regulated in human tumors. Individual patients are denoted by the letters E,F,G,H and K.
Figure imgf000236_0001
Figure imgf000237_0001
TABLE 19. Genes down-regulated in human tumors. Individual patients are denoted by the letters E,F,G,H and K.
Figure imgf000238_0001
CO c
CD CO
m co m m
c m l- n
Figure imgf000239_0001
CcO
CD CO
m co
Im m
H
*J
C m r cn
Figure imgf000240_0002
Figure imgf000240_0001
TABLE 20: Genes up-regulated in response to TΗFα
Figure imgf000241_0001
Figure imgf000242_0001
TABLE 21 : Genes down-regulated in response to TNFα
Figure imgf000242_0002
TABLE 22: Genes up-regulated in response to IL-17
Figure imgf000242_0003
Figure imgf000243_0001
TABLE 24: Genes up-regulated in response to IL- 15
Figure imgf000243_0002
TABLE 25: Genes down-regulated in response to IL-15
Figure imgf000244_0001
T ABLE 26 cross-references all protein and nucleotide sequences (SEQ ID Nos.) that are referenced herein to accession num bers in public databases available as of 8.12.00.
CO c
CD CO
m co m m
c m l- n
Figure imgf000245_0001
Figure imgf000246_0001
CO c
CD CO
m co m m
7 c. m l- n
Figure imgf000247_0001
CO c
CD CO
m co m m
c m l-O cn
Figure imgf000248_0001
CO c
CD CO
m co m m
7 c. m l-O cn
Figure imgf000249_0001
CO c
CD CO
m co m m
7 c. m l-O cn
Figure imgf000250_0001
Figure imgf000251_0001
CO c
CD CO
m co m m
c m l-O cn
Figure imgf000252_0001
Figure imgf000253_0002
co m m
C m l-O cn
Figure imgf000253_0001
TABLE 27 cross-references all protein and nucleotide sequences (SEQ ID Nos.) that are referenced herein to accession numbers in public databases available as of 8.12.01 .
t u
Figure imgf000254_0001
J-l
t
J
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000256_0002
Figure imgf000256_0003
Figure imgf000257_0001
Figure imgf000257_0002
Figure imgf000258_0001
Figure imgf000258_0002
Figure imgf000258_0003
t
Ul oo
Figure imgf000259_0001
t
Figure imgf000260_0001
to
Oϊ O
Figure imgf000261_0001
t
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000263_0002
cCO
CD CO t t m co m m c m l-O cn
Figure imgf000264_0002
Figure imgf000264_0001
Sequence listing
TLPQNFGNIFLGETFSSYISVHNDSNQVVKDI VKADLQTSSQRNLSASNAAVAE PDCCIDDVIHHEVKEIGTHILVCA VSYTTQAGEKMYFRKFFKFQVLKPLDVKTKFYNAESDLSSVTDEVFLEAQIQ MTTSPMFMEKVSLEPSIMYNVTE NSVSQAG ECVSTFGSRAY QPMDTRQY YCLKPKNEFAEKAGIIKGVTVIGK DIVWKTNLGERGRLQTSQ QRMAPGYGDVRLSLEAIPD TVNLEEPFHITCKITNCSERTMDLVLEMCNTNSIHWCGISGRQLGKLHPSSS CLA TLLSSVQGLQSISG RLTDTF KRTYE YDDIAQVCWSSAIKVES
AAAAAGTGCCGGTCAAAATGGAAGTGAATCCCCCTAAACAGGAGCACCTGCTGGCGCTAAAAGTGATGCGGCTGACTAAGCCTA CTTTATTCACCAATATCCCAGTAACATGTGAAGAGAAAGACTTACCTGGAGATCTCTTTAACCAGCTGATGAGAGATGATCCTT CAACCGTTAATGGTGCAGAAGTTTTAATGTTGGGATAAATGCTGACTTTACCACAGAATTTTGGGAATATATTTTTGGGAGAGA CCTTTTCCAGTTATATCAGCGTTCATAATGATAGCAATCAAGTTGTAAAAGACATATTAGTAAAAGCTGATCTTCAGACAAGTT CTCAGCGTTTAAATCTTTCAGCCTCCAATGCTGCAGTGGCTGAACTTAAACCGGATTGTTGTATTGATGATGTCATACATCATG AAGTCAAAGAAATTGGAACACACATCTTGGTATGTGCTGTGAGTTATACAACTCAGGCTGGAGAAAAAATGTATTTCAGAAAAT TCTTCAAATTTCAGGTTCTCAAACCATTGGATGTGAAAACCAAATTTTACAATGCAGAGAGTGACCTCAGTTCTGTGACTGATG AAGTATTTCTGGAAGCCCAGATTCAGAATATGACAACCTCACCTATGTTTATGGAGAAGGTTTCACTGGAGCCATCTATTATGT ACAATGTAACAGAATTAAATTCAGTCAGCCAAGCTGGAGAATGTGTGTCTACGTTTGGGTCAAGAGCATATTTGCAACCAATGG ATACACGCCAGTACTTATACTGCCTAAAGCCAAAGAATGAATTTGCAGAAAAAGCAGGCATCATTAAGGGAGTAACAGTAATTG GAAAATTGGATATAGTATGGAAAACAAATCTAGGTGAAAGGGGAAGGTTACAGACCAGCCAACTTCAAAGAATGGCTCCAGGTT ATGGAGATGTTAGGTTGTCTTTGGAGGCAATACCAGATACCGTAAACCTTGAAGAACCTTTTCATATTACCTGTAAAATAACAA ACTGCAGTGAAAGGACTATGGATCTGGTTTTGGAAATGTGCAATACCAATTCCATCCACTGGTGTGGAATTTCAGGAAGACAGC TGGGAAAGCTGCATCCAAGTTCTTCGCTCTGTCTTGCCCTTACTCTGCTTTCTTCAGTACAGGGACTGCAAAGCATCTCTGGCT TAAGACTAACAGACACATTCTTAAAGAGAACATATGAATATGATGACATCGCACAAGTCTGTGTGGTATCTTCTGCCATTAAAG TGGAAAGCTGAAGGAAACTTCCAATGTTAGGCTTTTCATTTAGTTTCACAGAACTGCTCTTTTTGTTACCTTTGTAAAATGATG ACGTCAACAACGAAGTAAATATGTTACTTAAATTTTCTTTCCTGTAAAATGGTTAAAATATTAAATATTTGTTTTGAAGAGATC TGATTTTATCTTGTAATTTATATTTGAAATGAACATGTGTATATTTTCTACACCTATTATTTAATTTCATTTCATTTTAGATGA CCATTGGACTTTGTTCTCCAAAAGCTGTGTATCTGAGACCATTTGTCCCTAGCAAGTTATCTAGAACACGAGTCAGCACACTTT TTATGTAAGGTACAAGATACTAAATATTTTAGGCTTTGCAGGCCGTAAGGTTTCTGTCACAAATACTGAACTCTGCCATCGTAC TTCAAGAGCAGCCAGTAGGCAAAAAAAGTACAGTGGTGTACACAAAAAGAAGCAGTTGGACTCGGGAAGCTGAGGCAGGAGAAT CACTTGAACCGGGGAGGCAGAGGTTGCAGTTAAGCCGAGATCATGCTACTGCACTCTAGCCTGAGCGACAGAGTGAGACTCTGT CTCAAAAAAAAAAGAGGCAGCTGGGCAGATTTGGCCTGCAGGGTATAGTTGGCTGACCTCAATCTAGAAGATAGAGTTGTTTCT TAGAACTTTGTAATATTTTGGTTAGAAATATTTCAGTTAACTCCAGTTTTTTCCTAGCTATTCGGTCAGCAGAAAAAGTTTGCT TAGAACAAAGGGGGTAGTCCTCTTATAACCTGATATTTGTCAACACAGTATAAGCTTTCTAGTTGTTTTCAAAATTACTGTAAT GGTTTGTGTCTGTATTTGTATATTATACCTACAAACATACATATCTTTCAGCTACTGAACACATCAGAATTGGTTTTACTTTTT AGGTTGTTGATTTTTTTTAATTAACTATTAACTAAGAATAATACTTATTTTCTAATTATAAGCCAAAAACCCCTGGGTTTTTTT CTCATTGATTAAGCCACTTATTTTTATAAGGTATATTTAAATAATTCCCATCTTCTGATATGATTTTAAACTCTAAATCATGTG TTACTGTTACAAAACTTTCTCTCTCCATGTAATCACACTTAGTTATGAGCAAAGCAGTGAGAAAGTTGAGGTGATAAACAACTT TGCAGCATTAATGTAACAAAAAGTTTCAGTATTTGTCAGGAAAACAAAAGCTTAGGCTGTTAAATAAAAGCTATTCTATTTTGG TAAGTTGAAATTCAAGAATGTATATATAATTTCTTAAATGTAAGAGTGCATTAAATCAAATACAAAAATTGGTTTTTCAATGCA TCATTATTTATTGCCATAACAAATTGTTTGGTCCAAAATGAAAGCTATATTCAGAAGGTTTGCACCTCAAMTTGAGTAATAAT TAATGAAATGTCTGTACAAAATAAAGTGCAAGCAGTGT
MQMRRVRTCRSGPRKRREARYKKSTEDIFPAQLLKLQRHERVWQQEPPVRDHRS GGSGAGGVAGRE TDQGQVALGGHY AE GEGYFAMSEDELACSPYIPLGGDFGGGDFGGGDFGGGDFGGGGSFGGHCLDYCESPTAHCi LMEQVQRLDGILSETIPIHGR GNFPTLELQPSLIVKWRRRLAEKRIGVRDVRLNGSAASHVLHQDSGLGYKDLDLIFCADLRGEGEFQTVKDWDCL DFLPE GWKEKITPLTLKEAYVQKMVKVCNDSDRWSLIS SNNSGKNVELKFVDSLRRQFEFSVDSFQIKLDSLLLFYECSENPMTETF HPTIIGESVYGDFQEAFDHLCNKIIATRNPEEIRGGGLLKYCN VRGFRPASDEIKTLQRYMCSRFFIDFSDIGEQQR ESY QNHFVGLEDRKYEYLMTLHGVWESTVCLMGHERRQTLN ITMAIRVLADQNVIPVANVTCYYQPAPYVADANFSNYYIAQ VQPVFTCQQQTYSTWLPCN
ACAACTGCTAAAGCTCCAGAGACACGAGCGTGTGTGGCAGCAAGAGCCGCCAGTTCGGGACCACCGCAGCTGGGGTGGCAGCGG CGCAGGAGGGGTCGCGGGGCGGGAGTGGTGAGCGCAGGCGGCAGGGGTCTGGGAAAGACGAAGTCGCTATTTGCTGTCTGAGCG CGCTCGCAGCTCCTGGAAGTGTTGCCGCCTCTCGGTTTCGCTCTCGCTCGCTGCGCTCCTAGAAGGGGCGGCCGCCTCCAGGAC TGACCAGGGCCAAGTGGCGCTCGGCGGGCACTACATGGCGGAGGGTGAAGGGTACTTCGCCATGTCTGAGGACGAGCTGGCCTG CAGCCCCTACATCCCCCTAGGCGGCGACTTCGGCGGCGGCGACTTCGGCGGCGGCGACTTCGGCGGCGGCGACTTCGGCGGCGG CGACTTCGGCGGTGGCGGCAGCTTCGGTGGGCATTGCTTGGACTATTGCGAAAGCCCTACGGCGCACTGCAATGTGCTGAACTG GGAGCAAGTGCAGCGGCTGGACGGCATCCTGAGTGAGACCATTCCGATTCACGGGCGCGGCAACTTCCCCACGCTCGAGCTGCA GCCGAGCCTGATCGTGAAGGTGGTGCGGCGGCGCCTGGCCGAGAAGCGCATTGGCGTCCGCGACGTGCGCCTCAACGGCTCGGC AGCCAGCCATGTCCTGCACCAGGACAGCGGCCTGGGCTACAAGGACCTGGACCTCATCTTCTGCGCCGACCTGCGCGGGGAAGG GGAGTTTCAGACTGTGAAGGACGTCGTGCTGGACTGCCTGTTGGACTTCTTACCCGAGGGGGTGAACAAAGAGAAGATCACACC ACTCACGCTCAAGGAAGCTTATGTGCAGAAAATGGTTAAAGTGTGCAATGACTCTGACCGATGGAGTCTTATATCCCTGTCAAA CAACAGTGGCAAAAATGTGGAACTGAAATTTGTGGATTCCCTCCGGAGGCAGTTTGAATTCAGTGTAGATTCTTTTCAAATCAA ATTAGACTCTCTTCTGCTCTTTTATGAATGTTCAGAGAACCCAATGACTGAGACATTTCACCCCACMTAATCGGGGAGAGCGT CTATGGCGATTTCCAGGAAGCCTTTGATCACCTTTGTAACAAGATCATTGCCACCAGGAACCCAGAGGAAATCCGAGGGGGAGG CCTGCTTAAGTACTGCAACCTCTTGGTGAGGGGCTTTAGGCCCGCCTCTGATGAAATCAAGGCCCTTCAAAGGTACATGTGTTC CAGGTTTTTCATCGACTTCTCAGACATTGGAGAGCAGCAGAGAAAACTGGAGTCCTATTTGCAGAACCACTTTGTGGGATTGGA AGACCGCAAGTATGAGTATCTCATGACCCTTCATGGAGTGGTAAATGAGAGCACAGTGTGCCTGATGGGACATGAAAGAAGACA GACTTTAAACCTTATCACCATGCTGGCTATCCGGGTGTTAGCTGACCAAAATGTCATTCCTAATGTGGCTAATGTCACTTGCTA TTACCAGCCAGCCCCCTATGTAGCAGATGCCAACTTTAGCAATTACTACATTGCACAGGTTCAGCCAGTATTCACGTGCCAGCA ACAGACCTACTCCACTTGGCTACCCTGCAATTAAGAATCATTTAAAAATGTCCTGTGGGGAAGCCATTTCAGACAAGACAGGAG AGAAAAAAAAAAAAAAAAAAAA 5
MKKFSRMPKSEGGSGGGAAGGGAGGAGAGAGCGSGGSSVGVRVFAVGRHQVTLEESLAEGGFSTVF VRTHGGIRCALKRMYV IrøPDL VCKREITIMKE SGHKNIVGYLDCAVNSISDV EVLILMEYCRAGQVV QMNKK QTGFTEPEVLQIFCDTCEAVAR LHQCKTPIIHRDLKVENIL NDGGNYV CDFGSATNKF NPQKDGVWEEEIKKYTT SYRAPEMINLYGGKPITTKADIWA GC LYKLCFFT PFGESQVAICDGNFTIPDNSRYSRNIHCLIRFM EPDPEHRPDIFQVSYFAFKFAKKDCPVSNI CCKQLL RHGALLTEILLFLQLFLNRMTASEAAARKSQIKARITDTIGPTETSIAPRQRPKANSATTATPSVLTIQSSATPVKVLAPGEFG NHRPKGALRPGNGPEILLGQGPPQQPPQQHRVLQQLQQGDWRLQQLHLQHRHPHQQQQQQQQQQQHHHHHHHHLLQDAYMQQYQ HATQQQQMLQQQFLMHSVYQPQPSASQYPTMPQYQQAFFQQQ LAQHQPSQQQASPEY TSPQEFSPALVSYTSSLPAQVGTI MDSSYSA RSVADKEAIANFTNQKNISNPPDMSGNPFGEDNFSK TEEE LDREFDL RSSKGHLKAYFASQ
AGCCGGGCAGCTGCAGCGGAGCCGCGGAGCGGGCGGCGGGGCCCAGGCTGTGCGCTTGGGGAGCGCGGAATGTGAGGCTTGGCG GGCCGCAGCACGCTCGGACGGGCCAGGGGCGGCGACCCCTCGCGGACGCCCGGCTGCGCGCCGGGCCGGGGACTTGCCCTTGCA CGCTCCCTGCGCCCTCCAGCTCGCCGGCGGGACCATGAAGAAGTTCTCTCGGATGCCCAAGTCGGAGGGCGGCAGCGGCGGCGG AGCGGCGGGTGGCGGGGCTGGCGGGGCCGGGGCCGGGGCCGGCTGCGGCTCCGGCGGCTCGTCCGTGGGGGTCCGGGTGTTCGC GGTCGGCCGCCACCAGGTCACCCTGGAAGAGTCGCTGGCCGAAGGTGGATTCTCCACAGTTTTCCTCGTGCGTACTCACGGTGG AATCCGATGTGCATTGAAGCGAATGTATGTCAATAACATGCCAGACCTCAATGTTTGTAAAAGGGAAATTACAATTATGAAAGA GCTATCTGGTCACAAAAATATTGTGGGCTATTTGGACTGTGCTGTTAATTCAATTAGTGATAATGTATGGGAAGTCCTTATCTT AATGGAATATTGTCGAGCTGGACAGGTAGTGAATCAAATGAATAAGAAGCTACAGACGGGTTTTACAGAACCAGAAGTGTTACA GATATTCTGTGATACCTGTGAAGCTGTTGCAAGGTTGCATCAGTGTAAGACTCCAATAATTCACCGGGATCTGAAGGTAGAAAA TATTTTGTTGAATGATGGTGGGAACTATGTACTTTGTGACTTTGGCAGTGCCACTAATAAATTTCTTAATCCTCAAAAAGATGG AGTTAATGTAGTAGAAGAAGAAATTAAAAAGTATACAACTCTGTCATACAGAGCCCCTGAAATGATCAACCTTTATGGAGGGAA ACCCATCACCACCAAGGCTGATATCTGGGCACTGGGATGTCTACTCTATAAACTTTGTTTCTTCACTCTTCCTTTTGGTGAGAG TCAGGTTGCTATCTGTGATGGCAACTTCACCATCCCAGACAATTCTCGTTACTCCCGTAACATACATTGCTTAATAAGGTTCAT GCTTGAACCAGATCCGGAACATAGACCTGATATATTTCAAGTGTCATATTTTGCATTTAAATTTGCCAAAAAGGATTGTCCAGT CTCCAACATCAATAAGTGTTGTAAACAATTACTGAGACACGGAGCACTGTTAACTGAAATTCTTCTATTCCTTCAGCTCTTCCT GAACCGATGACTGCTAGTGAAGCAGCTGCTAGGAAAAGCCAAATAAAAGCCAGAATAACAGATACCATTGGACCAACAGAAACC TCAATTGCACCAAGACAAAGACCAAAGGCCAACTCTGCTACTACTGCCACTCCCAGTGTGCTGACCATTCAAAGTTCAGCAACA CCTGTTAAAGTCCTTGCTCCTGGTGAATTCGGTAACCATAGACCAAAAGGGGCACTAAGACCTGGAAATGGCCCTGAAATTTTA TTGGGTCAGGGACCTCCTCAGCAGCCGCCACAGCAGCATAGAGTACTCCAGCAACTACAGCAGGGAGATTGGAGATTACAGCAA CTCCATTTACAGCATCGTCATCCTCACCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCACCACCACCACCACCACCACCAC CTACTTCAAGATGCTTATATGCAGCAGTATCAACATGCAACACAGCAGCAACAGATGCTTCAACAACAATTTTTAATGCATTCG GTATATCAACCACAACCTTCTGCATCACAGTATCCTACAATGATGCCGCAGTATCAGCAGGCTTTCTTTCAACAGCAGATGCTA GCTCAACATCAGCCGTCTCAACAACAGGCATCACCTGAATATCTTACCTCCCCTCAAGAGTTCTCACCAGCCTTAGTTTCCTAC ACTTCATCACTTCCAGCTCAGGTTGGAACCATAATGGACTCCTCCTATAGTGCCAATAGGTCAGTTGCTGATAAAGAGGCCATT GCAAATTTCACAAATCAGAAGAACATCAGCAATCCACCTGATATGTCAGGGTGGAATCCTTTTGGAGAGGATAATTTCTCTAAG TTAACAGAAGAGGAACTATTGGACAGAGAATTTGACCTTCTAAGATCAAGTAAGGGACACTTGAAGGCTTATTTTGCTTCACAG TAAAATAACAGCTCTATTATTATTCAGCAAGGCCAAAGACTTTTGAGAATGTGTATGGAAAATTCTTTTTGTGCATTTGAGGGC AAAATTCAGGCCATCTTCTTATACATATACTATCAAATTATGTTGTGTGCATTAGAMTCAGTTGCTTGATAGTAGCTATTAAA CCCAATATTGCTGATAGTATGCTAATATCCTAAAACTTAAATATTGCATATCTATGAATGTTAAATTCAGAATATCTCTAAAAC ATGGAAAATTGATGTTTCAATAAAAAGGGAGACATTTTATTATTTTGCCTTACTAATGATTTTGCAGCTCTGTTTTTCTGCACA CTCAATAGAAAATATTGTGGGTCTGAGATGCCCTTTGAAAATGCCTGAAAGAAAACATGGGCTACTACATTATGTTAATGTTTT GTAATGTCCTTTTAATGAGTGGTGACATAAAAGGGCTGCTTTGTTGTCCTGATATGGCAAAAATTAAATAAATTCTTTTTCACT TTAAAAAAAAAAAAAAAAAAAAAAAAA
MQWRAVLGLVLLRLGLHGVL LVFGLGPSMGFYQRFP SFGFQRLRSPDGPASPTSGPVGRPGGVSGPSWLQPPGTGAAQSPR KAPRRPGPGMCGPANWGYVGGRGRGPDEYEKRYSGAFPPQ RAQMRDLARGMFVFGYDNYMAHAFPQDE NPIHCRGRGPDRG DPSNNINDVLGNYSLTVDALDTLAI GNSSEFQKAVKLVINTVSFDKDSTVQVFEATIRVLGS SAHRIITDS QPFGDMT IKDYDNELLYMAHDAVR LPAFENTKTGIPYPRV LKTGVPPDTN ETCTAGAGS LVEFGILSRLLGDSTFE ARRAVKAL W LRSNDTGLLGNVVNIQTGHWVGKQSGLGAGLDSFYEYLLKSYILFGEKEDLEMFNAAYQSIQNYLRRGREACNEGEGDPPLY \nwmFSGQLMNTV3IDSLQAFFPGLQVLIGDVEDAIC HAFYYAIW RYGALPERYMIQLQAPDVLFYPLRPELVESTY LYQA TKNPFYLHVGMDILQSLEKYTKVKCGYATLHHVIDKSTEDRMESFFLSETCKYLYLLFDEDNPVHKSGTRYMFTTEGHIVSVDE HLRELP KEFFSEEGGQDQGGKSVHRPKPHELKVINSSSNCNRVPDERRYSLPLKSIYMRQIDQMVG I
GGTGGTCGGCGGGGAGGCCCCCGCGCTTTAAAATAATGCCCGCGGCGCCCGCGCGACCATGCAATGGCGAGCGCTCGTCCTGGG GCTGGTGCTCCTCCGGCTTGGCCTCCATGGAGTATTGTGGCTCGTCTTCGGGCTGGGGCCCAGCATGGGCTTCTACCAGCGCTT TCCGCTCAGCTTCGGCTTCCAGCGTCTGAGGAGCCCCGACGGCCCCGCGTCGCCCACCTCGGGGCCCGTGGGCCGGCCTGGGGG GGTATCCGGGCCGTCGTGGCTGCAGCCGCCGGGGACCGGGGCAGCGCAGAGCCCGCGCAAGGCTCCGCGGCGTCCTGGGCCGGG GATGTGCGGCCCAGCCAACTGGGGCTACGTGCTGGGCGGCCGGGGCCGCGGCCCGGACGAGTACGAGAAGCGCTACAGCGGCGC CTTCCCTCCGCAGCTGCGTGCCCAGATGCGCGACCTGGCACGGGGCATGTTCGTCTTTGGCTACGACAACTACATGGCTCACGC CTTCCCCCAGGACGAGCTCAACCCCATCCACTGCCGCGGCCGTGGGCCCGACCGCGGGGACCCTTCAAATCTGAACATCAATGA TGTACTAGGGAACTACTCATTGACTCTTGTTGATGCATTGGATACACTTGCAATAATGGGAAATTCATCCGAGTTCCAGAAAGC AGTCAAGTTAGTGATCAACACAGTTTCATTTGACAAAGATTCCACCGTCCAAGTCTTTGAGGCCACGATAAGGGTCCTGGGAAG CCTCCTTTCTGCTCACAGAATAATAACTGACTCCAAGCAGCCCTTTGGTGACATGACAATTAAGGACTATGATAATGAGTTGTT ATACATGGCCCATGACCTGGCGGTGCGGCTCCTCCCTGCTTTTGAAAACACCAAGACAGGGATTCCATATCCTCGGGTGAATCT AAAGACAGGAGTTCCTCCTGACACCAATAATGAGACATGCACAGCGGGAGCCGGTTCCCTCCTGGTGGAATTTGGGATTCTGAG TCGACTCCTGGGGGACTCCACATTTGAGTGGGTGGCCAGACGAGCAGTGAAAGCCCTTTGGAACCTCCGGAGCAATGATACAGG ATTACTAGGCAATGTCGTGAACATTCAGACGGGCCACTGGGTTGGAAAGCAGAGTGGCCTGGGTGCCGGGCTGGACTCCTTCTA TGAATACCTCTTGAAATCTTACATTCTCTTTGGAGAAAAAGAAGACCTAGAAATGTTTAATGCTGCATATCAGAGTATTCAGAA CTACTTAAGAAGAGGGCGGGAAGCCTGCAATGAAGGAGAAGGAGACCCTCCACTCTATGTCAACGTGAACATGTTCAGTGGGCA GCTGATGAACACCTGGATTGACTCTCTGCAGGCCTTTTTCCCTGGACTGCAGGTGCTGATAGGAGATGTGGAAGATGCCATCTG CCTTCATGCCTTCTACTATGCCATATGGAAACGATATGGTGCCCTCCCTGAGAGATATAACTGGCAGCTGCAGGCCCCTGACGT TCTCTTCTACCCACTGAGACCAGAGTTAGTGGAATCCACATATCTCCTCTACCAGGCAACCAAGAATCCCTTCTACCTCCATGT AGGAATGGATATTCTGCAGAGTCTGGAAAAGTACACAAAAGTCAAGTGTGGGTACGCCACGCTGCATCACGTCATTGACAAGTC CACAGAAGACCGGATGGAGAGCTTCTTTCTCAGTGAGACCTGTAAATATTTGTATCTGCTGTTTGATGAAGACAATCCAGTACA CAAGTCTGGAACCAGATACATGTTCACAACAGAGGGACACATTGTATCTGTGGATGAGCATCTTCGGGAATTGCCATGGAAGGA ATTCTTCTCTGAAGAGGGAGGGCAGGACCAAGGGGGAAAGTCTGTGCACAGGCCGAAACCTCATGAGTTAAAAGTCATCAACTC CAGCTCCAACTGCAATCGTGTACCTGATGAGAGGAGGTACTCCCTGCCCTTAAAGAGCATCTACATGCGACAGATTGACCAGAT GGTTGGTTTGATTTGATCTGCTCTCTGTGAGGCCTCATCTTGAACCAGACCTTAACGACCAAACCCAGACCATGCCAAAGTCCA GTCTGAAATGAAAGGGGACAGAAGTCTTGCTGTCCATGGTGGTGTAGGAATTTCTGTGCAACACCTCACCACGTCTGGTTAATC CTTGCACACTTCAGTGTTTCTCTCCTGTTCAATAAAATGCCCTGTTAAGGATATAATTTGAAGTGAGAAGATACATGGAAATTG CCCTCTTATGACATGTTGATGTTATAAGCACAATAGATGGGGCATCTTTGGATTGATGTTCACAGCTTTATACTTCAGAACCTA AGTCTCTTCACTTTGCTGGCACCTGCTATACTGGAGTATTGCTATGTCTTTAAAAAATTTTTTTTTATTATATTTTATTTTTTT GAGACAGGGTCTTGATATTTTTTTGGGACAGGGTTACCTGGGCTCAAGTGATCCTTCTGCCTCAGCCTCCCGAGTAGCTGGGAT TACAGGTGAGCACCACTGTACCTGGCTAGCTACTTCTTTGTTAGAGGATTGAGAATGAAATTTCTGCAAAAGGGCCCATGGTTC ATTTGGTATCCCTATTTAATTGCATTGAAAATGTCATCCTTTCTGTTGTTAGATAATTGGGGTCTTCCCCTGATATCCAACCGT GATTTTGGATCACATGGGAGAAAAAGTCATCCAGTTTTTCATGTTTGCCTCAAGTAATCTTTACAGTGTTACAAATTATTTGCT TAAGAAGAATGGTCTTAACCAGAATTCTTAACAGATAGTCTCTTAGGTTATTATGTTATGGTCTAAGAGGTTAACTGACATCTT TTGGATGGTATTTTGCATTTTGAATATGAACTTACCTGAGGAACTCCCATAGTTCCAGAATCAGGTGCCTTTTAGGGAGAGAAC AATACCTAAGATTGTCTGAGCTTCCATCTTTCTCATATTTCCTAAGCAAGGATTCTCACTTATGACCATATTTGGGTTAGAGTT CTGTTTTGTTTCTGTTTTCTGTGTCTAGTGCCAATTAGCTAAATCAGGGAGAAAGAAATGATCACATGACTTTTAGCATCCTTG AGCCATTTCTCTGTGTAATACAGGCTTTAGATTAGTGCCTTATATTGGTTTTGGTTTGGGGCACTGGATGTCGCAGCTACTGCT ATGGTTTCAGGAGGCCTGTTTAGCCACATGGTGAGACCGTGGTGAAAGGGGGATGGAAATTGCTTGGCCAGTCTTTGCCTTTCA TCCTGTAAAAGTAAGCATGTAGAAGGAGGAAGTTGTGCTAAAATGCCTTTGTTTTTTTGTTATTATTTTCTTAGCCAGAACATC TCTCTTTGAACTCACACTGATACACACCTGCTACTCTTACACAGTGCAGCAGGGCTGACTCTTAGTCTGGCTTCCATGAAGCGT CATGGGTGGAAACGCATTCTAGTAAAAAAGGTAGGAAATCCCTAAAACTTCCAGCCTCACATAGCACGGTTCTCACCTGTCACT GTTTTCCCACCTCTAAGGATTTCATGTACATCTTTTCAAAGCTAGAAATAAGCACTGTCTAAGTTTATGTTGCATTTTTAGTCA AAAGGGAGAAATCTTATTCCTTCTTGAAAATTTTAAGTGTTATGGTTTTATATAGTTCAGTTCTTTGAGATTTTTGAAAAGAGT ATTTTCAGTAATAAACGTGCCATCTCTATCTCTTAAACATTTATTACAACAATTGTTTTAAAATAGAAAAAATAAAATGCTTCT ATTTTACCTTTTTTCATTTCAGAAGCATTATTCTGTTTATTAACAGTGTCCCATCTACTGAATAGAAAACTTTGAGAATAATAT ATATATATATTTTAAATGTTTTCACTGACTCATTGAAAATGTTAATTACACACACATGCATGCATGCACACACGAGCATACTTG TACCTTTGTCTCTGGGCAAACAGGTGGGACTGTTAGTGACCCATTTGGGAAAATAGAGCATCTCAGAGAAGGAGGTGAGTTCTT CCTGCCTGTGATTTCTCTTGGCGCTCCCCTCCTCTCCCGCTCTGGCTTCTGTGGCGGCAGTGGTGGGTAAGCACTCCAGTGTTC TCTTAATGAGGCACTTTGCCTGTCACTCGAGCAAGCCTGGGTGTTCCTTCCTCCTCATGCTCCTGGAATAGGGAATAGGGATCT CATGCTTGCAAACTACACAATGCTGCAGGTGCTTCCCAGGGGCCACAGGCTGTCAGGAAACGTGTTTTATGTTAAGTCACAAAC CCACTTGACTTCTGGGTACTGGAATTAATACCAGTGGGTGAGACTGAGGGTGAGTGAGTTAGTACATATTAATCCTGGTTGTTG AGCTTCCAGACTACCCCGTCCAAAGTTTGATGCTATGTAGTCAGTGGTTTGTGGGGCTGGATGCCAGAAGGTTCTTTGAGCCAG TTTCAAAGGTTACTTGTTTTTTTTTTTTTTTTTTTAAGTCAGAATGTTAACAGCTGTGATATATCCTGCAGGGCTTTTGCAGTT TCTTCTGTTCTGTGTTCTGAAATCCTGGGTAGAGAATGGCTGAGGAGGAGATTACCAGAGAAGTTGCTTTGCTCAGTGCTTTGC CCCAGGATTGCCTCAAATCTGAGTGGACTTCATCCTTTGCGGCGGCTCTGAGCCTGGCCCATCTTCCTATTCCCACGTGTAGCT AGTGTCTAGTGTCAGCTTTGCTCAATGTGGTGGAAACATTTTGCAGAACTGTTGTAGAAAGCTGCCTTATAGTTGGCTTGACAA AGCATAATTCTCTCATAACAAACTTTCAAATCATTACAGTAGCTTAGCTACTTTAGTTGATGTGACCGAGGAATCCCTTCTAGA ATCATAGGTGGCAAGGGAGGGTTTGCTAGCTCTCCATTTGCACTGGCCATTGTGAAAAACCAGCTTCTGTATTCAAATCTTTCC TTCATTTTTTTAAATTTTTTTTTTGGCAGCGCTTGTGCTGGAACTTACTCATTGTAACTGAATCCTCAGGGCTTTTCTTGTTTT AGATCATGGACTGTGCACGTGACACTTAAATAATTTTCTATGTATTTAAAGAAAAATGCACCAGGATGGTGTCTGTGCACGTGA CTATTAGAGGAGCGTCTGTAGAAGTACCTGGTTTGGTCAGTGCAGTTGTGCAATCTGAGGGCCTTGTTTCCTCCTCCCCTTTCC CCTTCTCCCCACCAAAGGAAAATATCCCTCTTAATGATTTCGTAGTTCAGTTTACTGAATGATTACCACCTGTAATTCCTCTTT GGATTGTGTAGACTCAACATGAGACATTCCTTTCTGCTTTCTGGAGGGCACCAGGGGCCTTTCTCTTTGATAAATTTTTTTTGT CTGTTGACAAAAACAAAAATCTTTTTTCAAATGTAGTGCTGGTGAAAAGGTAGGGCTGAGTGATTACCTTAGCCACAGGGTGGC TGAGCAGGAACTTTAGAAGAAAATCCTGAGCTTTCCTGTCCATTCCCAGCATCCAGCTCCTATTCTAGTGCCTCTTCCCTGCAG GGCAGGGACCCCTTGGGAAATCGAGGAGGTGGGACGGGCTGGGCCCTGTGTCCCAGGTTTCACAGGGCTCAGGGTTATGCTCCC GCTTGAATCTGGACGTGAATCTGGTAAAAATATCAAGTACCTGTGGAACTCCCTGATTCTATACCCTCTTCCTTCTTTCTGCAA GGCAGAGGAATAATATTTTTAAAGGTTATTTTGTTTTAGTTTTAAATAGCAAAACACAAGCTGCATTTTTATTTATTTTGCATA AGAAAGGTAAATCTTTTTACAAAAAAAAGTATAGAGTTGGAAACTCTGGGAAAACTTACGGAAATACACAAATGCTTCTCTGTA ATGTGCAATATGCTTTGCAACTGTAGATGATATTTTATGTTTAATCTGTAAATAAGAAATGTATTTAAATTAAAAGGGATCTTT TTGTAAAAGGACCAAATGTTCTTTTATAAATGTAATAAGGAATATCTTGCTCTTTAAAATTTATTAGGATTTTTATGAGTAATT TTTATTAAAAGATTTCTTTTTTTG MACEI PLQSSQEDERP SPFYLSAHVPQVS VSATGELLERTIRSAVEQH FDVNSGGQSSEDSESGTLSASSATSARQRRR QSKEQDEVRHGRDKG INKENTPSGFNHLDDCILNTQEVEKVHKNTFGCAGERSKPKRQKSSTKLSELHDNQDGLVNMES NST RSHERTGPDDFE SDERKGNEKDGGHTQHFESPTMKIQEHPSLSDTKQQRNQDAGDQEESFVSEVPQSDLTA CDEK WEEPI PAFSSWQRENSDSDEAHLSPQAGR IRQLLDEDSDPM SPRFYAYGQSRQYLDDTEVPPSPPNSHSFMRRRSSSLGSYDDEQED LTPAQLTRRIQSLKKKIRKFEDRFEEEKKYRPSHSDKAANPEVLK TNDLAKFRRQLKESKLKISEEDLTPRMRQRSNTLPKSF GSQ EKEDEKKQELVDKAIKPSVEATLESIQRKLQEKRAESSRPEDIKDMTKDQIANEKVALQKALLYYESIHGRPVTKNERQV MKP YDRYRLVKQILSRA TIPIIGSPSSKRRSPL QPIIEGETASFFKEIKEEEEGSEDDSNVKPDFMVTLKTDFSARCFLDQ FEDDADGFISP DDKIPSKCSQDTGLSN HAASIPELLEHLQEMREEKKRIRKKLRDFEDNFFRQNGRNVQKEDRTPMAEEYSE YKHIKAKLRLLEVLISKRDTDSKSM
10
AAATGTAGAGAAGCAGCCGATAAAATAGCATTGCCTGAAGAAGTTTGGAGGCTGAGAGCAGCAGTAGACTGGCCAACTGCAGAG CAAGTTGTTTCTCCAGCCGTGCGGTGCAGCCTCATGCCCCCAACCCAGCTTAGCCACTGTAAGAAGACGTTCACTGTACAGACG ACCAAACTTGCCGTGGAAGAGACAGTTGTGAGATTCCCTTGCAAATTTACATACGAGAATGGCTTGTGAAATCATGCCTCTGCA AAGTTCACAGGAAGATGAAAGACCTCTGTCACCTTTCTATTTGAGTGCTCATGTACCCCAAGTCAGCAATGTGTCTGCAACCGG AGAACTCTTAGAAAGAACCATCCGATCAGCTGTAGAACAACATCTTTTTGATGTTAATAACTCTGGAGGTCAAAGTTCAGAGGA CTCAGAATCTGGAACACTATCAGCATCTTCTGCCACATCTGCCAGACAGCGCCGCCGCCAGTCCAAGGAGCAGGATGAAGTTCG ACATGGGAGAGACAAGGGACTTATCAACAAAGAAAATACTCCTTCTGGGTTCAACCACCTTGATGATTGTATTTTGAATACTCA GGAAGTCGAAAAGGTACACAAAAATACTTTTGGTTGTGCTGGAGAAAGGAGCAAGCCTAAACGTCAGAAATCCAGTACTAAACT TTCTGAGCTTCATGACAATCAGGACGGTCTTGTGAATATGGAAAGTCTCAATTCCACACGATCTCATGAGAGAACTGGACCTGA TGATTTTGAATGGATGTCTGATGAAAGGAAAGGAAATGAAAAAGATGGTGGACACACTCAGCATTTTGAGAGCCCCACAATGAA GATCCAGGAGCATCCCAGCCTATCTGACACCAAACAGCAGAGAAATCAAGATGCCGGTGACCAGGAGGAGAGCTTTGTCTCCGA AGTGCCCCAGTCGGACCTGACTGCATTGTGTGATGAAAAGAACTGGGAAGAGCCTATCCCTGCTTTCTCCTCCTGGCAGCGGGA GAACAGTGACTCTGATGAAGCCCACCTCTCGCCGCAGGCTGGGCGCCTGATCCGTCAGCTGCTGGACGAAGACAGCGACCCCAT GCTCTCTCCTCGGTTCTACGCTTATGGGCAGAGCAGGCAATACCTGGATGACACAGAAGTGCCTCCTTCCCCACCAAACTCCCA TTCTTTCATGAGGCGGCGAAGCTCCTCTCTGGGGTCCTATGATGATGAGCAAGAGGACCTGACACCTGCCCAGCTCACACGAAG GATTCAGAGCCTTAAAAAGAAGATCCGGAAGTTTGAAGATAGATTCGAAGAAGAGAAGAAGTACAGACCTTCCCACAGTGACAA AGCAGCCAATCCGGAGGTTCTGAAATGGACAAATGACCTTGCCAAATTCCGGAGACAACTTAAAGAATCAAAACTAAAGATATC TGAAGAGGACCTAACTCCCAGGATGCGGCAGCGAAGCAACACACTCCCCAAGAGTTTTGGTTCCCAACTTGAGAAAGAAGATGA GAAGAAGCAAGAGCTGGTGGATAAAGCAATAAAGCCCAGTGTTGAAGCCACATTGGAATCTATTCAGAGGAAGCTCCAGGAGAA GCGAGCGGAAAGCAGCCGCCCTGAGGACATTAAGGATATGACCAAAGACCAGATTGCTAATGAGAAAGTGGCTCTGCAGAAAGC TCTGTTATATTATGAAAGCATTCATGGACGGCCGGTAACAAAGAACGAACGGCAGGTGATGAAGCCACTATACGACAGGTACCG GCTGGTCAAACAGATCCTCTCCCGAGCTAACACCATACCCATCATTGGTTCCCCCTCCAGCAAGCGGAGAAGCCCTTTGCTGCA GCCAATTATCGAGGGCGAAACTGCTTCCTTCTTCAAGGAGATAAAGGAAGAAGAGGAGGGGTCAGAAGACGATAGCAATGTGAA GCCAGACTTCATGGTCACTCTGAAAACCGATTTCAGTGCACGATGCTTTCTGGACCAATTCGAAGATGACGCTGATGGATTTAT TTCCCCAATGGATGATAAAATACCATCAAAATGCAGCCAGGACACAGGGCTTTCAAATCTCCATGCTGCCTCAATACCTGAACT CCTGGAACACCTCCAGGAAATGAGAGAAGAAAAGAAAAGGATTCGAAAGAAACTTCGGGATTTTGAAGACAACTTTTTCAGACA GAATGGAAGAAATGTCCAGAAGGAAGACCGCACTCCTATGGCTGAAGAATACAGTGAATATAAGCACATAAAGGCGAAACTGAG GCTCCTGGAGGTGCTCATCAGCAAGAGAGACACTGATTCCAAGTCCATGTGAGGGGCATGGCCAAGCACAGGGGGCTGGCAGCT GCGGTGAGAGTTTACTGTCCCCAGAGAAAGTGCAGCTCTGGAAGGCAGCCTTGGGGCTGGCCCTGCAAAGCATGCAGCCCTTCT GCCTCTAGACCATTTGGCATCGGCTCCTGTTTCCATTGCCTGCCTTAGAAACTGGCTGGAAGAAGACAATGTGACCTGACTTAG GCATTTTGTAATTGGAAAGTCAAGACTGCAGTATGTGCACATGCGCACGCGCATGCACGCACACACACACACAGTAGTGGAGCT TTCCTAACACTAGCAGAGATTAATCACTACATTAGACAACACTCATCTACAGAGAATATACACTGTTCTTCCCTGGATAACTGA GAAACAAGAGACCATTCTCTGTCTAACTGTGATAAAAACAAGCTCAGGACTTTATTCTATAGAGCAAACTTGCTGTGGAGGGCC ATGCTCTCCTTGGACCCAGTTAACTGCAAACGTGCATTGGAGCCCTATTTGCTGCCGCTGCCATTCTAGTGACCTTTCCACAGA GCTGCGCCTTCCTCACGTGTGTGAAAGGTTTTCCCCTTCAGCCCTCAGGTAGATGGAAGCTGCATCTGCCCACGATGGCAGTGC AGTCATCATCTTCAGGATGTTTCTTCAGGACTTCCTCAGCTGACAAGGAATTTTGGTCCCTGCCTAGGACCGGGTCATCTGCAG AGGACAGAGAGATGGTAAGCAGCTGTATGAATGCTGATTTTAAAACCAGGTCATGGGAGAAGAGCCTGGAGATTCTTTCCTGAA CACTGACTGCACTTACCAGTCTGATTTTATCGTCAAACACCAAGCCAGGCTAGCATGCTCATGGCAATCTGTTTGGGGCTGTTT TGTTGTGGCACTAGCCAAACATAAAGGGGCTTAAGTCAGCCTGCATACAGAGGATCGGGGAGAGAAGGGGCCTGTGTTCTCAGC CTCCTGAGTACTTACCAGAGTTTAATTTTTTTAAAAAAAATCTGCACTAAAATCCCCAAACTGACAGGTAAATGTAGCCCTCAG AGCTCAGCCCAAGGCAGAATCTAAATCACACTATTTTCGAGATCATGTATAAAAAGAAAAAAAAGAAGTCATGCTGTGTGGCCA ATTATAATTTTTTTCAAAGACTTTGTCACAAAACTGTCTATATTAGACATTTTGGAGGGACCAGGAAATGTAAGACACCAAATC CTCCATCTCTTCAGTGTGCCTGATGTCACCTCATGATTTGCTGTTACTTTTTTAACTCCTGCGCCAAGGACAGTGGGTTCTGTG TCCACCTTTGTGCTTTGCGAGGCCGAGCCCAGGCATCTGCTCGCCTGCCACGGCTGACCAGAGAAGGTGCTTCAGGAGCTCTGC CTTAGACGACGTGTTACAGTATGAACACACAGCAGAGGCACCCTCGTATGTTTTGAAAGTTGCCTTCTGAAAGGGCACAGTTTT AAGGAAAAGAAAAAGAATGTAAAACTATACTGACCCGTTTTCAGTTTTAAAGGGTCGTGAGAAACTGGCTGGTCCAATGGGATT TACAGCAACATTTTCCATTGCTGAAGTGAGGTAGCAGCTCTCTTCTGTCAGCTGAATGTTAAGGATGGGGAAAAAGAATGCCTT TAAGTTTGCTCTTAATCGTATGGAAGCTTGAGCTATGTGTTGGAAGTGCCCTGGTTAATCCATACACAAAGACGGTACATAATC CTACAGGTTTAAATGTACATAAAAATATAGTTTGGAATTCTTTGCTCTACTGTTTACATTGCAGATTGCTATAATTTCAAGGAG TGAGATTATAAATAAAATGATGCACTTTAGGATGTTTCCTATTTTTGAAATCTGAACATGAATCATTCACATGACCAAAAATTG TGTTTTTTTAAAAATACATGTCTAGTCTGTCCTTTAATAGCTCTCTTAAATAAGCTATGATATTAATCAGATCATTACCAGTTA GCTTTTAAAGCACATTTGTTTAAGACTATGTTTTTGGAAAAATACGCTACAGAATTTTTTTTTAAGCTACAAATAAATGAGATG CTACTAATTGTTTTGGAATCTGTTGTTTCTGCCAAAGGTAAATTAACTAAAGATTTATTCAGGAATCCCCATTTGAATTTGTAT GATTCAATAAAAGAAAACACCAAGTAAGTTATATAAAAT 11
M KGVQRKRADKY EYTFKVWSD SVTTVTKTHQELQEFLLK PKELSSETFD TI RALNQGSL REERRHPDLEPILRQLF SSSSQAFLQSQKVHSFFQSISSDSLHSINN QSSLKTSKILEHLKEDSSEASSQEEDVQHAIIHKKHTGKSPIVN IGTSCSP LDG TMQYSEQNGIVDWRKQSCTTIQHPEHCVTSADQHSAEKRS SSINKKKGKPQTEKEKIKKTDNRNSRINGIRLSTPQHA HGGTVKDV DIGSGHDTCGETSSESYSSPSSPRHDGRESFESEEEKDRDTDSNSEDSGNPSTTRFTGYGSVNQTVTVKPPVQI ASLGNENGNLLEDPLNSPKYQHISFMPTLHCVMHNGAQKSEWVPAPKPADGKTIGMVPSPVAISAIRESANSTPVGI GPTA CTGESEKH ELLASPLPIPSTFLPHSSTPA HLTVQRLK PPPQGSSESCTV IPQQPPGSLSIASPNTAFIPIHNPGSFPGSP VATTDPITKSASQWGLNQMVPQIEGNTGTVPQPTVKWLPAAGLSAAQPPASYPLPGSPLAAGVLPSQNSSVLSTAATSPQP ASAGISQAQATVPPAVPTHTPGPAPSPSPA THSTAQSDSTSYISAVGNTNA GTWPPQQMGSGPCGSCGRRCSCGTNGN QL NSYYYPNPMPGPMYRVPSFFTLPSICNGSYNQAHQSNGNQ PFF PQTPYAGLVHDPVMGSQANYGMQQMAGFGRFYPVYPA PVVANTSGSGPKKNGNVSCYNCGVSGHYAQDCKQSSMEANQQGTYRLRYAPPLPPSNDTLDSAD
12
ATCGGAAAAGCACCTTGAGTTACTGGCTTCCCCTTTACCTATTCCATCAACCTTCCTTCCACACAGTAGTACTCCCGCTTTGCA TCTTACAGTTCAGAGGCTAAAGTTGCCACCACCACAGGGATCTTCTGAGAGCTGCACAGTTAACATCCCACAACAACCACCCGG AAGCCTGAGCATCGCATCACCAAACACTGCCTTTATTCCTATCCATAACCGAGGTAGTTTCCCAGGCTCTCCTGTTGCTACCAC GGACCCCATCACAAAATCTGCATCCCAAGTGGTAGGACTCAATCAAATGGTGCCTCAAATTGAGGGAAACACAGGGACAGTCCC TCAGCCTACCAATGTGAAGGTAGTTCTTCCAGCAGCTGGCCTCTCAGCTGCTCAGCCACCAGCTTCCTACCCCTTACCAGGCTC TCCCCTTGCTGCCGGCGTGTTACCCAGCCAGAACTCCAGTGTGCTCAGCACAGCAGCAACTTCTCCCCAGCCAGCGAGCGCAGG TATCAGCCAGGCCCAGGCAACTGTTCCTCCTGCAGTTCCTACCCACACCCCAGGCCCTGCCCCGAGCCCAAGCCCTGCCTTGAC ACACAGTACCGCGCAGAGTGACAGCACCTCTTACATCAGTGCTGTGGGGAACACGAACGCTAATGGGACAGTAGTGCCACCGCA GCAGATGGGCTCAGGTCCTTGTGGTTCTTGTGGGCGAAGGTGCAGCTGTGGGACCAATGGAAACCTTCAGCTAAATAGTTACTA TTATCCTAATCCAATGCCTGGACCAATGTACCGAGTCCCTTCATTCTTTACTCTGCCATCCATTTGCAATGGCAGCTACCTCAA CCAAGCACATCAGAGCAATGGAAACCAACTTCCTTTTTTTCTGCCTCAGACTCCATATGCAAATGGACTGGTACATGACCCAGT CATGGGGAGCCAAGCCAACTATGGCATGCAGCAGATGGCAGGATTTGGGAGATTCTATCCTGTATATCCAGCACCTAACGTAGT TGCCAACACCAGTGGTTCGGGGCCCAAGAAGAATGGGAATGTCTCATGTTACAATTGTGGTGTAAGCGGACACTACGCACAGGA CTGTAAGCAGTCGTCCATGGAGGCCAATCAACAAGGCACTTACAGACTGAGATACGCACCTCCCCTCCCCCCTTCTAATGATAC GTTGGATTCTGCAGACTGAAACGAGTAAAGCTTGCCTACTTAATACACTCAAGTGTGGGGAGTCATGGGGTGTGGAGGGGAGGA AAGGAAAGGTATTTTGTTTCTTTGTCTATACATT.TCCTAGATTTCTATGCAGTTGGGATTTTTCATTTCTCTTGTACCAATGTC CAAAACAAGAAAGAATGCAATGCTTTTGAGCCTCTGGTCTCCTGGTTCAACAACAGGCTTATATGTATGATACATGTAATTTAA ACCTTCAGACAAACTTAAATGTTGGTGCGTGCTTTTTTTTTTTTTTACACTGAATACTTGCTGTGTGCAATGTTTACTGAATCT TTAAAACTGTGTATTTGACCTTTTTTTTACAACACTGGTGACAGTCATATGGTTTTGAAAAAAAAAAGAAATTTTGCTTCTTCC CAGCTTTTCTCACTTTCACCCTAAACGACACTTCCTCCCCAGCCAGCCTCACTCTGTCTCCGGCCCGCAGCAGGAGCAGCCAGC AGTGCATTCACCCCACTTTTGTAAACTGCTCTGCATATAAACCAAGGGCAGAATGTTTCACCCTGATCTTATGGGAGGAATCGA ACTCCCAAAATAGTGTGTATATATGTAATAAACAGCGTCACGTAAATACATATATGCAGTGCTTGTTGTCCAAATAGAAATGAA AATAAGTGGAAGAGAGAGGAAGAAGTCAACCATATGAAACTGAAAAAATATGACGTACGAAATGGACAAAAAGCTTTTTCTGAA ACCAACTTTTTACTTCCATCATCCTTTTTTAGCCTGTTGCTTCAGAGAGACACAAAGTGAACACACTGGTGTGAATGTCGCTCT CTGTGTGCTTGTGTTTGTAATGAAAGTCTACAGCCAATTTTACTTGTCTACCACCGTGTTGTGCTCAAAGAGACACTACTTGAG TGAAGATTTCTTCTTTCCCTGTACCAGCTGTTACAGTGTTACGTTGTGTTTAAAATGTGTATGGTTTATTGCAATCTGAACAGA GCTATGGGTTTCTACCATAAGTCAGGTTGTTTGTTCCCTAACCTGTCTCTCGTAGCAAAGTCACTTTTATAACAGTTTACCACT ATGCTTGATTATAATGTGAAAGGCGGAATTCTGAGTGTGTTAAGATGGTATTAATCATGTCGGTGTCATGTCACTAAGTTTAAT GCTGCTGTTTTTAAAAAAAAAAAAAGTTTTTTTAAAAAGCCAATCTATGTACTAAATTGCTTCCAGGTAATTTTTGATTTCCTA AAGTGCACTGAGGTTATCTGGAAGATTGGGTGTATTTTTTGGTGACTGCTGCATTCATCAGCAATGAACAGTTTCCACTGTATA GTCCTAGGGGTCAGGGGGTGGGGGTTTCATTTTCCATTCCTCAGCACAGAGCAGAAATGATAGATTTTTATTGTTTGGAGTAAC GTTGGTATGCAGCAGAGGAACATAAACATTTGGTCTTGGTTCAGAAGCCTAACAGATTGCTAGACAAGAGAAAAAACTTGAAGA AAAAAGAAGCTTAATTTCATGCTTCATAAGTAGCATTTATATTTATAGCACCAATGTACATTTTGAAACTTTCTTTCAGGGGTG GGAGTTATGGGGAAGGGGTGGGTGTGAAGGGGTAGATGAAAGCTTTAATTTAGAAAGAAAGTTCAAGTAAAGGAAATTATTTTG ATTAAATATATTTTATTTGATCTGGGTATTTTTGGACCACATTATTAAATTAATTGTTAAGCTGCAGTTGAGTTGTTCAAGTGA GAGTTTTGATAAGCCACTTATGGGCCGCGTTGTGAATCACTTGCCAGTTGTACTTTATGGAGCTTATTTTATGATTTAAAATAC TGTACTGTACATAGGAGGTATGTTACCTTCTCCTTATTTGTATGTTTACCATATACTTTGATATTTGAAATGTTATGTACTGGA AAGGCCACTTATATTTCTAGAACAGATTGGATTTTATGCAACCTTTTTTCCTTGAATTAACAGCAATAAAAAAATGAAAAACAA AAAAAAAAAAAAAAAAAAA
13
RIFGASPPRNLAIQKCASRTAAAMGSEDHGAQNPSCKIMTFRPTMEEFKDFNKYVAYIESQGAHRAGAKIIPPKEWKPRQTYD DIDDVVIPAPIQQWTGQSGLFTQYNIQKKAMTVGEYRRliA SEKYCTPRHQDFDDLERKYWKNLTFVSPIYGADISGSLYDDD VAQraiGSLRTILD ERECGTIIEGWTPYLYFGM KTTFA HTEDMDLYSINYLHFGEPKS YAIPPEHGKRLERAIGFFP GSSQGCDAFLRHKMTLISPII KKYGIPFSRITQEAGEFMITFPYGYHAGFNHGFNCAESTNFAT RWIDYGKVATQCTCRKDM VKISMDVFVRILQPERYELWKQGKD TVLDHTRPTALTSPELSSWSASRASLKAKLLRRSHRKRSQPKKPKPEDPKFPGEGTAG AALLEEAGGSVKEEAGPEVDPEEEEEEPQPLPHGREAEGAEEDGRGKLRPTKAKSERKKKSFGLLPPQLPPPPAHFPSEEAWL PSPLEPPVLGPGPAAMEESPLPAPL WPPEVPSEELEAKPRPIIPM YWPRPGKAAFNQEHVSCQQAFEHFAQKGPTWKEPV SPMELTGPEDGAASSGAGRMET ARAGEGQAPSTFSK KMEIKKSRRHPLGRPPTRSP SWK EASSDEEASPFSGEEDVSDP DALRPL SLQWKNRAASFQAERKFNAAAARTEPYCAICTLFYPYCQALQTEKEAPIASLGEGCPATLPSKSRQKTRPLIPE CF TSGGENTEPLPANSYIGDDGTSPLIACGKCC QVHASCYGIRPELV EGWTCSRCAAHAWTAECCLCNLRGGALQMTTDRRWIH VICAIAVPEARFL VIERHPVDISAIPEQRWKLKCVYCRKRMKKVSGACIQCSYEHCSTSFHVTCAHAAGVLMEPDDWPYVVSI TCLKHKSGGHAVQLLRAVSLGQVVITKNRNGLYYRCRVIGAASQTCYEWFDDGSYSDNLYPESITSRDCVQLGPPSEGELVE RWTDGNLYKAKFISSVTSHIYQVEFEDGSQLTVKRGDIFT EEELPKRVRSRLSLSTGAPQEPAFSGEEAKAAKRPRVGTPLAT EDSGRSQDYVAFVESLLQVQGRPGAPF
14
GTCGCCAGCAACCGAGCGGGGCACGCCCGAGCGGGGCCTGGGGGTGCGAGCCGAGGGCGGGGGAGAGCGCGCCGCTGCTCCCGG ACCGGGCCGCGCACGCCGCCTCAGGAACCATCACTGTTGCTGGAGGCACCTGACAAATCCTAGCGAATTTTTGGAGCATCTCCA CCCAGGAACCTCGCCATCCAGAAGTGTGCTTCCCGCACAGCTGCAGCCATGGGGTCTGAGGACCACGGCGCCCAGAACCCCAGC' TGTAAAATCATGACGTTTCGCCCAACCATGGAAGAATTTAAAGACTTCAACAAATACGTGGCCTACATAGAGTCGCAGGGAGCC CACCGGGCGGGCCTGGCCAAGATCATCCCCCCGAAGGAGTGGAAGCCGCGGCAGACGTATGATGACATCGACGACGTGGTGATC CCGGCGCCCATCCAGCAGGTGGTGACGGGCCAGTCGGGCCTCTTCACGCAGTACAATATCCAGAAGAAGGCCATGACAGTGGGC GAGTACCGCCGCCTGGCCAACAGCGAGAAGTACTGTACCCCGCGGCACCAGGACTTTGATGACCTTGAACGCAAATACTGGAAG AACCTCACCTTTGTCTCCCCGATCTACGGGGCTGACATCAGCGGCTCTTTGTATGATGACGACGTGGCCCAGTGGAACATCGGG AGCCTCCGGACCATCCTGGACATGGTGGAGCGCGAGTGCGGCACCATCATCGAGGGCGTGAACACGCCCTACCTGTACTTCGGC ATGTGGAAGACCACCTTCGCCTGGCACACCGAGGACATGGACCTGTACAGCATCAACTACCTGCACTTTGGGGAGCCTAAGTCC TGGTACGCCATCCCACCAGAGCACGGCAAGCGCCTGGAGCGGCTGGCCATCGGCTTCTTCCCCGGGAGCTCGCAGGGCTGCGAC GCCTTCCTGCGGCATAAGATGACCCTCATCTCGCCCATCATCCTGAAGAAGTACGGGATCCCCTTCAGCCGGATCACGCAGGAG GCCGGGGAATTCATGATCACATTTCCCTACGGCTACCACGCCGGCTTCAATCACGGGTTCAACTGCGCAGAATCTACCAACTTC GCCACCCTGCGGTGGATTGACTACGGCAAAGTGGCCACTCAGTGCACGTGCCGGAAGGACATGGTCAAGATCTCCATGGACGTG TTCGTGCGCATCCTGCAGCCCGAGCGCTACGAGCTGTGGAAGCAGGGCAAGGACCTCACGGTGCTGGACCACACGCGGCCCACG' GCGCTCACCAGCCCCGAGCTGAGCTCCTGGAGTGCATCCCGGGCCTCGCTGAAGGCCAAGCTCCTCCGCAGGTCTCACCGGAAA CGGAGCCAGCCCAAGAAGCCGAAGCCCGAAGACCCCAAGTTCCCTGGGGAGGGTACGGCTGGGGCAGCGCTCCTAGAGGAGGCT GGGGGCAGCGTGAAGGAGGAGGCTGGGCCGGAGGTTGACCCCGAGGAGGAGGAGGAGGAGCCGCAGCCACTGCCACACGGCCGG GAGGCCGAGGGCGCAGAAGAGGACGGGAGGGGCAAGCTGCGGCCAACCAAGGCCAAGAGCGAGCGGAAGAAGAAGAGCTTCGGC CTGCTGCCCCCACAGCTGCCGCCCCCGCCTGCTCACTTCCCCTCAGAGGAGGCGCTGTGGCTGCCATCCCCACTGGAGCCCCCG GTGCTGGGCCCAGGCCCTGCAGCCATGGAGGAGAGCCCCCTGCCGGCACCCCTTAATGTCGTGCCCCCTGAGGTGCCCAGTGAG GAGCTAGAGGCCAAGCCTCGGCCCATCATCCCCATGCTGTACGTGGTGCCGCGGCCGGGCAAGGCAGCCTTCAACCAGGAGCAC GTGTCCTGCCAGCAGGCCTTTGAGCACTTTGCCCAGAAGGGTCCGACCTGGAAGGAACCAGTTTCCCCCATGGAGCTGACGGGG CCAGAGGACGGTGCAGCCAGCAGTGGGGCAGGTCGCATGGAGACCAAAGCCCGGGCCGGAGAGGGGCAGGCACCGTCCACATTT TCCAAATTGAAGATGGAGATCAAGAAGAGCCGGCGCCATCCCCTGGGCCGGCCGCCCACCCGGTCCCCACTGTCGGTGGTGAAG CAGGAGGCCTCAAGTGACGAGGAGGCATCCCCTTTCTCCGGGGAGGAAGATGTGAGTGACCCGGACGCCTTGAGGCCGCTGCTG TCTCTGCAGTGGAAGAACAGGGCGGCCAGCTTCCAGGCCGAGAGGAAGTTCAACGCAGCGGCTGCGCGCACGGAGCCCTACTGC GCCATCTGCACGCTCTTCTACCCCTACTGCCAGGCCCTACAGACTGAGAAGGAGGCACCCATAGCCTCCCTCGGAAAGGGCTGC CCGGCCACATTACCCTCCAAAAGCCGTCAGAAGACCCGACCGCTCATCCCTGAGATGTGCTTCACCTCTGGCGGTGAGAACACG GAGCCGCTGCCTGCCAACTCCTACATCGGCGACGACGGGACCAGCCCCCTGATCGCCTGCGGCAAGTGCTGCCTGCAGGTCCAT GCCAGTTGGTATGGCATCCGTCCCGAGCTGGTCAATGAAGGCTGGACGTGTTCCCGGTGCGCGGCCCACGCCTGGACTGCGGAG TGCTGCCTGTGCAACCTGCGAGGAGGTGCGCTGCAGATGACCACCGATAGGAGGTGGATCCACGTGATCTGTGCCATCGCAGTC CCCGAGGCGCGCTTCCTGAACGTGATTGAGCGCCACCCTGTGGACATCAGCGCCATCCCCGAGCAGCGGTGGAAGCTGAAATGC GTGTACTGCCGGAAGCGGATGAAGAAGGTGTCAGGTGCCTGTATCCAGTGCTCCTACGAGCACTGCTCCACGTCCTTCCACGTG ACCTGCGCCCACGCCGCAGGCGTGCTCATGGAGCCGGACGACTGGCCCTATGTGGTCTCCATCACCTGCCTCAAGCACAAGTCG GGGGGTCACGCTGTCCAACTCCTGAGGGCCGTGTCCCTAGGCCAGGTGGTCATCACCAAGAACCGCAACGGGCTGTACTACCGC TGTCGCGTCATCGGTGCCGCCTCGCAGACCTGCTACGAAGTGAACTTCGACGATGGCTCCTACAGCGACAACCTGTACCCTGAG AGCATCACGAGTAGGGACTGTGTCCAGCTGGGACCCCCTTCCGAGGGGGAGCTGGTGGAGCTCCGGTGGACTGACGGCAACCTC TACAAGGCCAAGTTCATCTCCTCCGTCACCAGCCACATCTACCAGGTGGAGTTTGAGGACGGGTCCCAGGTGACGGTGAAGCGT GGGGACATCTTCACCCTGGAGGAGGAGCTGCCCAAGAGGGTCCGCTCTCGGCTGTCACTGAGCACGGGGGCACCGCAGGAGCCC GCCTTCTCGGGGGAGGAGGCCAAGGCCGCCAAGCGCCCGCGTGTGGGCACCCCGCTTGCCACGGAGGACTCCGGGCGGAGCCAG GACTACGTGGCCTTCGTGGAGAGCCTCCTGCAGGTGCAGGGCCGGCCCGGAGCCCCCTTCTAGGACAGCTGGCCGCTCAGGCGA CCCTCAGCCCGGCGGGGAGGCCATGGCATGCCCCGGGCGTTCGCTTGCTGTGAATTCCTGTCCTCGTGTCCCCGACCCCCGAGA GGCCACCTCCAAGCCGCGGGTGCCCCCTAGGGCGACAGGAGCCAGCGGGACGCCGCACGCGGCCCCAGACTCAGGGAGCAGGGC CAGGCGGGCTCGGGGGCCGGCCAGGGGAGCACCCCACTCAACTACTCAGAATTTTAAACCATGTAAGCTCTCTTCTTCTCGAAA AGGTGCTACTGCAATGCCCTACTGAGCAACCTTTGAGATTGTCACTTCTGTACATAAACCACCTTTGTGAGGCTCTTTCTATAA ATACATATTGTTTAAAAAAAAGCAAGAAAAAAAGGAAAACAAAGGAAAATATCCCCAAAGTTGTTTTCTAGATTTGTGGCTTTA AGAAAAACAAAACAAAACAAACACATTGTTTTTCTCAGAACCAGGATTCTCTGAGAGGTCAGAGCATCTCGCTGTTTTTTTGTT GTTGTTTTAAAATATTATGATTTGGCTACAGACCAGGCAGGGAAAGAGACCCGGTAATTGGAGGGTGAGCCTCGGGGGGGGGGC AGGACGCCCCGGTTTCGGCACAGCCCGGTCACTCACGGCCTCGCTCTCGCCTCACCCCGGCTCCTGGGCTTTGATGGTCTGGTG CCAGTGCCTGTGCCCACTCTGTGCCTGCTGGGAGGAGGCCCAGGCTCTCTGGTGGCCGCCCCTGTGCACCTGGCCAGGGGAAGC CCGGGGGTCTGGGGCCTCCCTCCGTCTGCGCCCACCTTTGCAGAATAAACTCTCTCCTGGGGTTTGTCTATCTTTGTTTCTCTC ACCTGAGAGAAACGCAGGTGTTCCAGAGGCTTCCTTGCAGACAAAGCACCCCTGCACCTCCTATGGCTCAGGATGAGGGAGGCC CCCAGGCCCTTCTGGTTGGTAGTGAGTGTGGACAGCTTCCCAGCTCTTCGGGTACAACCCTGAGCAGGTCGGGGGACACAGGGC CGAGGCAGGCCTTCGGGGCCCCTTTCGCCTGCTTCCGGGCAGGGACGAGGCCTGGTGTCCTCGCTCCACCCACCCACGCTGCTG TCACCTGAGGGGAATCTGCTTCTTAGGAGTGGGTTGAGCTGATAGAGAAAAAACGGCCTTCAGCCCAGGCTGGGAAGCGCCTTC TCCAGGTGCCTCTCCCTCACCAGCTCTGCACCCCTCTGGGGAGCCTTCCCCACCTTAGCTGTCTCCTGCCCCAGGGAGGGATGG AGGAGATAATTTGCTTATATTAAAAACAAAAAATGGCTGAGGCAGGAGTTTGGGACCAGCCTGGGCTATATAGCAAGACCCCAT CACTACAAATTTTTTACAAATTAGCTAGGTGTGGTGGTGCGCACCTGTGGTCCCAGCTACTCGGGAGGCTGTGGTGGGAGGATT GCTTGAGTCCAGGAGGTTGAGGCTGCAGTCAGCTCAGATTGCACCACTGCACTCCAGCCTGGGCAACAGAGCGAGACCCTGTCT CCAAAAAAAAAAAAAAGCAATGTTTATATTATAAAAGAGTGTCCTAACAGTCCCCGGGCTAGAGAGGACTAAGGAAAACAGAGA GAGTGTTACGCAGGAGCAAGCCTTTCATTTCCTTGGTGGGGGAGGGGGGCGGTTGCCCTGGAGAGGGCCGGGGTCGGGGAGGTT GGGGGGTGTCAGCCAAAACGTGGAGGTGTCCCTCTGCACGCAGCCCTCGCCCGGCGTGGCGCTGACACTGTATTCTTATGTTGT TTGAAAATGCTATTTATATTGTAAAGAAGCGGGCGGGTGCCCCTGCTGCCCTTGTCCCTTGGGGGTCACACCCATCCCCTGGTG GGCTCCTGGGCGGCCTGCGCAGATGGGCCACAGAAGGGCAGGCCGGAGCTGCACACTCTCCCCACGAAGGTATCTCTGTGTCTT ACTCTGTGCAAAGACGCGGCAAAACCCAGTGCCCTGGTTTTTCCCCACCCGAGATGAAGGATACGCTGTATTTTTTGCCTAATG TCCCTGCCTCTAGGTTCATAATGAATTAAAGGTTCATGAACGCTGCG
15 TTTVATDYDNIEIQQQYSDV RWDVDDWDNENSSAR FERSRIKALADEREAVQKKTFTKVNSHLARVSCRITDLYTD RD GRM IKLLEVLSGERLPKPTKGRMRIHCLE VDKALQF KEQRVH EMGSHDIVDGNHRT GLI TIILRFQIQDISVETED NKEKKSAKDALLL CQMKTAGYPNV IHNFTTSWRDGMAFNA IHKHRPDLIDFDK KKSNAHYNLQNAFNLAEQHLGLTKLLD PEDISVDHPDEKSIITYWTYYHYFSKMKAAVEGKRIGKVLDNAIETEKMIEKYES ASDLLEWIEQTIIILNRKFANSLVG VQQQ QAFNTYRTVEKPP FTEKGN EV FTIQSMRA QKVYMPREGKLISDINKAWERLEKAEHERELA RNE IRQEK EQLARRFDRKAAMRET LSENQRLVSQDNFGFDLPAVEAATKKHEAIETDIAAYEERVQAWAVARE EAENYHDIKRITARKD IRLWEY LELLRARRQR Effl G QKIFQEM YIMDWMDEMKVLV SQDYGKH GVEDL QKHTLVEADIGIQAERVRGVN ASAQKFATDGEGYKPCDPQVIRDRVAHMEFCYQELCQLAAERRARLEESRRWKFFWEMAEEEG IREKEKILSSDDYGKDLTS VMR LSKHRAFEDEMSGRSGHFEQAIKEGEDMIAEEHFGSEKIRERIIYIREQ ALEQLSAIRKKRLEEASLLHQFQADADDI DAM DILKIVSSSDVGHDEYSTQS VKKHKDVAEEIAYRPT DTLHEQASA PQEHAESPDVRGR SGIEERYKEVAELTRL RKQALQDT A YKMFSEADACELWIDEKEQ N QIPEKLEDLEVIQHRFESLEPEMrøQASRVAVVNQIARQLMHSGHPSEK EIKAQQDKLNTRWSQFRELVDRKKDALLSA SIQNYHLECNETKSWIREKTKVIESTQDLGNDLAGVMA QRK TGMERDLVAI EAK SDLQKEAEKLESEHPDQAQAILSRLAEISDVWEEMKTTLKNREASLGEASKLQQF RDLDDFQSW SRTQTAIASEDMPN TLTEAEK LTQHENIKNEIDNYEEDYQKMRDMGEI-VTQGQTDAQYMFLRQRLQA DTGWELHKM ENRQNL SQSHAYQQFLR DTKQAEAF raQEYVLAHTEMPTT EGAEAAIKKQEDFMTTMDANEEKINAWETGRRLVSDGNINSDRIQEKVDSIDDRHRKN RETASELLMRLKDNRDLQKFLQDCQELSLWINEK LTAQDMSYDEAR LHSKWLKHQAFMAELASNKE DKIEKEGMQ ISEK PETEAVVKEKLTGLHKMWEV ESTTQTKAQRLFDANKAELFTQSCADLDKW HGLESQIQSDDYGKHLTSVNIL KKQQMLENQ MEVRKKEIEELQSQAQALSQEGKSTDEVDSKRLTVQTKFME LEPLNERKHNL ASKEIHQFNRDVEDEIL GERMPLATSTD HGHNLQTVQLLIKKNQTLQKEIQGHQPRIDDIFERSQNIVTDSSS SAEAIRQRADLKQLWGLLIEETEKRHRRLEEAHRAQQ YYFD EAEAMSEQELYMSEEKAKDEQSAVSM KKHQILEQAVEDYAETVHQLSKTSRAVADSHPESERISMRQSKVDK Y AGLKDLAEERRGKLDERHR FQLNREVDD EQWIAEREVVAGSHELGQDYEHVT LQERFREFARDTGNIGQERVDTV H ADE LINSGHSDAATIAEWKDGLNEAWAD LE IDTRTQILAASYE HKFYHDAKEIFGRIQDKHKKLPEELGRDQNTVETLQRMHTT FEHDIQALGTQTOQLQED RLQ YAGDKADDIQKRENEV EAWKSLLDACESRRVRLVDTGDKFRFFSMVRDLML MEDVIR QIEAQEKPRDVSSVELLMNNHQGIKAEIDARNDSFTTCIELGKSLLARKHYASEEIKEKL QLTEKRKEMIDKWEDRWEWLRLI LEVHQFSRDASVAEAWLLGQEPYLSSREIGQSVDEVEKLIKRHEAFEKSAATWDERFSA ERLTTLE EVRRQQEEEERKRRP PSPEPSTKVSEEAESQQQWDTSKGEQVSQNGLPAEQGSPRMAETVDTSEMVNGATEQRTSSKESSPIPSPTSDRKAKTA PAQS T PARTQETPSAQMEGFLNRKHEWEAHNKKASSRSWHVYCVINNQEMGFYKDAKTAASGIPYHSEVPVSLKEAVCEVA DY KKKKHVFKLRLNDGNEYLFQAKDDEEMNTWIQAISSAISSDKHEVSASTQSTPASSRAQTLPTSWTITSESSPGKREKDKEKD KEKRFSLFGKKK
16
GTGAGCTGAAGCAGGGCAGGGCATCAACTCACCCAGGAAGTGCAAGGGGTTTGGGGATTTTCCTTTCCTAGCCAAGGGAAGGCA TGACAGACTGTACCTGGAAAAACAGGACACTCTTGCCCAAATACTGCACTTTTTGCACAGTCTTAGCAACTGGCAGACCAGGAG ATTCTCTCCTGTGCCTGATTCATTGGGTCCCACACCCATAGGGCCTTGCTTACTGCCAGTGCAGCAGTCTGAGATTAACACCCC ATCCCCGGGAGAACTCTAAGAAGGAGCTGATGTGGAGGAGCAGCTGAGACAGTTCAAGATGACGACCACAGTAGCCACAGACTA TGACAACATTGAGATCCAGCAGCAGTACAGTGATGTCAACAACCGCTGGGATGTCGACGACTGGGACAATGAGAACAGCTCTGC GCGGCTTTTTGAGCGGTCCCGCATCAAGGCTCTGGCAGATGAGCGTGAAGCCGTGCAGAAGAAGACCTTCACCAAGTGGGTCAA TTCCCACCTTGCCCGTGTGTCCTGCCGGATCACAGACCTGTACACTGACCTTCGAGATGGACGGATGCTCATCAAGCTGCTGGA GGTCCTCTCTGGAGAGAGGCTGCCTAAACCCACCAAGGGACGAATGCGCATCCACTGCTTAGAGAATGTGGACAAGGCCCTTCA GTTCCTGAAGGAGCAGAGAGTCCATCTTGAGAACATGGGGTCCCATGACATCGTGGATGGAAACCACCGGCTGACCCTTGGCCT CATCTGGACCATCATCCTGCGCTTCCAGATCCAGGATATCAGTGTGGAAACTGAAGACAACAAAGAGAAGAAATCTGCCAAGGA TGCATTGCTGTTGTGGTGCCAGATGAAGACAGCTGGGTACCCCAATGTCAACATTCACAATTTCACCACTAGCTGGAGGGACGG CATGGCCTTCAATGCACTGATACACAAACACCGGCCTGACCTGATAGATTTTGACAAACTAAAGAAATCTAACGCACACTACAA CCTGCAGAATGCATTTAATCTGGCAGAACAGCACCTCGGCCTCACTAAACTGTTGGACCCCGAAGACATCAGCGTGGACCATCC TGATGAGAAGTCCATAATCACTTATGTGGTGACTTATTACCACTACTTCTCTAAGATGAAGGCCTTAGCTGTTGAAGGAAAACG AATTGGAAAGGTGCTTGACAATGCTATTGAAACAGAAAAAATGATTGAAAAGTATGAATCACTTGCCTCTGACCTTCTGGAATG GATTGAACAAACCATCATCATTCTGAACAATCGCAAATTTGCCAATTCACTGGTCGGGGTTCAACAGCAGCTTCAGGCATTCAA CACTTACCGCACTGTGGAGAAACCACCCAAATTTACTGAGAAGGGGAACTTGGAAGTGCTGCTCTTCACCATTCAGAGCAAGAT GAGGGCCAACAACCAGAAGGTCTACATGCCCCGGGAGGGGAAGCTCATCTCTGACATCAACAAGGCCTGGGAAAGACTGGAAAA AGCGGAACACGAAAGAGAACTGGCTTTGCGGAATGAGCTCATAAGACAGGAGAAACTGGAACAGCTCGCCCGCAGATTTGATCG CAAGGCAGCTATGAGGGAGACTTGGCTGAGCGAAAACCAGCGTCTGGTGTCTCAGGACAACTTTGGGTTTGACCTTCCTGCAGT TGAGGCCGCCACAAAAAAGCACGAGGCCATTGAGACAGACATTGCCGCATACGAGGAGCGTGTGCAGGCTGTGGTAGCCGTGGC CAGGGAGCTCGAGGCCGAGAATTACCACGACATCAAGCGCATCACAGCGAGGAAGGACAATGTCATCCGGCTCTGGGAATACCT ACTGGAACTGCTCAGGGCCCGGAGACAGCGGCTCGAGATGAACCTGGGGCTGCAGAAGATATTCCAGGAAATGCTCTACATTAT GGACTGGATGGATGAAATGAAGGTGCTAGTATTGTCTCAAGACTATGGCAAACACTTACTTGGTGTGGAAGACCTGTTACAGAA GCACACCCTGGTTGAAGCAGACATTGGCATCCAGGCAGAGCGGGTGAGAGGTGTCAATGCCTCCGCCCAGAAGTTCGCAACAGA CGGGGAAGGTTACAAGCCCTGTGACCCCCAGGTGATCCGAGACCGCGTGGCCCACATGGAGTTCTGTTATGAAGAGCTTTGCCA GCTGGCGGCTGAGCGCAGGGCCCGTCTGGAAGAGTCCCGCCGCCTCTGGAAGTTCTTCTGGGAGATGGCAGAAGAGGAAGGCTG GATACGGGAGAAGGAGAAGATCCTGTCCTCGGACGATTACGGGAAAGACCTGACCAGCGTCATGCGCCTGCTCAGCAAGCACCG GGCGTTCGAGGACGAGATGAGCGGCCGCAGTGGCCACTTTGAGCAGGCCATCAAGGAAGGCGAAGACATGATCGCGGAGGAGCA CTTCGGGTCGGAGAAGATCCGTGAGAGGATCATTTACATCCGGGAGCAGTGGGCCAACCTAGAGCAGCTCTCGGCCATTCGGAA GAAGCGCCTGGAGGAGGCCTCCCTGCTGCACCAGTTCCAGGCAGATGCTGATGACATTGATGCCTGGATGCTGGACATCCTCAA GATTGTCTCCAGCAGCGACGTGGGCCACGATGAGTATTCCACACAGTCTCTGGTCAAGAAACACAAGGACGTGGCGGAAGAGAT CGCCAATTACAGGCCCACCCTTGACACGCTGCACGAACAAGCCAGCGCCCTCCCCCAGGAGCATGCCGAGTCTCCAGACGTGAG GGGCAGGCTGTCGGGCATCGAGGAGCGGTATAAGGAGGTGGCAGAGCTGACGCGGCTGCGGAAGCAGGCACTCCAGGACACTCT GGCCCTGTACAAGATGTTCAGCGAGGCTGATGCCTGTGAGCTCTGGATCGACGAGAAGGAGCAGTGGCTCAACAACATGCAGAT CCCAGAGAAGCTGGAGGATCTGGAGGTCATCCAGCACAGATTTGAGAGCCTAGAACCAGAAATGAACAACCAGGCTTCCCGGGT TGCAGTGGTGAACCAGATTGCACGCCAGCTGATGCACAGCGGCCACCCAAGTGAGAAGGAAATCAAAGCCCAGCAGGACAAACT CAACACAAGGTGGAGCCAGTTCAGAGAACTGGTTGACAGGAAGAAGGATGCCCTCCTGTCTGCCCTGAGCATCCAGAACTACCA CCTCGAGTGCAATGAAACCAAATCCTGGATTCGGGAAAAGACCAAGGTCATCGAGTCCACCCAGGACCTGGGCAATGACCTGGC TGGCGTCATGGCCCTGCAGCGCAAGCTGACCGGCATGGAGCGGGACTTGGTGGCCATTGAGGCAAAGCTGAGTGACCTGCAGAA GGAGGCGGAGAAGCTGGAGTCCGAGCACCCCGACCAGGCCCAGGCCATCCTGTCTCGGCTGGCCGAGATCAGCGACGTGTGGGA GGAGATG GACCACCCTGAAAMCCGAGAGGCCTCCCTGGGAGAGGCCAGCAAGCTGCAGCAGTTCCTACGGGACTTGGACGA CTTCCAGTCCTGGCTCTCTAGGACCCAGACAGCGATCGCCTCGGAGGACATGCCAAACACCCTGACCGAGGCTGAGAAGCTGCT CACGCAGCACGAGAACATCAAGAATGAGATCGACAACTACGAGGAGGACTACCAGAAGATGAGGGACATGGGCGAGATGGTCAC CCAGGGGCAGACCGATGCCCAGTACATGTTTCTGCGGCAGCGGCTGCAGGCCCTGGACACTGGATGGAACGAGCTCCACAAGAT GTGGGAGAACAGACAAAATCTCCTATCCCAGTCACATGCCTACCAGCAGTTCCTCAGAGACACGAAGCAAGCCGAAGCCTTTCT TAACAACCAGGAGTATGTTCTGGCTCACACTGAAATGCCTACCACCTTGGAAGGAGCTGAAGCAGCAATTAAAAAGCAAGAGGA CTTCATGACCACCATGGACGCCAATGAGGAGAAGATCAATGCTGTGGTGGAGACTGGCCGGAGGCTGGTGAGCGATGGGAACAT CAACTCAGATCGCATCCAGGAGAAGGTGGACTCTATTGATGACAGACATAGGAAGAATCGTGAGACAGCCAGTGAACTTTTGAT GAGGTTGAAGGACAACAGGGATCTACAGAAATTCCTGCAAGATTGTCAAGAGCTGTCTCTCTGGATCAATGAGAAGATGCTCAC AGCCCAGGACATGTCTTACGATGAAGCCAGAAATCTGCACAGTAAATGGTTGAAGCATCAAGCATTTATGGCAGAACTTGCATC CAACAAAGAATGGCTTGACAAAATCGAGAAGGAAGGAATGCAGCTCATTTCAGAAAAGCCTGAGACGGAAGCTGTGGTGAAGGA GAAACTCACTGGTTTACATAAAATGTGGGAAGTCCTTGAATCCACTACCCAGACAAAGGCCCAGCGGCTCTTTGATGCAAACAA GGCCGAACTTTTCACCCAGAGCTGTGCAGATCTAGACAAATGGCTGCACGGCCTGGAGAGTCAGATTCAGTCTGATGACTATGG CAAACACCTGACCAGTGTCAATATCCTGCTGAAAAAGCAACAGATGCTGGAGAATCAGATGGAAGTGCGGAAGAAGGAGATCGA AGAGCTCCAAAGCCAAGCCCAGGCCCTGAGTCAGGAAGGGAAGAGCACCGACGAGGTAGACAGCAAGCGCCTCACCGTGCAGAC CAAGTTCATGGAGTTGCTGGAGCCCTTGAACGAGAGGAAGCATAACCTGCTGGCCTCCAAAGAGATCCATCAGTTCAACAGGGA TGTGGAGGACGAGATCTTGTGGGTTGGAGAGAGGATGCCTTTGGCAACTTCCACGGATCATGGCCACAACCTCCAGACTGTGCA GCTGTTAATAAAGAAAAATCAGACCCTCCAGAAAGAAATCCAGGGGCACCAGCCTCGCATTGACGACATCTTTGAGAGGAGCCA AAACATCGTCACTGACAGCAGCAGCCTCAGCGCTGAGGCCATCAGACAGAGGCTTGCCGACCTGAAGCAGCTGTGGGGTCTCCT CATTGAGGAGACAGAGAAACGCCACAGGCGGCTGGAGGAGGCGCACAGGGCCCAGCAGTACTACTTTGACGCTGCTGAGGCCGA AGCCTGGATGAGCGAGCAGGAGCTGTACATGATGTCAGAGGAGAAGGCCAAGGATGAGCAGAGTGCTGTCTCCATGTTGAAGAA GCACCAGATCTTAGAACAAGCTGTGGAGGACTATGCAGAGACCGTGCATCAGCTCTCCAAGACCAGCCGGGCCCTGGTGGCCGA CAGCCATCCTGAAAGTGAGCGCATTAGCATGCGGCAGTCCAMGTGGATAMCTGTACGCTGGTCTGAAAGACCTTGCTGAAGA GAGAAGAGGCAAGCTGGATGAGAGACACAGGTTATTCCAGCTCAACCGGGAGGTGGACGACCTGGAGCAGTGGATCGCTGAGAG GGAGGTGGTCGCAGGGTCCCATGAACTGGGACAGGACTATGAGCATGTCACGATGTTACAAGAACGATTCCGGGAGTTTGCCCG AGACACCGGGAACATTGGGCAGGAGCGCGTGGACACGGTCAATCACCTGGCAGATGAGCTCATCAACTCTGGACATTCAGATGC CGCCACCATCGCTGAATGGAAGGATGGCCTCAATGAAGCCTGGGCCGACCTCCTGGAGCTCATTGACACAAGAACACAGATTCT TGCCGCTTCCTATGAACTGCACAAGTTTTACCACGATGCCAAGGAGATCTTTGGGCGTATACAGGACAAACACAAGAAACTCCC TGAGGAGCTTGGGAGAGATCAGAACACAGTGGAGACCTTACAGAGAATGCACACTACATTTGAGCATGACATCCAGGCTCTGGG CACACAGGTGAGGCAGCTGCAGGAGGATGCAGCCCGCCTCCAGGCGGCCTATGCGGGTGACAAGGCCGACGATATCCAGAAGCG CGAGAACGAGGTCCTGGAAGCCTGGAAGTCCCTCCTGGACGCCTGTGAGAGCCGCAGGGTGCGGCTGGTGGACACAGGGGACAA GTTCCGCTTCTTCAGCATGGTGCGCGACCTCATGCTCTGGATGGAGGATGTCATCCGGCAGATCGAGGCCCAGGAGAAGCCAAG GGATGTATCATCTGTTGAACTOTTAATGAATAATCATCAAGGCATCAAAGCTGAAATTGATGCACGTAATGACAGTTTCACAAC CTGCATTGAACTTGGGAAATCCCTGTTGGCGAGAAAACACTATGCATCTGAGGAGATCAAGGAAAAATTACTGCAGTTGACGGA AAAGAGGAAAGAAATGATCGACAAGTGGGAAGACCGATGGGAATGGTTAAGACTGATTCTGGAGGTCCATCAGTTCTCAAGAGA CGCCAGTGTGGCCGAGGCCTGGCTGCTTGGACAGGAGCCGTACCTATCCAGCCGAGAGATAGGCCAGAGCGTGGACGAGGTGGA GAAGCTCATCAAGCGCCACGAGGCATTTGAAAAGTCTGCAGCAACCTGGGATGAGAGGTTCTCTGCCCTGGAAAGGCTGACTAC ATTGGAGTTACTGGAAGTGCGCAGACAGCAAGAGGAAGAGGAGAGGAAGAGGCGGCCGCCTTCTCCCGAGCCGAGCACGAAGGT TTCAGAGGAAGCCGAGTCCCAGCAGCAGTGGGATACTTCAAAAGGAGAACAAGTTTCCCAAAACGGTTTGCCAGCTGAACAGGG ATCTCCACGGATGGCAGAAACGGTGGACACAAGCGAAATGGTCAACGGCGCTACAGAACAAAGGACGAGCTCTAAAGAGTCCAG CCCCATCCCCTCCCCGACCTCTGATCGTAAAGCCAAGACTGCCCTCCCAGCCCAGAGTGCCGCCACCTTACCAGCCAGAACCCA GGAGACACCTTCGGCCCAGATGGAAGGCTTCCTCAATCGGAAACACGAGTGGGAGGCCCACAATAAGAAAGCCTCAAGCAGGTC CTGGCACAATGTTTATTGTGTCATAAATAACCAAGAAATGGGTTTCTACAAAGATGCAAAGACTGCTGCTTCTGGAATTCCCTA CCACAGCGAGGTCCCTGTGAGTTTGAAAGAAGCTGTCTGCGAAGTGGCCCTTGATTACAAAAAGAAGAAACACGTATTCAAGCT AAGACTAAATGATGGCAATGAGTACCTCTTCCAAGCCAAAGACGATGAGGAAATGAACACATGGATCCAGGCTATCTCTTCCGC CATCTCCTCTGATAAACACGAGGTGTCTGCCAGCACCCAGAGCACGCCAGCATCCAGCCGCGCGCAGACCCTCCGCACCAGCGT CGTCACCATCACCAGCGAGTCCAGTCCCGGCAAGCGGGAAAAGGACAAAGAGAAAGACAAAGAGAAGCGGTTCAGCCTTTTTGG CAAAAAGAAATGAACTCCTTTCCTTCACCTCCTGCCCTTCTCTTACCTTTTCAGTGAAATTCCAGCATGCAAGCTCAGAACCAA CACATTACTCTCTGTGCCTAATGTTCCTCAATGTGGTTGATTTATTTTTTTTTTTAATTTATAGAGCATTTCGGGGGGGGTGGG G
17
MQPP DLKQI PFPLEPAPTLGLFSNYSTMDPVQKAV SHTFGGPLLKTKRPVISCNICQIRFNSQSQAEAHYKGNRHARRVKG IEAAKTRGREPGVREPGDPAPPGSTPTNGDGVAPRPVSMENG GPAPGSPEKQPGSPSPPSIPETGQGVTKGEGGTPAPASLPG GSKEEEEKAKR LYCA CKVAVNSLSQLEAHNKGTKHKTILEARSGLGPIKAYPRLGPPTPGEPEAPAQDRTFHCEICVKV S EVQLKQHISSRRHRDGVAGKPNPL SRHKKSRGAGE AGTLTFSKELPKSLAGGLLPSPLAVAAVMAAAAGSPLSLRPAPAAP LQGPPITHP LHPAPGPIRTAHGPI FSPY
18
AGAGCGACGCGGAACCCCGGGCGCCTGGGTCCCCAGCATGATCCTCGGCAGCCTGAGCCGGGCAGGGCCCCTGCCTCTGCTACG GCAGCCCCCGATCATGCAGCCCCCACTGGACCTCAAGCAGATCCTGCCCTTCCCACTCGAGCCAGCCCCTACCCTTGGCCTCTT CAGCAACTACAGCACCATGGACCCTGTGCAGAAGGCTGTGCTCTCCCACACTTTTGGGGGACCCTTGCTCAAGACCAAGCGACC CGTCATTTCCTGTAATATCTGTCAAATCCGCTTCAATTCTCAGAGCCAGGCTGAGGCGCACTACAAAGGTAATCGCCACGCCCG ACGAGTCAAAGGCATTGAGGCTGCCAAGACCAGAGGCAGGGAGCCTGGCGTCCGAGAACCTGGAGACCCAGCTCCCCCAGGCAG CACCCCAACAAATGGGGATGGTGTAGCACCCCGTCCAGGTACTAAGCACAAGACAATTCTGGAGGCCCGAAGTGGGCTCGGGCC CATCAAAGCTTACCCTCGGCTGGGGCCTCCCACCCCGGGGGAACCAGAGGCTCCTGCCCAGGACCGAACTTTCCACTGTGAGAT CTGCAATGTCAAGGTCAACTCGGAGGTCCAACTGAAACAGCACATCTCCAGCCGGCGGCACCGAGACGGCGTGGCCGGGAAGCC CAACCCACTACTGAGCCGTCACAAGAAGTCTAGGGGCGCCGGGGAGCTGGCGGGCACGCTGACTTTCTCCAAGGAGCTGCCCAA GTCCCTGGCGGGCGGCCTGCTCCCCAGCCCCCTGGCGGTGGCTGCAGTGATGGCAGCGGCAGCAGGCTCGCCGCTGTCCCTGCG CCCGGCTCCAGCCGCACCTCTTCTCCAGGGACCGCCGATCACTCACCCTCTGCTTCACCCGGCCCCCGGACCCATCCGAACTGC GCACGGACCCATCCTCTTCTCCCCGTACTGACCTCAACCCTGAACCCCTCCCATTCAACTCCCCACCTCCAGCCGGGACCCAGG CGTCCGGACTCCCAGCCCGCCCCTCCTCCCGGCACTCCCTAAATGATCTCTCCTTCCCCCCCCCCACCCCGAGATACGGGGTTC CAGGAAAGGGGAGGGGTAGCGGGGGAGGGGGGCTTCAGAAGGGGGGGAACACCCCAGATCTCAGGGAACCCCGCCCCCTGCCTT TCCCTCTCCCCTAGAAAAGGGGGGGCCGTCTCACCCCCGAGCCCCCTTGGAGACACCCCCCCTCCCAAAAGCCATGTCCATCCA GCCCTTCCCCCCAAACCTAGCACAAAACGGGGTTCACAAGCCATGGTCGGGGTCCGGGGGGGACAGAAATGGATTTTCTTGGCA ATAAGCGGACTCTGGGACTCCGGCTCCCTACCCCAAACTGAAGCGCTTCCGTGAACACCCCCGTCCTCCGTAGGGGGAGGGGAG CAGGCGGGATCCTGGGTCCCTCATAAGCACTTTGGTTTTACCGCCTGCAACCTCACTGTGCCCGCCCCGCACCATGCCCTAGCC CCAGGTCTAGCCGGGCCCATTGCAGGGGGCAGCACTTGGGGGCATCTCCGGCACTTGGGTGGGACCAAGGAGATGCCACCATAG ACCTTTCCCTCGCCTTCTTCCTCCCTAGTCCGGGTTC.CATTCTTTTCACCAGCACCCATCGCCCAAGGGGTACCGAGGGGGGCA AGGGGTGTCCAGTCCAAGCCCACCCCCGCCTCGCCTTCCGCAAAACTGTGAGCAAAAAGCAATAGAAGCCTCGCCCCCGCCCTT CCCCTTCGCAGGATTCGCCGAGTCTGTAGCCTCCCCGATTCAAGTTCCTAGACCTCATGGCTGTCCCCTCCCACCAGTCACCTC CACTGCACAACTCGGGCGGGGGTGTGACACCTCTCCCCCACCCCCGACTCCGTGGTTTCCGTATCGTCAACCCTTCAGCCGCCG ACCCGGGAGGGGTCTGGCCTACACTGGTCTTCCCCTTCCCATCAACTCTTTCTGCTTGACAATGTAGCAACCCAGGCCCCCCAC CCACGGCCCTCCCCTTTTTCCTCTCCCTGACAATAAAGTCTGAATTTGTTCTGCCCTCCG
19 MYKS LDKAG GSITSVRFLGDQQSVFVSKDLLKPIQDVNSLRLSLTDNQTVSKEFQALIVKHLDESHLLQGDKNLVGSEVRIY SLDPSTQWFSATWHGNPSSKTLQVNCEEIPALKIVDPALIHVEVVHDNFVTCGNSTRIGAVKRKSSENGSSVSKQAKSCSEV SPSMCPVQSVPTTVCKEIL GCTAATPSSNRQQNTPQAA SPPNIGAKLPQGCHKQSLPEEISSCLNTKSEVLRTKPDVCKAGL LSSKSSQVGAGDLKILSEPKGSCIQPKTNTDQESRLESTPQPVTGLTKECLVTKTSSKAELDNATAPE QKRLEHTASTPDG S DKPEVEAGVTRLNSCSEKKVGPSDLGSQSQN KETSVKVDHDSCCTRSSNKTQTPPARKSVLTDPDKLKKLQQSGEAFVQDDSC V IVAQ PKCRECR DS RKDKDQQKDSPVFCRFFHFRRLQFNKHGVLRVEGFLTPNKYDSEAIGL LPLTKNWGTDLDTAKY ILANIGDHFCQMVISEKEAMSTIEPHRQVA KRAVKGVREMCDVCDTTIFN HWVCPRCGFGVCVDCYRLKRK CQQGAAYKTF SWIRCVKSQIHEPENLMPTQIIPGKALYDVGDIVHSVRAKWGIKANCPCSNRQFKLFSKPALKEDLKQASLSGEKPSLGTMVQQ SSPVLEP VCGEAPSKPASWKPICPANTSPLNWLADLTSGNV KENKEKQLTMPILKNEIKCLPP PPLNKSSTVLHTFNST ■ I TPVSNNNSGFLR L NSSTGKTENGLKNTPKILDDIFASLVQNKTTSDLSKRPQGLTIKPSI GFDTPHYWLCDNRL CLQD PrøKSNWVFRECWKQGQPVMVSGVHHK NSE WKPESFRKEFGEQEVDLVNCRTNEIITGATVGDF DGFEDVPNR KNEKEP MVLK KDWPPGEDFRDMMPSRFDDLMA IPLPEYTRRDGKLNLASR PNYFVRPDLGPKMYNAYGLITPEDRKYGTTN HLDVS DAAVMVYVGIPKGQCEQEEEVLKTIQDGDSDELTIKRFIEGKEKPGAWHIYAAKDTEKIREFLKKVSEEQGQENPADHDPIH DQS YLDRSLRKRLHQEYGVQGWAIVQFLGDVVFIPAGAPHQVHN YSCIKVAEDFVSPEHVKHCFWLTQEFRY SQTHTNHED K QVK VIYHAVKDAVAMLKAV PVLA LN PAHWK
20
GGAGAGCATTTTTAGTAGAACATAATTTGGTTTTAGCTGAACGAAAGTCACCTGAAATTTCTGAACGAATTGTACAGTGGCCTG CAATAACGTACAAACCTCTGTTGGACAAAGCTGGTTTGGGATCCATAACTTCTGTTCGCTTTCTGGGAGATCAACAAAGAGTAT TTCTTTCTAAAGACCTTTTGAAGCCTATACAGGATGTAAACAGTCTTCGACTTTCTCTTACGGATAATCAGATTGTCAGTAAAG AATTTCAAGCTTTGATTGTGAAGCATTTAGATGAAAGCCATCTTTTAAAAGGTGACAAAAACTTAGTTGGTTCAGAAGTAAAAA TTTATAGCTTGGACCCATCTACTCAGTGGTTTTCAGCAACCGTTGTAAATGGAAACCCAGCATCAAAAACTCTTCAAGTCAACT GTGAGGAGATTCCAGCACTGAAAATTGTTGATCCGTCACTGATTCATGTTGAAGTTGTACACGATAACCTTGTGACATGTGGTA ATTCTGCAAGAATTGGAGCTGTAAAACGCAAGTCTTCTGAGAATAATGGAACCCTGGTTTCCAAACAAGCAAAATCTTGCTCTG AGGCCTCTCCCAGTATGTGTCCTGTGCAGTCTGTACCTACAACAGTTTTTAAGGAGATACTGCTTGGCTGTACTGCAGCAACTC CACCTAGTAAGGACCCAAGACAGCAAAGTACTCCCCAGGCTGCCAACTCTCCACCTAACCTTGGAGCAAAAATTCCTCAAGGAT GTCATAAACAAAGTTTACCAGAGGAAATTTCTTCCTGTCTAAATACAAAGTCTGAAGCTCTGAGAACAAAACCAGATGTCTGCA AAGCAGGGTTGCTCTCAAAGTCCTCTCAGATTGGAACTGGAGACTTGAAAATTCTGACTGAGCCAAAAGGCAGCTGTACTCAGC CTAAGACAAACACTGATCAGGAAAACAGATTGGAGTCTGTTCCACAAGCATTGACTGGCCTTCCTAAGGAGTGCTTACCTACAA AGGCTTCTTCTAAGGCAGAATTGGAAATTGCCAATCCTCCTGAACTGCAGAAGCACCTAGAACATGCACCTTCCCCATCGGATG TTTCAAATGCACCAGAAGTGAAAGCAGGTGTCAATAGTGATAGCCCTAATAACTGTTCAGGAAAAAAGGTAGAACCTTCAGCTT TAGCTTGCCGATCACAGAATTTAAAGGAATCTTCAGTAAAAGTAGATAATGAAAGCTGTTGTTCAAGAAGCAACAATAAAATCC AGAATGCCCCATCCAGGAAGTCGGTTTTGACAGACCCAGCTAAACTCAAAAAGCTGCAACAGAGTGGCGAGGCCTTCGTACAGG ATGATTCTTGTGTGAACATCGTGGCACAGTTGCCTAAATGCCGAGAGTGTCGCTTGGACAGTCTCCGCAAGGATAAGGAGCAAC AGAAGGACTCACCTGTGTTTTGCCGCTTCTTTCACTTCAGGAGGTTACAATTCAACAAACATGGTGTGTTGCGGGTAGAAGGCT TCTTAACACCAAACAAGTATGACAATGAAGCAATTGGCTTGTGGTTACCTTTAACCAAAAACGTTGTGGGGATTGATTTGGACA CAGCAAAGTACATCTTGGCCAACATTGGAGACCACTTCTGTCAAATGGTGATTTCTGAAAAGGAAGCTATGTCAACTATTGAGC CACACAGACAGGTTGCTTGGAAGCGAGCTGTCAAAGGTGTTCGAGAAATGTGTGATGTGTGCGACACCACCATCTTCAACCTGC ACTGGGTGTGTCCTCGGTGTGGGTTTGGAGTATGTGTGGACTGCTACCGGATGAAGAGAAAGAATTGCCAACAGGGTGCTGCTT ACAAGACTTTCTCTTGGCTAAAATGTGTGAAGAGTCAGATACATGAACCAGAGAACTTAATGCCCACACAGATCATTCCTGGAA AAGCACTCTATGATGTTGGAGACATTGTTCATTCTGTAAGAGCGAAATGGGGAATAAAGGCAAACTGCCCTTGTTCAAACAGGC AATTCAAACTCTTTTCAAAGCCAGCCTCAAAGGAAGACCTAAAACAGACTTCTTTAGCTGGAGAAAAACCGACTCTTGGTGCAG TGCTCCAGCAGAATCCCTCAGTGTTGGAGCCAGCAGCTGTGGGTGGGGAAGCAGCCTCCAAGCCAGCCGGCAGCATGAAGCCTG CCTGTCCAGCCAGCACATCTCCTCTAAACTGGCTGGCCGACCTAACCAGCGGGAATGTCAACAAGGAAAACAAGGAAAAACAAC CAACAATGCCAATTTTAAAGAATGAAATCAAATGCCTTCCACCCCTCCCACCTTTAAGCAAATCCAGCACAGTCCTCCATACGT TTAACAGCACAATTTTGACACCCGTAAGCAACAACAATTCTGGTTTCCTCCGGAATCTCTTGAATTCTTCTACAGGAAAGACAG AAAATGGACTCAAGAATACACCAAAAATCCTTGATGACATCTTTGCCTCTTTGGTGCAAAATAAGACGACTTCTGATTTATCTA AGAGGCCTCAAGGACTAACCATCAAGCCCAGCATTCTGGGCTTTGACACTCCTCACTATTGGCTTTGTGATAATCGCTTGCTGT GCTTGCAAGACCCCAACAATAAGAGCAACTGGAATGTGTTTAGGGAGTGCTGGAAACAAGGGCAGCCAGTGATGGTGTCTGGAG TGCATCATAAATTGAACTCTGAACTTTGGAAACCTGAATCCTTCAGGAAAGAGTTTGGTGAGCAGGAAGTAGACCTAGTTAATT GTAGGACCAATGAAATCATCACAGGAGCCACAGTAGGAGACTTCTGGGATGGATTTGAAGATGTTCCAAATCGTTTGAAAAATG AAAAAGAACCAATGGTGTTGAAACTTAAGGACTGGCCACCAGGAGAAGATTTTAGAGATATGATGCCTTCCAGGTTTGATGATC TGATGGCCAACATTCCACTGCCCGAGTACACAAGGCGAGATGGCAAACTGAATTTGGCCTCTAGGCTGCCAAACTACTTTGTTC GGCCAGATCTGGGCCCCAAGATGTATAATGCTTATGGATTAATCACTCCTGAAGATCGGAAATATGGAACAACAAATCTTCACT TAGATGTATCTGATGCAGCTAATGTCATGGTCTATGTGGGAATTCCCAAAGGACAGTGTGAGCAAGAAGAAGAAGTCCTTAAGA CCATCCAAGATGGAGATTCTGACGAACTCACAATAAAGCGATTTATTGAAGGAAAAGAGAAGCCAGGAGCACTGTGGCACATAT ATGCTGCAAAGGACACGGAGAAGATAAGGGAATTTCTTAAAAAGGTATCAGAAGAGCAAGGTCAAGAAAACCCAGCAGACCACG ATCCTATTCATGATCAAAGCTGGTATTTAGACCGATCATTAAGAAAACGTCTTCATCAAGAGTATGGAGTTCAAGGCTGGGCTA TTGTACAGTTTCTTGGGGATGTGGTGTTTATCCCGGCAGGAGCTCCACATCAGGTTCATAACTTATATAGCTGCATCAAAGTGG CTGAAGATTTTGTTTCTCCAGAGCATGTTAAACACTGCTTCTGGCTTACTCAGGAATTCCGATATCTGTCACAGACTCATACCA ATCACGAAGATAAATTACAGGTGAAGAATGTTATCTACCATGCAGTGAAAGATGCAGTTGCTATGCTGAAAGCCAGTGAATCCA GTTTTGGCAAACCTTAATCTCCCTGCACATTGGAAATGAATTACAGGCAGCTGTTCAAACTCTTCAGGCAGGATTCCTGTGGAC TTTGAGATTCATGTTACCTCATCTTCTTTTTTAAACTGTACCCAACTTGTGAGGGTACTCTGTCTAATGTATATTTCTAGTGTT TACAGACAGTAAATGTGTATATGTAGTAACTATTTACAGAACATGCATCCTTAAACTGTGACTTCTCACCTAGTGCAGAACTTT TACCAGGCTGTAAAAGCAAAACCTCGTATCAGCTCTGGAACAATACCTGCAGTTATTCTTCAGCTGTTTGGACAACTTAGATTG GGTTTATAACTATTAGGAATCACTGCACAGTTTATTTGGGTTGTGTTTTGTGTCTGAGTCCCCTCCCTCATCCCTTAGGGTCCA GAAGAGCAATGGAGGAAGTGACAGCTAATGTTGCAGTTCTTATTGTATGGCATAGGACTGGCATTATATAGCAGAAATCAACTA CTGTACAATTTCTTGGGGTTAACCATCTTTAGTTAAATGGAATTTTAATTTAAATGACGCTTTGCTAATTTTAAGTGTTAAGCA TTTTGCATTAAAATATTCATATAAT
21 MKAGGG AGSVSGHSESLASLSRSPQTKAGQK QHKNYPVCVLYIFITKFNKQKPL NQVILSSVKR
22
CAGAAGACTACATTAGTGAGATGTAAGAATTATTAAATATTCCATTTCCGCTTTGGCTACAATTATGAAGAAGTTGAAGGTACT TCTTTTAGACCACCAGTAAATAATCCTCCTTCAAAAAATAAAAATAAAAGAAAAAGGAAAATCATTCAGGAAGAAATGACCTGT CTAAAAAAACCTAAGGAAGAATAATAATATAAGAAAGGAAATTTAAAAACATTCCACAAGAAGAAAAATTATTGTTTATACTCC TACTTATGGTTATATCTTATATTCTCTATTCAAGTGACCTGTCTTTTAAAAAGGCAGTGCTGTCTTACCTCTTGCTAGTGGGTT AAATGTTTTCAAAAATTATAGCAGTAGTAGAAGTTTTGTATAAAATTTGTCCTTATTTGTTAATTGTATATAAATGTTAATTAT TTGATACGAATGTTATGCATTTAGTATGCACATTGAAGTCTAAACTGTAGAAGAGTCTAAAACAAGTTCTCTTTTTGCAGATTC ACATACTAATGGTTTAATTCTGTGCTCTGTTTAAAGTACTATTATAACTAGAGTAGATCTGAATGAGGATAACCCTAAAATCAT GAGGAATGGAAGAATGGACCTTGAAACTACCTAGGCTTTTATGCATGGCACCTCTTTATAATGAAGACACTTTTTAAAGTTTTT GTTTTTGTTTCAATTACCGCTAGATTTTTTTTTCTCTTTTTTTAAAATCCATTTTACTGGAAAGTTGGCCAGCAGAGGGAGTAG AAATTATTAAAATTCTAGTGTTTGGATTGGGCCCTTCTCTAACAGTACATACTCATTCCCAAAGCAATCCAAAAACAAAATGTG AACCATTTGGGTTTCAAATGTTAAGAACACTAAATAGCATGATTTAAAAAATGAAAAATGCTAACACCCAAGAAAAGAAGATAT TAAGTGCCTTTTAACAACTCCTAGAGTACAAAATGAGTACATCATAATGCTGGCTCTTCTACTAATGAACCATCGAGTGATATT GAATAAATTATTTATCTTCTCAGTTTCCTTATCTGTAAATTACAATATTAGACTAAGTAAGTTTTTCCAACTCTTCACTACCAA TTACCTTAGGCTTTTATAATGCTCCGCCTACTTCAGTCCCATGTTTCAGAAGCTTTTGTCTATTTTTTAAACTCATTGATTAAA TAATGATTAATGCATTCTCCACATTTTAATATTGCAAAGGCCCATTGGAGTTTCTGAAGTGGCTCCACAGAATTGAAATAATTT CAAATAACTGTAAAGGAACTGAAAATCTTCACAGAGATGAAGTGGGGTTTCCATTAGGTGCTTTGAAATTTGATAACAAATCAT CAACTTCCACTGGTCAATATATAGATTTTGGGTGTCTGAGGCCCCAAGATTAGATGCCACTAATCTCCAAAGATTCCCTCCAAT TATGAAATATTTTAATGTCTACTTTTAGAGAGCACTAGCCAGTATATGACCATGTGATTAATTTCTTTTCACACTAGATAAAAT TACCTGGTTCAAAAGTGGTTTTTGTTTATTAAATTTGGTAATAAATATATATAATACACAGACAGGATAGTTTTTATGCTGAAG TTTTTGGCCAGCTTTAGTTTGAGGACTCCTTGATAAGCTTGCTAAACTTTCAGAGTGCCCTGAGACACTTCCAGCCATCCCTCC TCCTGCCTTCATTGGGGCAGACTTGCATTGCAGTCTGACAGTAATTTTTTTTCTGATTGAGAATTATGTAAATTCAATACAATG TCAGTTTTTAAAAGTCAAAGTTAGATCAAGAGAATATTTCAGAGTTTTGGTTTACACATCAAGAAACAGACACACATACCTAGG AAAGATTTACACAATAGATAATCATCTTAATGTGAAAGATATTTGAAGTATTAATTTTAATATATTAAATATGATTTCTGTTAT AGTCTTCTGTATGGAATTTTGTCACTTAAGATGAGCTGCAAATAAATAATACCTTCAATGGAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAA
23
MGNFRGHA PGTFFFIIGLWWCTKSILKYICKKQKRTCY GSKTLFYRLEILEGITIVGMALTGMAGEQFIPGGPHLMLYDYKQ GHNQLLGWHHFTMYFFFG LGVADI CFTISSLPVSLTKLMLSNA FVEAFIFYNHTHGREMLDIFVHQLVVVF TGLVAF LEFLVR WLLELLRSSLI LQGS FFQIGFVLYPPSGGPAWDLMDHENILFLTICFCWHYAVTIVIVGMNYAFITWLVKSRLK RLCSSEVGLLK AEREQESEEEM
24
GAAGCACATCTGGACAGCTGTGCGGCCTCCTTGCGGGCCGACGTCAGCCGAGCACGTCCCCCACGTCCTCTCCTTCTCGCCACT TATTATTTATTCGTTTTCCCAAAGAAGCGACTAGGGACCCAAGTTTAAAAATTCCTCCCCGCACTCAATGCGAGACGTGGCCAG ATCCCATCCAACACACGGTTTAATTTTCATGGGGCTCTGGGATCAAAAGAACAGAAACAGCAACAACAAAAGCCCAGCCGCTGT CTGATTTTAAGCTGGCAAAGTGGGAAAAATAAAGTGTTGAGTAAACAGACCAAGTTGGATCATGGGGAATTTCAGAGGTCATGC CCTCCCTGGAACCTTCTTTTTTATTATTGGTCTTTGGTGGTGTACAAAGAGTATTCTGAAGTATATCTGCAAAAAGCAAAAGCG AACCTGCTATCTTGGTTCCAAAACATTATTCTATCGATTGGAAATTTTGGAGGGAATTACAATAGTTGGCATGGCTTTAACTGG CATGGCTGGGGAGCAGTTTATTCCTGGAGGGCCCCATCTGATGTTATATGACTATAAACAAGGTCACTGGAATCAACTCCTGGG CTGGCATCATTTCACCATGTATTTCTTCTTTGGGCTGTTGGGTGTGGCAGATATCTTATGTTTCACCATCAGTTCACTTCCTGT GTCCTTAACCAAGTTAATGTTGTCAAATGCCTTATTTGTGGAGGCCTTTATCTTCTACAACCACACTCATGGCCGGGAAATGCT GGACATCTTTGTGCACCAGCTGCTGGTTTTGGTCGTCTTTCTGACAGGCCTCGTTGCCTTCCTAGAGTTCCTTGTTCGGAACAA TGTACTTCTGGAGCTATTGCGGTCAAGTCTCATTCTGCTTCAGGGGAGCTGGTTCTTTCAGATTGGATTTGTCCTGTATCCCCC CAGTGGAGGTCCTGCATGGGATCTGATGGATCATGAAAATATTTTGTTTCTCACCATATGCTTTTGTTGGCATTATGCAGTAAC CATTGTCATCGTTGGAATGAATTATGCTTTCATTACCTGGTTGGTTAAATCTAGACTTAAGAGGCTCTGCTCCTCAGAAGTTGG ACTTCTGAAAAATGCTGAACGAGAACAAGAATCAGAAGAAGAAATGTGACTTTGATGAGCTTCCAGTTTTTCTAGATAAACCTT TTCTTTTTTACATTGTTCTTGGTTTTGTTTCTCGATCTTTTGTTTGGAGAACAGCTGGCTAAGGATGACTCTAAGTGTACTGTT TGCATTTCCAATTTGGTTAAAGTATTTGAATTTAAATATTTTCTTTTTAGCTTTGAAAATATTTTGGGTGATACTTTCATTTTG CACATCATGCACATCATGGTATTCAGGGGCTAGAGTGATTTTTTTCCAGATTATCTAAAGTTGGATGCCCACACTATGAAAGAA ATATTTGTTTTATTTGCCTTATAGATATGCTCAAGGTTACTGGGCTTGCTACTATTTGTAACTCCTTGACCATGGAATTATACT TGTTTATCTTGTTGCTGCAATGAGAAATAAATGAATGTATGTATTTTGGTGC
25
MPS DRFSSSSTSSSPSS PRTPTPDRPPRSAGSATREEGFDRSTSLESSDCES DSSNSGFGPEEDTAYLDGVSLPDFE L SDPEDEHLCAN MQ LQES AQARLGSRRPARLLMPSQLVSQVGKELLRLAYSEPCGLRGA D¥CVEQGKSCHSVGQLALDPS LVPTFQ TLVLRLDSRLWPKIQGLFSSANSPFLPGFSQS TLSTGFRVIKKKLYSSEQLLIEEC
26
GCAGCAGGCCAAGGGGGAGGTGCGAGCGTGGACCTGGGACGGGTCTGGGCGGCTCTCGGTGGTTGGCACGGGTTCGCACACCCA TTCAAGCGGCAGGACGCACTTGTCTTAGCAGTTCTCGCTGACCGCGCTAGCTGCGGCTTCTACGCTCCGGCACTCTGAGTTCAT CAGCAAACGCCCTGGCGTCTGTCCTCACCATGCGTAGCCTTTGGGACCGCTTCTCGTCGTCGTCCACCTCCTCTTCGCCCTCGT CCTTGCCCCGAACTCCCACCCCAGATCGGCCGCCGGGCTCAGCCTGGGGGTCGGCGACCCGGGAGGAGGGGTTTGACCGCTCCA CGAGCCTGGAGAGCTCGGACTGCGAGTCCCTGGACAGCAGCAACAGTGGCTTCGGGCCGGAGGAAGACACGGCTTACCTGGATG GGGTGTCGTTGCCCGACTTCGAGCTGCTCAGTGACCCTGAGGATGAACACTTGTGTGCCAACCTGATGCAGCTGCTGCAGGAGA GCCTGGCCCAGGCGCGGCTGGGCTCTCGACGCCCTGCGCGCCTGCTGATGCCTAGCCAGTTGGTAAGCCAGGTGGGCAAAGAAC TACTGCGCCTGGCCTACAGCGAGCCGTGCGGCCTGCGGGGGGCGCTGCTGGACGTCTGCGTGGAGCAGGGCAAGAGCTGCCACA GCGTGGGCCAGCTGGCACTCGACCCCAGCCTGGTGCCCACCTTCCAGCTGACCCTCGTGCTGCGCCTGGACTCACGACTCTGGC CCAAGATCCAGGGGCTGTTTAGCTCCGCCAACTCTCCCTTCCTCCCTGGCTTCAGCCAGTCCCTGACGCTGAGCACTGGCTTCC GAGTCATCAAGAAGAAGCTGTACAGCTCGGAACAGCTGCTCATTGAGGAGTGTTGAACTTCAACCTGAGGGGGCCGACAGTGCC CTCCAAGACAGAGACGACTGAACTTTTGGGGTGGAGACTAGAGGCAGGAGCTGAGGGACTGATTCCAGTGGTTGGAAAACTGAG GCAGCCACCTAAGGTGGAGGTGGGGGAATAGTGTTTCCCAGGAAGCTCATTGAGTTGTGTGCGGGTGGCTGTGCATTGGGGACA CATACCCCTCAGTACTGTAGCATGGAACAAAGGCTTAGGGGCCAACAAGGCTTCCAGCTGGATGTGTGTGTAGCATGTACCTTA TTATTTTTGTTACTGACAGTTAACAGTGGTGTGACATCCAGAGAGCAGCTGGGCTGCTCCCGCCCCAGCCTGGCCCAGGGTGAA GGAAGAGGCACGTGCTCCTCAGAGCAGCCGGAGGGAGGGGGGAGGTCGGAGGTCGTGGAGGTGGTTTGTGTATCTTACTGGTCT GAAGGGACCAAGTGTGTTTGTTGTTTGTTTTGTATCTTGTTTTTCTGATCGGAGCATCACTACTGACCTGTTGTAGGCAGCTAT CTTACAGACGCATGAATGTAAGAGTAGGAAGGGGTGGGTGTCAGGGATCACTTGGGATCTTTGACACTTGAAAAATTACACCTG GCAGCTGCGTTTAAGCCTTCCCCCATCGTGTACTGCAGAGTTGAGCTGGCAGGGGAGGGGCTGAGAGGGTGGGGGCTGGAACCC CTCCCCGGGAGGAGTGCCATCTGGGTCTTCCATCTAGAACTGTTTACATGAAGATAAGATACTCACTGTTCATGAATACACTTG ATGTTCAAGTATTAAGACCTATGCAATATTTTTTACTTTTCTAATAAACATGTTTGTTAAAACAAAAAAAAAAAAAAAAA
27 GGPGGPECPMRTPQLALLQVFFLVFPDGVRPQPSSSPSGAVPTSLELQRGTDGGTLQSPSEATATRPAVPGLPTVVPTVTPSA PGNRTVDLFPVLPICVCDLTPGACDINCCCDRDCY LHPRTVFSFC PGSVRSSSWVCVDNSVIFRSNSPFPSRVFMDSNGIRQ FCVHVmSN NYFQKLQKVNATNFQALAAEFGGESFTSTFQTQSPPSFYRAGDPILTYFPKWSVISLLRQPAGVGAGGLCAESN PAGFLESKSTTCTRFFKNASSCTLDSANAASYYNFTVKVPRSMTDPQNMEFQVPVILTSQANAPLLAGNTCQWSQVTYE IETNGTFGIQKVSVSLGQTNTVEPGASLQQHFILRFRAFQQSTAASLTSPRSGNPGYIVGKPLLALTDDISYSMTLLQSQGNG SCSVKRHEVQFGVNAISGCKLRLKKADCSHLQQEIYQTLHGRPRPEYVAIFGNADPAQKGGWTRILNRHCSISAINCTSCCLIP VSLEIQVLWAYVGLLSNPQAQVSGVRFLYQCQSIQDSQQVTEVS TTWFVDITQKPQPPRGQPKMDKWPFDFFPFKVAFSR GVFSQKCSVSPILILCL LLGVLNLETM
28 GGGGGGACCCGGAGGCCCTGAATGCCCCATGCGCACCCCACAGCTCGCGCTCCTGCAAGTGTTCTTTCTGGTGTTCCCCGATGG CGTCCGGCCTCAGCCCTCTTCCTCCCCATCAGGGGCAGTGCCCACGTCTTTGGAGCTGCAGCGAGGGACGGATGGCGGAACCCT CCAGTCCCCTTCAGAGGCGACTGCAACTCGCCCGGCCGTGCCTGGACTCCCTACAGTGGTCCCTACTCTCGTGACTCCCTCGGC CCCTGGGAATAGGACTGTGGACCTCTTCCCAGTCTTACCGATCTGTGTCTGTGACTTGACTCCTGGAGCCTGCGATATAAATTG CTGCTGCGACAGGGACTGCTATCTTCTCCATCCGAGGACAGTTTTCTCCTTCTGCCTTCCAGGCAGCGTAAGGTCTTCAAGCTG GGTTTGTGTAGACAACTCTGTTATCTTCAGGAGTAATTCCCCGTTTCCTTCAAGAGTTTTCATGGATTCTAATGGAATCAGGCA GTTTTGTGTCCATGTGAACAACTCAAACTTAAACTATTTCCAGAAGCTTCAAAAGGTCAATGCAACCAACTTCCAGGCCCTGGC TGCAGAGTTTGGAGGCGAATCATTCACTTCAACATTCCAAACTCAATCACCACCATCTTTTTACAGGGCTGGGGACCCCATTCT TACTTACTTCCCCAAGTGGTCTGTAATAAGCTTGCTGAGACAACCTGCAGGAGTTGGAGCTGGGGGACTCTGTGCTGAAAGCAA TCCTGCAGGTTTCCTAGAGAGTAAAAGTACAACTTGCACTCGTTTTTTCAAGAACCTGGCTAGTAGCTGTACCTTGGATTCAGC CCTCAATGCTGCCTCTTACTATAACTTCACAGTCTTAAAGGTTCCAAGAAGCATGACTGATCCACAGAATATGGAGTTCCAGGT TCCTGTAATACTTACCTCACAGGCTAATGCTCCTCTGTTGGCTGGAAACACTTGTCAGAATGTAGTTTCTCAGGTCACCTATGA GATAGAGACCAATGGGACTTTTGGAATCCAGAAAGTTTCTGTCAGTTTGGGACAAACCAACCTGACTGTTGAGCCAGGCGCTTC CTTACAGCAACACTTCATCCTTCGCTTCAGGGCTTTTCAACAGAGCACAGCTGCTTCTCTCACCAGTCCTAGAAGTGGGAATCC TGGCTATATAGTTGGGAAGCCACTCTTGGCTCTGACTGATGATATAAGTTACTCAATGACCCTCTTACAGAGCCAGGGTAATGG AAGTTGCTCTGTTAAAAGACATGAAGTGCAGTTTGGAGTGAATGCAATATCTGGATGCAAGCTCAGGTTGAAGAAGGCAGACTG CAGCCACTTGCAGCAGGAGATTTATCAGACTCTTCATGGAAGGCCCAGACCAGAGTATGTTGCCATCTTTGGTAATGCTGACCC AGCCCAGAAAGGAGGGTGGACCAGGATCCTCAACAGGCACTGCAGCATTTCAGCTATAAACTGTACTTCCTGCTGTCTCATACC AGTTTCCCTGGAGATCCAGGTATTGTGGGCATATGTAGGTCTCCTGTCCAACCCGCAAGCTCAAGTATCAGGAGTTCGATTCCT ATACCAGTGCCAGTCTATACAGGATTCTCAGCAAGTTACAGAAGTATCTTTGACAACTCTTGTGAACTTTGTGGACATTACCCA GAAGCCACAGCCTCCAAGGGGCCAACCCAAAATGGACTGGAAATGGCCATTCGACTTCTTTCCCTTCAAAGTGGCATTCAGCAG AGGAGTATTCTCTCAAAAATGCTCAGTCTCTCCCATCCTTATCCTGTGCCTCTTACTACTTGGAGTTCTCAACCTAGAGACTAT GTGAAGAAAAGAAAATAATCAGATTTCAGTTTTCCCTATGAGAAACTCTGAGGCAGCCACTTATCTTGGCTAAATAGAACCTCA CCTGCTCATGACCAGAGAGCATTTAGGATAATAGAGGACCTAACTGAAGGAATCCTTGTATATGAAAGGAGTTATTTTAGAAAA GCAATAAAAATATTTTATTCATCATAGCTCTCTGCTTTGGGCTCTGCAGGCCACCAGATACACATGAGGCCCCTACTTCTCAAG CTGGGAAGGCCAAGAGCCTTCCTTCAGCCTTTCTGGTTATGTTACACCTAGCTGAATGTTTACAAGGTCTGGATCCATCAGCCC TCAGGCACAGTTGGGCCAAGCAGAAAGAGAGAAACTCTTCTGCTGTCACCTTGAATGAACTCAGGAATAGCTTCCCTCTGGACT GTAGAGGAGCTAACTGTTTGGAACAGAAAACTGCTGGCTGTTGATTTTGTCTGGTTCCTTTGCCAACATCTGGGCACACCCTTT GCCCAGACACGAGTGGGGAAAGCAGTTCTTTCTCCTCAGTTTCCAAAGTAAATGGGGAATCCCAGCTTTCTTTTCTACTAGCAA ATGACCCTACCATTTATTTCTGCCTTTTTCTTCCGTTCATTGTGAGGAAAAATAAAACTGGTTGAGAGCTTTGTTGTACCAAAA AAAAAAAAAAAAAAA
29
RSHFICDLDFFVLHYIFIDFVINMV GKVKSLTISFDCLNDS VPVYSSGDTVSGRWLEVTGEIRVKSLKIHARGHAKVRWTE SRNAGSNTAYTQNYTEEVEYFNHKDILIGHERDDDNSEEGFHTIHSGRHEYAFSFELPQTPLATSFEGRHGSVRY VKAE HRP LLPVKLKKEFTVFEHIDINTPSLLSPQAGTKEKTLCC FCTSGPISLSAKIERKGYTPGESIQIFAEIENCSSRMWPKAAIY QTQAFYAKGKMKEVKQLV RGES SSGKTETTOGK LKIPPVSPSI DCSIIRVEYS MVYVDIPGAMDLFLNLPLVIGTIP HPFGSRTSSVSSQCSMrøNWLS SLPERPEAPPSYAEVVTEEQRRN LAPVSACDDFERALQGPLFAYIQEFRF PPPLYSEI DPNPDQSADDRPSCPSR
30 GACCACTGAGACGAGCGGGAGCGCGGAGCAGCAGCCTCTGCTGCCCTGACTTTTTAAGAAATCTCAATGAACTATTTGTAGAGA ATCACTGATCCGGCCTGCAAGCATTTTGCACGGCAAAAATATCGATCAGTGTTAAGTGAAGATCACATTTTATATGCGATCTTG ACTTTTTTGTCTTACATTATATTTTTATAGATTTTGTTATAAACATGGTGCTGGGAAAGGTGAAGAGTTTGACAATAAGCTTTG ACTGTCTTAATGACAGCAATGTCCCTGTGTATTCTAGTGGGGATACCGTCTCAGGAAGGGTAAATTTAGAAGTTACTGGGGAAA TCAGAGTAAAATCTCTTAAAATTCATGCAAGAGGACATGCGAAAGTACGCTGGACTGAATCTAGAAACGCCGGCTCCAATACTG CCTATACACAGAATTACACTGAAGAAGTAGAGTATTTCAACCATAAAGACATCTTAATTGGGCACGAAAGAGATGATGATAATT CCGAAGAAGGCTTCCACACTATTCATTCAGGAAGGCATGAATATGCATTCAGCTTCGAGCTTCCACAGACACCACTCGCTACCT CATTCGAAGGCCGACATGGCAGTGTGCGCTATTGGGTGAAAGCCGAATTGCACAGGCCTTGGCTACTACCAGTAAAATTAAAGA AGGAATTTACAGTCTTTGAGCATATAGATATCAACACTCCTTCATTACTGTCACCCCAAGCAGGCACAAAAGAAAAGACACTCT GTTGCTGGTTCTGTACCTCAGGCCCAATATCCTTAAGTGCCAAAATTGAAAGGAAGGGCTATACCCCAGGTGAATCAATTCAGA TATTTGCTGAGATTGAGAACTGCTCTTCCCGAATGGTGGTGCCAAAGGCAGCCATTTACCAAACACAGGCCTTCTATGCCAAAG GGAAAATGAAGGAAGTAAAACAGCTTGTGGCTAACTTGCGTGGGGAATCCTTATCATCTGGAAAGACAGAGACGTGGAATGGCA AGTTGCTGAAAATTCCACCAGTTTCTCCCTCTATCCTCGACTGTAGTATAATCCGCGTGGAATATTCACTAATGGTATATGTGG ATATTCCTGGAGCTATGGATTTATTTCTTAATTTGCCACTTGTCATCGGTACCATTCCTCTACATCCATTTGGTAGCAGAACCT CAAGTGTAAGCAGTCAGTGTAGCATGAATATGAACTGGCTCAGTTTATCACTTCCTGAAAGACCTGAAGCACCACCCAGCTATG CAGAAGTGGTAACAGAGGAACAAAGGCGGAACAATCTTGCACCAGTGAGTGCTTGTGATGACTTTGAGAGAGCCCTTCAAGGAC CACTGTTTGCATATATCCAGGAGTTTCGATTCTTGCCTCCACCTCTTTATTCAGAGATTGATCCAAATCCTGATCAGTCAGCAG ATGATAGACCATCCTGCCCCTCTCGTTGAAGGAACACTTGGTTGAATCAAGTTGATGTGGGTTCCGAACTGTATCTCTTCCGGC TGAGGACAGAGAAGTATCTTGGAGACACGTTTCAGAGGAAGTGGAATTACTTTTGCCCAGAAAAATGGCGAATACATGAAACAA CCAGTGATCATGCTTTAGAAGCCTACAGCAACATTCTGAGACTGCTCCAACATGCTTGAAGATCTAAGCTTTTCTCTTTTAAAA CTGGCACATACTCAGAGCAGTCTTCTTAGCCTATGGTCGTACGTGTCAAGACATCACGTTGTAAAGAGGGATGATTTCCTTCTT TTGATTTGAAAATTTGCACATGCTCAATGCTTACATTGTGCGGTTCGACGTCACTACAGCTTCTTTTTTTTTTTTTTTTTTTTT CTATTTTTGCCAGACTCTTGATACTCTTAAAACTTGTTTGTGGTCAGCACAACAAGGAACAAAACAAAGCTTTGAAAAAACTTT AACATGAAAAAACGCACTGACATTTTTTTTTATTTAATATAGCCTGGACTTTACCTGCGTATGCACATGCTCAGAATTGTCTAC TAGGCTGACTATGTATCACCTCTTCAGCTTGGATCCAATTGTGGATTTATTTACAAACATCAAATGCCTTCAAGCCAATCCTTT TTGCTGTATGTTTTGCAGCCTACTGTAGTAGATACGCAACAGATAATGTGGGAAAAAAAGAGATAAGAGGAGGAAGCTAATAAG AGACTGTCAAGATTGTATACCTTCTTGGTTTCTTTTAAGAATTTGTTGCCTTTCTACTATTACAGCAAAGCAGCATTTTGTTAC TGACTGCCTAAAATCACTTAATCTCAGGTGAACGCATCACTTGCCAAACTGTTGGAATGCTATTTGTGTTTTGTTGCACTGTTT TTTTCGTTTGTTTGTTTGTTTATTTGGTTGGCTTTTTGGAGAGGGAAATTTGGAAACGGGACATACACAAAAGTTACACACCCA CATTCCCTTTTTATCATGACATACAAGAAGAAACTAGCAGAGCTAAGAATGGAGTGAAGAAAGGCAGTATGGCAGGCACCAGCA AAGAGTTGAGGGCTGTTGCTCTTAAAAATTATTTTTTTTATTATTATTTTGAAAGTATGGAAGTTTTCCATTCACTGGGGAAAG GAGGGAAAAGTGCATTTATTTTTATACAGAGTTACTTAATTACCTCCAAAACACATATGTTGGAAATCGCTTTTGCTGGTGCAA AGTATATTAATGAGCAGGAATACATACATTGAGGTTATGAATAGAGAGCTCAATTTGTACCTTTGCTGTCTTGCTCAAGCTTGG TATGGCATGAAAACTCGACTTTATTCCAAAAGTAACTTCAAAATTTAAAATACTAGAACGTTTGCTGCGATAAATCTTTTGGAT TTTTGTGTTTTTCTAATGAGAATACTGTTTTTCATTACCTAAAGAACAATTTGCTAAACATGAGAAATCACTCACTTTGATTAT GTATAGATTACATAGGAAGAACAATCACATCAGTAAGTTATAGTTTATATTAAAGGTAATTTTCTGTTGGCTCATAACAAATAT ACCAGCATTCATGATAGCATTTCAGCATTTTCCAAGGTACCAAGTGTACTTATTTTGTTGTTGTTGTTGTTGTTGTATTTTAGA AGGAATTCAGCTCTGATGTTTTTAAAGAAAACCAGCATCTCTGATGTTGCAACATACGTGTAAAATGGGTGTTACATCTATCCT GCCATTTAACCCCACAGTTAATAAAGTGGCTGAAAATAATAGTAGCTCTGGCTTGGTGCTTGACCTGGTTAAATACTGTCTTAA AGCTCATACAAAACAAATAGGCTTTTCCATAAGTGGCCTTTAAGAAAACATGGAAGACAATTCATGTTTGACAAATGCTGACAG GGTGAAGAAAGCCCAGTGTAAAAATGAATCGCGTTTTAAGTGATTCGGTTAAAGAGTTTGGGCTCCCGTAGCAAACTAATACTA GATAATAAGGAAATGGGGGTGAAATATTTTTTTATTGTTGAATCATTTTGTGAATGTCCCCCTCAAAAAAAGCTAATGGAATAT TTGGCATAAAGGGCATTTGGTGGTTTTATTTTTGTTTGAGGGGGATTGTCAGAAAATCCCTTTTCTCTCTTACGTCTAACTGAC TAGGGAACAATTGTTGATATGCATAGCATTGGAATACTTGTCATTATATACTCTTACAAATAACACATGAAGCAAGAATGACCA ATATTCTGATAATTGGCACTGGATCACAAAATGTGATAAAACTTTAAATGTATAAAACTTTATCAAATAAAGTTTTATTTTCCC CTTTAAAATGTATTTCTTTAGAGGCATTACTTTTTTAAAAATATTGGTCAATTCCTGACATAAGATGTGAGGTTCACAGTTGTA TTCCAGTATTCAAGATAGATTCCTGATTTTTCAATTAGGAAAAGTAAAATCCAAAATGTTAGCAAAACAAAGTGCAATATTAAA TGTTTGCTTTATAGATTATATTCTATGGCTGTTTGTAATTTCTCTTTTTTTCCTTTTTTATTTGGTGCTGAATATGTCCTTGTA GGCTCTGTTTTAAGAAAACAATATGTGGGAAATGATTTMTTTTTCCTATTGCTCTTCCTTGTGGAAAATAAAGTGTTTTGTTT TTTTCTGTTTTGTAT 31
MLGKGGKRKFDEHEDGLEGKIVSPCDGPSKVSYTLQRQTIFNISLMKLYNHRPLTEPSLQKTVLI NMRRIQEELKQEGS RP MFTPSSQPTTEPSDSYREAPPAFSH ASPSSHPCDLGSTTP EACLTPAS LEDDDDTFCTSQAMQPTAPTKLSPPA LPEKDS FSSA DEIEELCPTSTSTEAATAATDSVKGTSSEAGTQKLDGPQESRADDSKLMDSLPGNFEITTSTGFLTDLTLDDILFADID TSMYDFDPCTSSSGTASKMAPVSADDL KTLAPYSSQPVTPSQPFK DLTELDHIMEVLVGS
32
CTCCTGCACGGCGAGTGCTGGAGCACGAGCTACCGCTCGCTCGGTCAGGGCGCCCCCTCCGCCCGCCTCCTGCTTCCTCCTCCG CTGCCTGCCGCCGCCGCCTCCACCATTGTATAATGCTCGGGGCGCGCAGGCAGAGAACGGCGGAGTCTTAGCTTCAGCCTCGCC TGCTGCCCGCTCCCCGGCGCCACCCTCGGGCCCCTGGAGCGGGGCACTCCGCATGGAGCGGGAGTAGCTGAGGAGTGGGCGGAA ACCCCTCCTGATGCGTTAGTTCCCAGGTGGAGCTGCATGTGATATATGTTGGGTAAAGGAGGAAAACGGAAGTTTGATGAGCAT GAAGATGGGCTGGAAGGCAAAATCGTGTCTCCCTGTGACGGTCCATCCAAGGTGTCTTACACCTTACAGCGCCAGACTATCTTC AACATTTCCCTTATGAAACTCTATAACCACAGGCCCCTGACAGAGCCCAGCTTGCAAAAGACCGTTTTAATTAACAACATGTTG AGGCGGATCCAGGAGGAACTCAAACAGGAAGGCAGCCTGAGGCCCATGTTCACCCCCTCCTCCCAGCCCACCACCGAGCCCAGC GACAGCTACCGAGAGGCCCCGCCGGCCTTCAGCCACCTGGCGTCCCCGTCCTCCCACCCCTGCGACCTCGGAAGCACTACGCCC CTGGAGGCCTGCCTCACCCCGGCCTCACTGCTCGAGGACGACGATGACACGTTTTGCACCTCCCAGGCCATGCAGCCCACGGCT CCCACCAAACTGTCACCTCCAGCCCTCTTGCCAGAAAAGGACAGTTTCTCCTCTGCCTTGGACGAGATCGAGGAGCTCTGTCCC ACATCTACCTCCACAGAGGCGGCCACGGCTGCGACTGACAGTGTGAAAGGGACCTCCAGCGAGGCTGGCACCCAGAAACTCGAC GGTCCTCAAGAGAGCCGCGCAGATGACTCAAAACTGATGGACTCTCTGCCTGGGAATTTTGAAATAACGACGTCCACGGGTTTC CTGACAGACTTGACCCTGGATGACATCCTGTTTGCTGACATTGATACGTCCATGTATGATTTTGACCCCTGCACTTCCTCATCA GGGACAGCCTCAAAAATGGCCCCTGTGTCTGCCGACGACCTCCTCAAAACTCTGGCTCCTTACAGCAGTCAGCCTGTCACCCCA AGTCAGCCTTTCAAAATGGACCTCACAGAGCTGGACCACATCATGGAGGTGCTTGTTGGGTCCTAAGACCCAGGGACCCAGCGA CTATGCCCACCCAGACCCCAGAGCGTTCCCATAACCCTGACAGTTCTCCACACTGTGCATGCACCCTTGCTTGCCTTTTTCAGA GAAAAAGAAAATTTTACAACAGGATCACACTAGTTTTTGCTTTGAGCAGAGTTGGAGTGCCTTCATCCAAGTATGACCACTTTT AATACACTTTTTTGAGTGGTTCCTCAGAGACCTACTACCCTGGTATAGGAAAGAATCCATTTGAAGACAATGTTGCAATGTTGA ATGACAAAAATAAACAGTTCAAGTGAAGCACAAGGATTAAGTTGGAAAAGCTGTAAATTGCATGTGCATATTTGTCTATTTTTT CTATAAGTTTTATTGCAAGAGGTAAAGAAGAAAACTATATATATATATCTTATTTAGATAATCTCAGTACCTTTTCTGGCATTT TTGCCCTGTATAGGTTGACTTGGCAATTCGGCCTTTTTAGAGGCATTAACTACTCCTCGTAAGTGTTGCATTTACATGGCTGTT TAGAAAACTGCTGCCCAAATTTATTTTATATTTTTGTACAGATTCTGCAGTTTATGATATTGTTTTTCTAAAAACAAATGCTGT TTATACATATGAGATAGCTATTTTGATAGGATTTGCTCACATAGTTCCTGCAAACTTCAGATGTACAAGTTGCACTTGTACTTT TATAGAGTTGTAATGTTTTATATGTGTATGGTGCAAGAGAAAATTGGATCAAATCAATCTGCAGTTGATGTCCCCAAATGCAAA CACAGGCACACACATGCACACACCCATAAACACACACACAGTGCTTTAAGAAAGGGCCAGGTGATATCACACCCAAATTTCACA AGCACTGACCCCCTGGCACCAACACCCGCCAGTACTGTGACTTCCAAAGCCAGAGCCACATGTGCTCATCAAACTTGCATTAAG CAGTTGGCGGGAGATGGCTGTGGAGCTGGGGGTTTAAGTGATGGTTCTCTTTTGCTCCCTCTTTTGAGGGTAAAGCTACTGTCT TTCTTAAGAGTGTATTTATGCCAAGTTTGCGCTTTTAATTGTTTTTATTTTGTTTTTTAATGAAAACCCAGATCTTTCCTTTTT GGCATAATTTTTATGATGACCTGAAATTTTACATCCGAACAAAATTTTACATCCGAAAAGCAACCAACTTCTTCATGGAACTCA GCCCTGTTGCAATGCTTAGGGCCCTTAAAGAAGAAAATCTCCCCAGAAGGCATCCATCATGTTGCTTAATTGTCTTCTGCAGCT TCCTTTCCCTAGAGCTTTCCCTGTGTTGCTAAGAGCTGAAAATGGCATCTTCGTGATCACCACAGTGAGCTTGGCTCGCCTCGG CCGGCCCGGGATGCACTCTTACAACATGTGTGACTCTTGAACCTGGAGTTCATCACATTACGTCACAGCTTCCCATCTGGTTGC TTTCCTGAGTCAGCTACTTCACACTTGTCAAGGCTGTTTTACCCCAAAACTCAGACAGGACTTTCTATGCATGTTTTCCCTCCT CCCCCCAATTCCCCCCCCATCACCTTATCTCCCAGGACACACTTGAGAAGTAGCTTTTTATTCCTAGTGGTGTACATTTAATTT TAAAAAGGTTGCAATGTATCATGCTTGTTGCCGAAACTGTTTATGGCCTTCTTGTTTCAGTTTTTTCTTTTCTTCCAATGGTAC TTTAGCTGTTGAGTGCAGGTTACAACCTATATTGTTATGCAGATGGCTTCTTTAGGAATAACTTTTATATTTATTTAAAAATTT TTAAATTATGGGATGTTTTGTTGTTGTTGTTGTCTTTGTTGTTGGTCATTTGTCAATATTCAGTCACCAATTCTGCTCACTTCT TGCCATGGATAAAATTGGGTCTTTCTGGCTAATTAAAAAAGACAACTTTATAAAATGGCACTTTAAGCAAGCCATAGTTAGTTT TATTTTTGTAATGCACATGGCAAAGCAAAGACGTTTGTGATGAAGGAACTGCTCATCTAAGCAAAAGATTTGAGTATGATATGA TAAAGGCTTTCTACATTCTAATTTACTTTTTCCCCCCACTTGAATGTGTTTTAAAGGCTAATTATCAGCTCAGTAGAGCAGTGA GAAACTGATCAAATTGCACTTGTTCTCCTACAAGCAACCTCCACGCAGACACCTCGTACTGCTACAGGTGTGTCATTTCCTTTA ATAGGACCAGGGACCATGTAACTGAGGTGAGGGTTGTAGTAGATGCTTCCAGTGTCAGTATGCCTGTTAATTTTAAGAGCTTCC CTTTCTTGCAGAGAACAAGTCTGCCCAGATTCCATGCTTTCTATAACTGGAGGACCTGGCAAACCTGCCGCATGCTGCACACAT CTACCTACGTACACATATACAATAGTATTGATGATTCTGAACAATAACAGGGTAAAACAGTTGGTTTGCCATTGTTAAAAACTG ATTTACAGTAACTTACAACAACTGTACTTTTGTTGGATTAGCAAATCATGTGTTTAAACAAATCCCATATGTTGGGCAACAGTT CAAATAAGCACGGAGAAGTGTTGCCCAAACTTGGTTCTCTGACTCTTATGTATTTGTAAGGCTGGGCTTCAAAATCAAAACAAA AACCCCAAAAACAGCAGGCAAATGCTTTTTAACTCTGACACCGTTGCCATAAATCCCTGATACTCAAAGTCTAACAAGAAAGAC ATGGAAAATTAGCAGCCCATTTTCAGAAAGATCAAAATGATCTAGGGTTCTAATTGCTTTTGCATCCTATTCTTACAAAGTGAT GTCCCAACAGGGAACAGTAGGAGCTGGAGTGGGATCTCCAAGTCCCAGTTTGAGTGTGGGATGTGCTTCCAGCAGTGCCTTCCC TTTATGAAAGACATCACATGGCATCCAGGGCCAGGCAGGCAGCTTGAGGTGCCTTTACGAGAAAACCGAGCTGGGGCTGGGAGA GGACAGTTATTGACACTGATGTGCAATGAAGTGACAAGATGAGAGCAGAATCGTAAGAGCTTTGAATTTGAAGTGAGTTTTTTT CCCCCCATAAGTTATTTATTCCTTTTTTCTGTGTAAATATATTTATTTTACTGTGGAGCGCTAACATCTGGATCGTAACATGTG CAGAATGTATGGTAGGAATGTATTCTCTTGTAGGAATGTAAATCTGTATTAAAAGGGGGTCCAAGCCAGGCCCCCAGGTCTTCT CATTGTATGCACAGTCCGCATTCATTTTTACTCTTCTCTAATATGGGTCTATTTGAAATATGCAAAAGGTATGAGGAATGTTTT AATACCTCCAAATTTTTAAGAAAAGCATCAAAGGGTTGATATTTTTTAAAGTTTTTTTAGTAGCACTTTCTCTGGATGACAGAA GGGGCAACCACATGGGCACCCTTGTTCATACCAAAGGGTGAGCAGTGGCCAGAGCCTCCTCTGCACCTCTCGAGTGTCTTTACC AATTGAGCTTTTTATCGCCATAGCCCCTTGGAGTGCCCCAGCTGCCCTGAGGTCAATCAAGGAAAATTTCTTAATGAAATAAGC TCCAAAGAGCCAAAGTATCAACTTACAGATCGTTTTTAAAGCTTAAATTTATGAACCACCTTTGTGGTAAACAATGAATTATGA ATACCGCAGGGCAGCCTTCTTAAATGACAAATGTAAAAAAAAAAAAAAAAGACTCTACTTCGTGCAGCAATTGCTACTCTATAC GAATTGTCTTAATTTGAAAACCTTGCTGTTACAAATTGGACCTTTATACATTTTCTGAAAACAATGAAAAGAGTATATTTAACC TTTTCTGGCTGTAAATGGTTACCTTCCTGTAACTGCCCCGCACCTGGAGGCATGGAGTTGTGTGCATCCTGCTTATGTACAATT GTTTTCAGTGTTTCTAAGAATGAGTCTGAATGGTTCTTGAAAATTAGCCAGGATCAAATGCTATTGCAGACAAAGCCAATAAAA AGTTGGACTTCTTTTGGGGATAACAAGTTTTGGAAGAGAAATGCAGGCCATATGTGCGCATGACCGAGATTTTGAAAAAAGATG TACATAGTGACATGTTTGGTGCATGGTTTTTGAGGAGGGCTTTTGTCAAAAAGGAGGTATAACCTTTCCCCCACAGACCTGAGA GCTGTGCCTTTTCTATGCAATATTACAGACGTTACATCGGAACCCAGATGGCTGTATTCACATGTAGGTTTGGGCTGTAATCTA AACAATTGGACAGATTAAATGTACATGGAAATGAGCAGTCTTACTTTTGTAGTTTTATATTATACAATAAACAGTTAAAAGATG
33
MTSRDNYI-AGSREAAAAAAAAVAAAAAAAAAAEPYPVSGAKRKYQEDSDPERSDYEEQQLQKEEEARKVKSGIRQMRLFSQDEC AKIEARIDEWSRAEKGLYNEHTVDRAPLR KYFFGEGYTYGAQLQKRGPGQER YPPGDVDEIPEWVHQLVIQK VEHRVIPE GFV SAVINDYQPGGCIVSHVDPIHIFERPIVSVSFFSDSA CFGCKFQFKPIRVSEPVLS PVRRGS¥TV SGYAADEITHCI RPQDIKERRAVII RKTR DAPRLETKS SSSV PPSYASDRLSGN RDPALKPKRSHRKADPDAAHRPRI EMDKEENRRSVL LPTHRRRGSFSSENYWRKSYESSEDCSEAAGSPARKVKMRRH
34
AAGTGTTACTTCTGCTCTAAAAGCTGCGGAATTCCTCGAGCACTGGCGGCCGCCAGCGGCTACACGGACCTGCGTGAGAAGCTC AAGTCCATGACGTCCCGGGACAACTATAAGGCGGGCAGCCGGGAGGCCGCCGCCGCTGCCGCAGCCGCCGTAGCCGCCGCAGCC GCAGCCGCCGCTGCCGCCGAACCTTACCCTGTGTCCGGGGCCAAGCGCAAGTATCAGGAGGACTCGGACCCCGAGCGCAGCGAC TATGAGGAGCAGCAGCTGCAGAAGGAGGAGGAGGCGCGCAAGGTGAAGAGCGGCATCCGCCAGATGCGCCTCTTCAGCCAGGAC GAGTGCGCCAAGATCGAGGCCCGCATTGACGAGGTGGTGTCCCGCGCTGAGAAGGGCCTGTACAACGAGCACACGGTGGACCGG GCCCCACTGCGCAACAAGTACTTCTTCGGCGAAGGCTACACTTACGGCGCCCAGCTGCAGAAGCGCGGGCCCGGCCAGGAGCGC CTCTACCCGCCGGGCGACGTGGACGAGATCCCCGAGTGGGTGCACCAGCTGGTGATCCAAAAGCTGGTGGAGCACCGCGTCATC CCCGAGGGCTTCGTCAACAGCGCCGTCATCAACGACTACCAGCCCGGCGGCTGCATCGTGTCTCACGTGGACCCCATCCACATC TTCGAGCGCCCCATCGTGTCCGTGTCCTTCTTTAGCGACTCTGCGCTGTGCTTCGGCTGCAAGTTCCAGTTCAAGCCTATTCGG GTGTCGGAACCAGTGCTTTCCCTGCCGGTGCGCAGGGGAAGCGTGACTGTGCTCAGTGGATATGCTGCTGATGAAATCACTCAC TGCATACGGCCTCAGGACATCAAGGAGCGCCGAGCAGTCATCATCCTCAGGAAGACAAGATTAGATGCACCCCGGTTGGAAACA AAGTCCCTGAGCAGCTCCGTGTTACCACCCAGCTATGCTTCAGATCGCCTGTCAGGAAACAACAGGGACCCTGCTCTGAAACCC MGCGGTCCCACCGCAAAGCAGACCCTGATGCTGCCCACAGGCCACGGATCCTGGAGATGGACAAGGAAGAGAACCGGCGCTCG GTGCTGCTGCCCACACACCGGCGGAGGGGTAGCTTCAGCTCTGAGAACTACTGGCGCAAGTCATACGAGTCCTCAGAGGACTGC TCTGAGGCAGCAGGCAGCCCTGCCCGAAAGGTGAAGATGCGGCGGCACTGAGTCTACCCGCCGCCCTCCTGGGAACTCTGGCTC ATCCTTACGTAGTTGCCCCTCCTTTTGTTTTGAGGGTTTTGTTTTTGTTCATTGGGGGGTTTTTGTTTTTTGTTTTTTGTTTTT TTTGATTCTATATATTTTTCCTTGGTTTTGTTGCCTGTTAGGGCTGAAGAATAGAATTGGCCAGGACCTAGGTTCTCATATTCT TGGTATTCCTCCTGGATGGAAAGGCTGTTGGCATCAATAGGGGACAGAGGCTGATGCTGGAGTGGCCAGTAGAGGTGGTGGAGC AGAGCAGCCATCTTTTAAGTGGGGCTGTATCAGGCTGGGTTTATTTAAAAGCAACAAAATGTTTTGGTTAAGAAAATTATTTTG CTTTCAGTGTAAATCTTCGCAGTGTTCTAAACAAAGTTCAGTCTTCTGCTCGCCCCTTTCCCTCACTGATGTCTGCACTTGGTT GAGGTCTCCTGGAGCCTCACAGGCTCTGCTGTTCTCCACTTCTCACCTGCCATCCACGCCCTGCAAGCTCATGCAAACACCCTT TCTTCCTCCTGCGGCAGAGTTGTTCAGGTTGCCTGGGCAGGGGCTTAAACAGTGCCAGCCCCTGCCATCCCAAAGCTATTGTTA AGCCCCCCAGGCGTCCTCCACCCACGCCCACTAGCCTGCCATGTCCACAGTTCCTTGGGCTGCTGAGGGGCTAGTGCAGTGGTC CTGACCTCTCTTATCAAGAGCACACTTCTTTGCTGGTTGCTCCTTTTGAGCATATGCGTGTGATTATTTGGAACAGTTAGACTT GCCACGTTGGGTCAGTTTTAGAAATTGTTTCTAGCTAGAGGGACTGGTGTCCTTCCAAGTCTAGCATTTGGGGTATGGAAAATT GTTGTGGTGTGTGGTAGGGTTTTTGTTTTCTTTTTTGAGTTTTTTTTCCCCCTTTAGTCTCCTGGCTTTTTCCTTTCCCTTCCC TTCTCCACTGGCCAGCTTGGGCCTCATCCTCATGTCATCCTTCTAGGAAGGCGCCTGCCCCATCTTGTCTGCCGGCAGCATGCA TCCAAGGCCAGAGCTCAGGCCTGCAGACTGGGCTGGTGCCTCCTCCGCTTCAGGGTATGGGAGTTGGTGAAGGGGCTTTCAAAA AAAAAAAAAAAAAAAAAAA
35
MAATV LELDPIFLKA GFLHSKSKDSAEKLKALLDESLARGIDSSYRPSQKDVEPPKISSTKNISIKQEPKISSSLPSG N G KVLTTEKVKKEAEKRPADKMKSDITEGVDIPKKPRLEKPETQSSPITVQSSKDLPMADLSSFEETSADDFAMEMGLAC CRQM ASGNQ VECQECHNLYHRDCHKPQVTDKE DPRLV YCARCTRQMKRMAQKTQKPPQKPAPAVVSVTPAVKDPLVKKPETK LKQETTFLAFKRTEVKTSTVISGNSSSASVSSSVTSGIjTGWAAFAAKTSSAGPSTA LSSTTQMTGKPATSSA QKPVGLTGL ATSSKGGIGSKIGSN STTPTVPLKPPPP TLGKTGLSRSVSCD VSKVGLPSPSS VPGSSSQLSGNGNSGTSGPSGSTTSKT TSESSSSPSASLKGPTSQDHSSML 36
GTGAGTTGACCAGAGAAGGATGAGAGAATTGCCAAGTTGTACTGAACGCCAAGCTGAGAATGGTGATTCTGAAGATAGAATGCG TTTGCAATGGCTGCTACTGTGAACTTGGAACTTGATCCCATTTTTTTGAAAGCACTAGGTTTCTTGCATTCAAAGAGTAAAGAT TCTGCTGAAAAGCTAAAAGCACTGCTTGATGAATCTTTGGCTCGGGGCATTGATTCCAGTTACCGTCCATCTCAAAAGGATGTG GAGCCACCCAAAATTTCAAGCACAAAAAACATTTCCATTAAGCAAGAGCCCAAAATATCATCCAGTCTTCCTTCTGGTAATAAT AATGGCAAGGTCCTCACAACTGAAAAGGTAAAGAAGGAAGCTGAAAAGAGACCTGCTGATAAAATGAAATCAGACATCACTGAA GGAGTTGATATTCCAAAGAAACCTAGATTGGAGAAACCAGAAACACAGTCATCTCCCATTACTGTCCAAAGTAGCAAGGATTTA CCTATGGCTGACCTTTCCAGTTTTGAGGAGACCAGTGCTGATGATTTTGCCATGGAGATGGGATTGGCCTGCGTTGTTTGTAGG CAAATGATGGTGGCATCTGGCAATCAATTAGTAGAATGTCAGGAGTGCCATAATCTCTACCACCGAGATTGTCATAAACCCCAG GTGACAGACAAGGAAGCGAATGACCCTCGCCTGGTGTGGTATTGTGCCCGATGTACCAGACAAATGAAAAGAATGGCTCAAAAA ACTCAGAAACCACCGCAGAAACCAGCCCCTGCAGTTGTTTCTGTAACTCCAGCTGTCAAAGATCCATTGGTTAAGAAACCAGAA ACTAAACTGAAACAAGAGACAACTTTTCTAGCGTTTAAGAGAACAGAAGTCAAGACATCCACAGTTATTTCAGGAAATTCTTCT AGTGCCAGCGTTTCCTCGTCAGTAACTAGTGGCTTAACTGGATGGGCAGCTTTTGCAGCCAAAACTTCCTCTGCTGGTCCTTCA ACAGCAAAATTGAGTTCAACAACACAAAACAATACTGGGAAACCTGCTACTTCGTCAGCTAACCAGAAACCTGTGGGTTTGACT GGTCTGGCAACATCATCCAAAGGTGGAATAGGTTCCAAAATAGGTTCCAATAACAGCACTACGCCCACTGTACCTTTAAAACCA CCTCCACCTCTAACCTTGGGTAAAACTGGCCTTAGTCGCTCAGTTAGTTGTGACAATGTCAGCAAAGTAGGTCTTCCTAGTCCA AGTAGTTTAGTTCCAGGAAGCAGCAGCCAACTAAGTGGGAATGGAAATAGTGGAACATCAGGACCTAGTGGAAGTACTACCAGC AAAACTACTTCAGAATCCAGCAGCTCTCCCTCAGGATCCCTTAAAGGCCCAACTTCACAAGATCACAGCTCAATGCTATGAAGC GATTACAGATGGTCAAGAAGAAAGCTGCCCAAAAGAAACTCAAGAAGTAATGTGGCCAAGTAGGTTTTTGTATCATATTAGCCT AAAGATGAAAGGCTTATTATTATGATATAATCTGTAATACACTGTAATTTAATAAAAGTCTTCATAATCAAAAAAAAAAAAAAA AA
37
VDSAMELLF DTFKHPSAEQSSHIDWRFPCWYINEVRVIPPGVRAHSSLPDNRAYGETSPHTFQLDLFFNNVSKPSAPVFDR GSLEYDENTSIIFRPNSKVNTDGLVLRGWYNCLTAIYGSVDRVISHDRDSPPPPPPPPPPPQPQPSLKRNPKHADGEKEDQF NGSPPRPQPRGPRTPPGPPPPDDDEDDPVP PVSGDKEEDAPHREDYFEPISPDRNSVPQEGQYSDEGEVEEEQQEEGEEDEDD VDVEEEEDEDEDDRRTVDSIPEEEEEDEEEEGEEDEEGEGDDGYEQISSDEDGIAD ERETFKYPNFDVEYTAEDLASVPPMTY DPYDRELVPLLYFSCPYKTTFEIEISRMKDQGPDKENSGAIEASVKLTELLDLYREDRGAKWVTALEEIPSLIIKGLSYLQLKN TKQDSLGQLVD TMQALNLQVALRQPIANVRQLKAGTKLVSSLAECGAQGVTGLLQAGVISGLFELLFADHVSSS KLNAFKA DSVISMTEGMEAFLRGRQNEKSGYQKLLELILLDQTVRWTAGSAILQKCHFYEVLSEIKRLGDHAEKTSSLPNHSEPDHDT DAGLERTNPEYENEVEASMDMDLLESSNISEGEIERLINLLEEVFHLMETAPHTMIQQPVKSFPTMARITGPPERDDPYPV FR YLHSHHFLEVTLLLSIPVTSAHPGVLQATKDVLKFLAQSQKGLLFFMSEYEATNL IRALCHFYDQDEEEGLQSDGVIDDAFA LW QDSTQTLQCITE FSHFQRCTASEETDHSD LGTLHNLYLITFNPVGRSAVGHVFSLEKNLQSLITLMEYYSKEALGDSKS KKSVAYNYACILIL VQSSSDVQMLEQHAASLLK CKADENNAKLQE GKWLEPLKN RFEINCIPNLIEYVKQNIDNLMTPE GVGLTTALRVLCWACPPPPVEGQQKDLKMLAVIQLFSAEG DTFIRVLQKLNSILTQPWRLHVNMGTTLHRVTTIS ARCTL TLLKTMLTELLRGGSFEFKDMRVPSALVTLHM CSIPLSGRLDSDEQKIQNDIIDILLTFTQGV EKLTISEETLA TWS M LKEVLSSILKVPEGFFSGLILLSELLPLPLP QTTQVIEPHDISVALNTRKLWSMHLHVQAKL QEIVRSFSGTTCQPIQHMLR RICVQLCDLASPTAL IMRTVLDLIVEDLQSTSEDKEKQYTSQTTRLLAL DALASHKACKLAILHLINGTIKGDERYAEIFQD LLALVRSPGDSVIRQQCVEYVTSILQS CDQDIALILPSSSEGSISELEQLSNSLPNKE MTSICDC LATLANSESSYNCL T CVRTMFLAEHDYGLFH KSSLRKNSSALHSLLKRWSTFSKDTGEASSFLEFMRQILNSDTIGCCGDDNGLMEVEGAHTSRT MSINAAELKQLLQSKEESPENLFLELEKVLEHSKDDDNDS LDSWGKQMLESSGDP P SDQDVEPVLSAPESLQN F RTAYV ADVMDDQLKSM FTPFQAEEIDTDLDLVKVD IE SEKCCSDFDLHSELERSFLSEPSSPGRTKTTKGFKLGKHKHET FITSSGKSEYIEPAKRAHWPPPRGRGRGGFGQGIRPHDIFRQRKQNTSRPPSMHVDDFVAAESKEVVPQDGIPPPKRPLKVSQ KEQEAPVGVLRILLEEITMKWEARAILTEALFHHYDPLVLQVTAQVLGTVLLEVVGDLDLPGVQIAAVEAQEES VEAVVE MYAP HDKNPFGNI TVYEHFTRTIKIRH 38
GGTGGACTCGGCGATGGAGCTGTTATTTTTAGATACTTTTAAACACCCGAGCGCTGAGCAAAGTTCTCATATAGATGTGGTTCG TTTTCCATGTGTGGTTTATATCAATGAAGTCCGAGTCATACCCCCAGGAGTAAGAGCCCATAGCAGTCTGCCAGACAATAGAGC ATATGGAGAGACATCTCCCCATACATTTCAATTAGACTTATTCTTCAACAATGTAAGCAAACCAAGTGCCCCTGTTTTCGATAG GTTGGGAAGCCTGGAATATGATGAGAATACTTCCATCATCTTTAGACCTAACTCAAAGGTGAATACTGATGGTCTGGTGCTAAG AGGCTGGTATAACTGTCTGACACTGGCAATATATGGATCAGTGGATAGAGTGATAAGTCATGACAGAGACTCTCCACCACCACC ACCTCCACCGCCACCACCTCCCCAGCCACAACCAAGTTTGAAAAGGAATCCAAAACATGCTGATGGGGAGAAAGAAGATCAGTT TAATGGAAGCCCTCCAAGACCACAGCCAAGGGGACCAAGAACTCCTCCAGGACCCCCTCCACCTGATGATGATGAAGATGATCC TGTGCCTCTGCCAGTGTCTGGTGACAAGGAAGAGGATGCTCCTCATAGAGAAGATTACTTTGAGCCCATTTCTCCTGATCGGAA TTCTGTTCCCCAGGAAGGGCAATATTCTGATGAAGGAGAAGTAGAAGAGGAACAACAAGAAGAAGGAGAAGAAGATGAAGATGA TGTGGATGTAGAGGAAGAAGAGGATGAGGATGAGGATGATCGACGAACAGTAGACAGTATTCCTGAGGAGGAAGAGGAAGATGA AGAGGAAGAAGGTGAAGAGGATGAAGAAGGTGAAGGGGATGATGGTTATGAACAAATTTCCAGTGATGAAGATGGAATTGCTGA CTTGGAACGTGAAACATTTAAGTATCCAAACTTTGATGTTGAATACACTGCTGAAGACTTAGCTTCAGTTCCTCCTATGACATA TGATCCATATGACAGGGAGCTTGTACCACTCTTATACTTCAGTTGTCCATACAAGACTACTTTTGAAATTGAAATCAGTAGAAT GAAGGATCAAGGTCCAGATAAAGAAAATTCAGGGGCAATCGAAGCCTCAGTGAAGTTAACAGAACTCTTAGATTTGTATAGAGA AGATAGAGGTGCAAAATGGGTAACAGCTTTAGAAGAAATTCCAAGTTTAATAATAAAAGGGTTAAGCTATTTGCAATTGAAAAA CACAAAACAAGACTCCCTTGGCCAGTTGGTAGACTGGACCATGCAAGCTTTAAATTTACAAGTAGCGCTTCGCCAACCTATCGC CTTAAATGTTCGACAGCTCAAAGCTGGGACCAAATTAGTGTCCTCACTAGCAGAATGTGGGGCTCAAGGAGTTACAGGACTGCT ACAAGCAGGAGTGATCAGTGGATTATTTGAACTTCTGTTTGCTGATCACGTATCATCTTCTCTTAAGTTAAATGCTTTTAAAGC TTTGGACAGTGTCATTAGTATGACAGAAGGAATGGAAGCTTTTTTAAGAGGTAGGCAGAATGAAAAAAGTGGTTATCAAAAGCT TCTGGAACTCATACTTTTAGATCAGACTGTGAGGGTTGTTACTGCTGGTTCAGCTATTCTCCAAAAATGCCATTTCTATGAAGT CTTGTCAGAGATTAAAAGACTTGGTGACCATTTAGCAGAGAAGACTTCATCTCTTCCTAACCACAGTGAACCTGATCACGACAC AGATGCTGGACTTGAGAGAACAAACCCAGAATATGAAAATGAGGTGGAAGCTTCTATGGATATGGATCTTTTGGAATCCTCAAA TATAAGTGAAGGGGAAATAGAAAGGCTTATTAACCTCCTAGAAGAAGTTTTTCATTTAATGGAAACTGCCCCTCATACAATGAT CCAACAACCTGTTAAGTCTTTCCCAACGATGGCACGAATTACTGGACCTCCAGAGAGGGATGATCCATACCCTGTTCTCTTTAG ATATCTTCACAGTCATCACTTCTTGGAGTTGGTTACCTTGCTTCTGTCAATTCCAGTAACAAGTGCTCACCCTGGTGTGCTGCA AGCCACAAAAGATGTTTTGAAGTTTCTTGCACAGTCACAGAAGGGTCTTCTTTTTTTTATGTCGGAATATGAAGCAACAAATTT ATTGATCCGAGCTCTGTGTCACTTTTATGATCAAGATGAGGAGGAAGGTCTCCAATCTGATGGTGTTATTGATGATGCATTTGC CTTGTGGCTACAGGACTCAACACAGACATTGCAATGTATTACAGAACTGTTCAGCCATTTTCAGCGTTGTACAGCCAGTGAAGA AACAGACCATTCAGATCTCTTGGGAACCCTGCACAATCTTTATTTGATTACTTTTAATCCTGTGGGAAGATCAGCTGTTGGCCA TGTTTTTAGTCTGGAGAAAAATCTCCAAAGTCTTATTACTCTAATGGAGTACTATTCCAAAGAAGCCTTGGGTGATTCCAAATC TAAGAAGTCAGTAGCTTATAATTACGCATGCATACTTATTTTGGTGGTGGTTCAGTCTTCCAGTGATGTTCAAATGCTAGAACA ACATGCAGCATCTCTCTTGAAGCTTTGTAAAGCAGATGAAAATAATGCTAAATTGCAAGAACTTGGCAAGTGGCTTGAACCTCT GAAAAACCTTAGATTTGAAATTAACTGCATCCCAAACTTAATTGAGTATGTTAAGCAGAATATCGATAACTTGATGACCCCAGA AGGAGTTGGCCTTACCACTGCCTTACGTGTTCTCTGTAATGTTGCATGCCCACCACCTCCTGTTGAAGGTCAACAGAAAGATCT GAAATGGAATCTTGCCGTTATTCAGCTTTTTTCTGCTGAAGGAATGGACACGTTTATTCGAGTTCTGCAAAAATTGAACAGTAT TCTGACTCAGCCTTGGAGGCTCCATGTCAACATGGGGACTACCCTTCACAGAGTTACTACTATTTCAATGGCTCGCTGCACACT CACTCTTCTTAAAACTATGTTAACGGAACTCCTGAGAGGTGGATCCTTTGAGTTTAAGGACATGCGTGTTCCTTCAGCGCTTGT TACTTTACATATGCTCCTGTGCTCTATCCCCCTCTCAGGTCGTTTGGATAGTGATGAACAGAAAATTCAGAATGATATCATTGA TATTTTACTGACTTTTACACAAGGAGTTAATGAAAAACTCACAATCTCAGAAGAGACTCTGGCCAATAATACTTGGTCTTTAAT GTTAAAAGAAGTTCTTTCTTCAATCTTGAAGGTTCCTGAAGGATTTTTTTCTGGACTCATACTCCTTTCAGAGCTGCTGCCTCT TCCATTGCCCATGCAAACAACTCAGGTTATTGAGCCACATGATATATCAGTGGCACTCAACACCCGAAAATTGTGGAGCATGCA CCTTCATGTTCAAGCAAAGTTGCTCCAAGAAATAGTTCGCTCTTTCTCTGGCACAACCTGCCAGCCCATTCAACATATGTTACG GCGTATTTGTGTTCAATTGTGTGACCTTGCCTCACCAACTGCACTTCTGATTATGAGAACTGTGTTGGATTTGATTGTAGAAGA CTTGCAAAGCACTTCAGAAGATAAAGAAAAACAGTATACTAGCCAAACCACCAGGTTGCTTGCTCTTCTTGATGCTCTGGCTTC ACACAAAGCTTGTAAATTAGCTATTTTGCATCTAATTAATGGAACTATTAAAGGTGATGAAAGATATGCAGAGATATTCCAGGA TCTTTTAGCTTTGGTGCGGTCTCCTGGAGACAGTGTTATTCGCCAACAGTGTGTTGAATATGTCACATCCATTTTGCAGTCTCT CTGTGATCAGGACATTGCACTTATCTTACCAAGCTCTTCTGAAGGTTCTATTTCTGAACTGGAGCAGCTCTCCAATTCTCTACC AAATAAAGAATTGATGACCTCAATCTGTGACTGTCTGTTGGCTACGCTAGCTAACTCTGAGAGCAGTTACAACTGTTTACTGAC ATGTGTCAGAACAATGATGTTTCTTGCAGAGCATGATTATGGATTATTTCATTTAAAAAGTTCTTTAAGGAAAAACAGTAGTGC TCTGCATAGTTTACTGAAACGAGTGGTCAGCACATTTAGTAAGGACACAGGAGAGCTTGCATCTTCATTTTTAGAATTTATGAG ACAAATTCTTAACTCTGACACAATTGGATGCTGTGGAGATGATAATGGTCTCATGGAAGTAGAGGGAGCTCATACATCACGGAC GATGAGTATTAATGCTGCAGAGTTAAAACAGCTTCTACAAAGCAAAGAAGAAAGTCCAGAAAATTTGTTCCTTGAACTAGAGAA GCTTGTTTTGGAACATTCAAAAGATGATGACAATCTGGATTCTTTGTTGGACAGTGTAGTTGGACTTAAGCAGATGCTGGAGTC ATCAGGTGACCCTTTACCTCTCAGTGACCAGGATGTAGAACCAGTACTTTCAGCTCCAGAATCTCTTCAGAATCTGTTTAACAA TAGGACTGCCTATGTGCTTGCTGATGTCATGGATGATCAGTTGAAATCTATGTGGTTCACTCCATTTCAGGCTGAAGAGATAGA TACAGATCTGGATTTGGTAAAGGTTGACTTAATTGAACTCTCTGAAAAATGCTGTAGTGACTTTGATTTGCACTCAGAATTAGA GCGCTCATTTTTGTCAGAACCATCATCTCCAGGAAGAACCAAGACTACTAAAGGATTCAAACTTGGGAAGCACAAGCATGAGAC CTTTATAACGTCAAGTGGAAAATCTGAATACATTGAACCTGCCAAAAGAGCTCATGTTGTGCCACCACCAAGAGGAAGGGGCAG GGGAGGATTTGGACAGGGTATACGACCTCATGATATTTTTCGTCAGAGAAAACAGAACACAAGTAGACCACCATCTATGCATGT GGATGACTTTGTTGCTGCTGAAAGTAAAGAAGTGGTTCCTCAAGATGGAATACCTCCACCAAAACGGCCACTCAAAGTATCACA GAAGGAACAAGAGGCTCCAGTTGGAGTGCTCAGAATACTCCTCGAGGAAATTACAATGAAAGTCGTGGAGGCCAGAGCAATTTT AACAGAGGCCCTCTTCCACCATTACGACCCCTTAGTTCTACAGGTTACCGCCCAAGTCCTCGGGACCGTGCTTCTAGAGGTCGT GGGGGACTTGGACCTTCCTGGGCTAGTGCAAATAGCGGCAGTGGAGGCTCAAGAGGAAAGTTTGTTAGTGGAGGCAGTGGTAGA GGTCGTCATGTACGCTCCTTTACACGATAAAAATCCTTTTGGGAACATCTTAACTGTATATGAACATTTCACGAGGACAATAAA AATAAGACATTGAAGGACCAATTTAGACTTAGCAGTTATCTGGAGACATCTGAGAGAATATTTTTATCTGAAGAAAGCAGAATT TGTTTGATACCTAACAAGATTTCAATAAAAATCCAAACTTTGTATGT
39
MAARDSDSEEDLVSYGTGLEPLEEGERPKKPIPLQDQTVRDEKGRYKRFHGAFSGGFSAGYFNTVGSKEGWTPSTFVSSRQNRA DKSVLGPEDFMDEED SEFGIAPKAIVTTDDFASKTKDRIREKARQLAAATAPIPGAT LDDLITPAKLSVGFELLRKMGWKEG QGVGPRVKRRPRRQKPDPGVKIYGCALPPGSSEGSEGEDDDYLPDNVTFAPKDVTPVDFTPKD VHGAYKGLDPHQALFGTSG EHFN--FSGGSERAGDLGEIGLNKGRKLGISGQAFGVGA EEEDDDIYATETLSKYDTVLKDEEPGDGLYG TAPRQYKNQKESE KDLRYVGKI DGFSLASKPLSSKKIYPPPELPRDYRPVHYFRPMVAATSENSHLLQVLSESAGKATPDPGTHSKHQLNASKRAE LLGETPIQGSATSVLEFLSQKDKERIKEMKQATDLK QLKARSLAQNAQSSRAQLSPAA GHCSWMALGGGTAT KASNFK PFAKDPEKQKRYDEFLVH--KQGQKDA ERC DPSMTEWERGRERDEFARAALLYASSHSTLSSRFTHAKEEDDSDQVEVPRDQE NDVGDKQSAVKMKMFGKLTRDTFEWHPDKLLCKRFNVPDPYPDSTVGLPRVKRDKYSVFNFLTLPETASLPTTQASSEKVSQH RGPDKSRKPSRWDTSKHEKKEDSISEFLSLARSKAEPPKQQSSPLWKEEEHAPELSA QTV KDVDAQAEGEGSRPSMDLFRA IFASSSDEKSSSSEDEQGDSEDDQAGSGEA FQSSQDTDLGETSSVAHALVPAPQEPPPSFPIQKMQIDEREEFGPRLPPVFCP NARQT E¥PQKEKHK KDKHAKKEHRRKKEKKKKHRKHKHKGKQKNKKPEKSSSSESSDSSDSQSDEETADVSPQE LRRLK S PLRRQ
40 GTGTTAGAATTTCTGTCCCAAAAAGACAAAGAGAGAATCAAAGAAATGAAGCAGGCAACTGACCTGAAAGCAGCTCAGCTCAAG GCCAGGAGTCTGGCCCAGAACGCTCAGAGCAGCAGAGCCCAGCTCTCCCCTGCAGCGGCTGCTGGGTACTGCTCTTGGAACATG GCATTAGGTGGTGGGACGGCCACCTTAAAAGCCAGCAACTTCAAGCCTTTCGCCAAAGATCCGGAAAAGCAAAAGCGATACGAC GAGTTCTTAGTACACATGAAACAGGGTCAGAAAGATGCTCTGGAACGCTGTCTGGACCCCAGCATGACGGAGTGGGAGCGAGGC CGTGAGCGGGATGAGTTTGCCCGGGCGGCCCTGCTGTACGCATCTTCCCATTCGACCTTGTCCTCCAGGTTCACTCACGCCAAG GAGGAGGATGACTCAGATCAGGTTGAAGTCCCTCGAGACCAAGAGAATGATGTCGGGGATAAGCAGTCGGCTGTGAAGATGAAG ATGTTTGGGAAGCTCACCCGAGACACGTTTGAGTGGCACCCTGACAAGCTTCTATGTAAGAGATTTAATGTCCCTGACCCTTAT CCAGATTCAACTTTAGTTGGCTTACCAAGAGTGAAGCGTGACAAGTACTCAGTCTTCAACTTTCTGACGCTCCCAGAGACAGCT TCCTTGCCCACCACTCAAGCATCAAGTGAAAAAGTATCACAGCACCGAGGTCCCGACAAATCAAGAAAACCATCCAGATGGGAT ACCTCTAAACACGAAAAGAAAGAAGATTCCATTAGTGAATTTTTAAGTTTGGCTAGATCAAAAGCCGAGCCACCTAAACAACAG TCCAGCCCCTTAGTAAACAAAGAGGAAGAGCATGCACCAGAATCATCCGCAAATCAGACAGTCAACAAAGATGTGGACGCACAG GCTGAAGGAGAAGGGAGCCGCCCATCCATGGACTTATTCAGGGCCATCTTTGCCAGTTCCTCAGATGAAAAGTCCTCATCCTCC GAGGATGAGCAAGGTGACAGTGAAGATGATCAGGCAGGCTCTGGGGAGGCCAACTTCCAAAGCTCCCAAGACACTGACTTGGGG GAAACATCATCTGTGGCTCACGCTCTTGTGCCAGCACCCCAGGAGCCGCCACCTTCCTTCCCGATACAAAAGATGCAGATAGAT GAAAGAGAAGAGTTCGGCCCGCGGCTGCCTCCCGTCTTCTGCCCCAATGCTCGTCAGACACTTGAGGTTCCTCAAAAAGAGAAA CATAAAAAGAACAAAGACAAGCACAAGGCCAAGAAAGAGCACAGGCGGAAGAAAGAGAAGAAAAAGAAACACAGGAAGCACAAA ' CACAAAGGCMGCAAAAGAATAAAA CCAGAGAAAAGTAGTAGCTCCGAGAGTTCCGACAGCAGCGACAGCCAGAGTGACGAG GAAACCGCAGACGTGTCGCCCCAGGAGCTGCTGAGACGGCTGAAAAGTCTTCCACTAAGAAGGCAGTAATTGAATGCTGCCCTG GCTCGTCCTAGAATCATTTCTCCTCCATGATGGAAGCCCAGTGATTGTTCAGTTAACGCATTGTACAGAGTGTATTTATATGTA AATTCCTGCTGTAAAATAATTTTTAAAACCTTGACATTTCAAAGACTGCCTTGAAAGGTCGCAGAAATTGATTTCTATTTTTAA TTTCAGTTAGTATCGGGGGAAAAAAATCCAGATTGAACAGTTTAATTAAAGTGGAATTTTTCT
41
MAQVSIN DYSE DLSTDAGERARLLQSPCVDTAPKSEWEASPGGLDRGTTSTLGAIFIVV ACLGAG LNFPAAFSTAGGVAA GIALQ GMLVFIISGLVILAYCSQASNERTYQEVVWAVCGKLTGV CE¥AIAVYTFGTCIAFLIIIGDQQDKIIAVMAKEPEGA SGPMTDRKFTISLTAFLFILPLSIPREIGFQKYASFLSWGTWYVTAIVIIKYIWPDKEMTPGNILTRPAS MAVFNAMPTIC FGFQCHVSSVPVFNSMQQPEVKTWGGVVTAAMVIALAVYMGTGICGFLTFGAAVDPDVL SYPSEDMAVAVARAFII SVLTSY PI HFCGRAWEGLWLRYQGVPVEEDVGRERRRRVLQTLVWF LT LLALFIPDIGKVISVIGG AACFIFVFPGLCLIQAKLS EMEEVKPAS WVLVSYGVLLVTLGAFIFGQTTA AIFVDLLA
42
ATGTGATGCATGCTCACGTGTCTCCGCAGCCGGCTCGGGAAAGAATCCCCCAAGCTCCATTTCATGAGTAAGCGTGAGAGCCGC TCAGTTTCCTCCAGCTCTGCTGAAGCCAGCACAGAAGTAGCCCAAACTCTTCCCTCTGCTGACAGCAAATTTTAGGCAAAGTCT TGAGAAAGAAGAAATTGGGTCCAGAAAGGGAAGTGAGGAGAATCAGATCCCAGACCTTTGGGGAGAAGGAGCAACCGCCTCTGG CACAGCCCATCAGGGAGAAAGAGCAGGTTGAGAAGAGTCCTAAGCTAACAGCCCCAAACAGGTGGGTGTTGCTCAGCTCCCTGA GGCATGTGGTTGTAAGGCAGAACCCACAGACCTTGCAGGAAGAAGGCTCTCGGGGCCATGGCCCAGGTCAGCATCAACAATGAC TACAGCGAGTGGGACTTGAGCACGGATGCCGGGGAGCGGGCTCGGCTGCTGCAGAGTCCCTGTGTGGACACAGCCCCCAAGAGT GAGTGGGAAGCCTCTCCTGGGGGTCTGGACAGAGGCACCACTTCCACACTTGGGGCCATCTTCATCGTCGTCAACGCGTGCCTG GGTGCAGGGTTACTCAACTTCCCAGCAGCCTTCAGCACTGCGGGGGGCGTGGCAGCAGGCATCGCACTGCAGATGGGTATGCTG GTTTTCATCATCAGTGGCCTTGTCATCCTGGCCTACTGCTCCCAGGCCAGCAATGAGAGGACCTACCAGGAGGTGGTATGGGCT GTGTGTGGCAAGCTGACAGGTGTGCTATGTGAGGTGGCCATCGCTGTCTACACCTTTGGCACCTGCATTGCCTTCCTAATCATC ATTGGCGACCAGCAGGACAAGATTATAGCTGTGATGGCGAAAGAGCCGGAGGGGGCCAGCGGCCCTTGGTACACAGACCGCAAG TTCACCATCAGCCTCACTGCCTTCCTCTTCATCCTGCCCCTCTCCATCCCCAGGGAGATTGGTTTCCAGAAATATGCCAGCTTC
CTGAGCGTCGTGGGTACCTGGTACGTCACAGCCATCGTTATCATCAAGTACATCTGGCCAGATAAAGAGATGACCCCAGGGAAC
■ ATCCTGACCAGGCCGGCTTCCTGGATGGCTGTGTTCAATGCCATGCCCACCATCTGCTTCGGATTTCAGTGCCACGTCAGCAGT
GTGCCCGTCTTCAACAGCATGCAGCAGCCTGAAGTGAAGACCTGGGGTGGAGTGGTGACAGCTGCCATGGTCATAGCCCTCGCT
GTCTACATGGGGACAGGCATCTGTGGCTTCCTGACCTTTGGAGCTGCTGTGGATCCTGACGTGCTCCTGTCCTATCCCTCGGAG GACATGGCCGTGGCCGTTGCCCGAGCCTTCATCATCCTGAGCGTGCTCACCTCCTACCCTATCCTGCACTTCTGTGGGCGGGCG GTGGTGGAAGGCCTGTGGCTGCGCTACCAGGGGGTGCCAGTGGAGGAGGACGTGGGGCGGGAGCGGCGGCGGCGAGTGCTGCAG ACGCTGGTCTGGTTCCTGCTCACCCTGCTGCTGGCGCTCTTCATCCCTGACATCGGCAAGGTGATCTCAGTCATTGGAGGCCTG GCCGCCTGCTTCATCTTCGTCTTCCCAGGGCTGTGCCTCATTCAAGCCAAACTCTCTGAGATGGAAGAGGTCAAACCAGCCAGC TGGTGGGTGCTGGTCAGCTACGGAGTCCTCTTGGTCACCCTGGGAGCCTTCATCTTCGGCCAGACCACAGCCAACGCCATCTTT GTGGATCTCTTGGCATAACCACTGCCTCCCAGGGAACACAAGGCCTTTGCCATTGGTCGCAGGAACCCATCTCTTAGAGCTATG GGGCCATTCTTAGTCCACGATCATTCCAACTGGTGGGATGACATCCGGACATCCTCTTCCAGGGACTGGGGCAAACTCAGGCCC CACACCTCTGGACAGCTCAAATCCAGTCCCCTTCCTGCTCCCCAGTCCTGGCAGTGCCGTGGATGGCGGCAGGAAGTCTCACAT CATAGAGGACCCCTCCTCCTCTCCCAGTTCTCAACTTCTCCATGCCTGGAATCCACGGGTGAAGAGAGTCGGTAGATCTCATAA GAAAGAATCCAGTCTGACTTCCCTCTGGAGAATGACTATGGACAGAAGGCCACCATCCTCCACAGAGCACCCTGTCCTGAGTAG GGGTTGTGCTCATTACCCCAGGCCAGTGGTAGCTTCCTCAGGAGCCTGGCCACTTCCAAAGGTAGCACTGAAGTCGTGCAAATA CATAGTCAGGTAGATTCAGACCTTGTCCACACCTTCCTGGGCAACCCCCACCATGAACCTGTCAGCCTCTTTCCCATAGCTAAT AGACATTTCCCAGGCCTTGAGGGGCCCCACCCTGTCTCTTTCATCAAACCTGATGGTCCAGGCTGGGCATCCCTCTCCTCCTCC ATCCCCAGACATCACCAGGTCTAATGTTTACAAACGGTGCCAGCCCGGCTCTGAAGCCAAGGGCCGTCCCGTGCCACGGTGCTG TGAGTATTCCTCCGTTAGCTTTCCCCATAAGGTTGGGAGTATCTGCTTTTGTGTCTGAGATGGGCCCCTCTTTTCAGAGGCCGC AGGGTGGGTGATGGAGAAGGCTGAGAACCTTTCAGACCCTCTGTGTGGGCTGGGCTGGTCAGAATCAGGGTGTACCTCCCCGAC ACCTTCTTTTTCAGTGATGTTTTCTCTTCTCCCTGCCTTTCCTCTGCCTCCTCCCCTGCCAGCCCTAGCGTGACTACCCAGAGA C
43
MAQVSI NDYSEWDLSTDAGERARLLQSPCVDTAPKSE EASPGGLDRGTTSTLGAIFIWNACLGAGLLNFPAAFSTAGGVAA GIA QMG--LVFIISGLVILAYCSQASNERTYQEWWAVCGK TGVLCEVAIAVYTFGTCIAF IIIGDQQDKIIAVMAKEPEGA SGPMTDRKFTISLTAFLFILPLSIPREIGFQKYASF SWGTWYVTAIVIIKYIWPDKEMTPGNILTRPAS AVFNAMPTIC FGFQCHVSSVPVFNSMQQPEVKT GGWTAAMVIALAVYMGTGICGFLTFGAAVDPDV LSYPSED AVAVARAFIILSVLTSY PILHFCGRAWEGL LRYQGVPVEEDVGRERRRRV QT V FLLTLLLALFIPDIGKVISVIGGLAACFIFVFPG CLIQAK S EMEEVKPASWWVLVSYGVLLVTLGAFIFGQTTANAIFVDLLA 44
GAGGCCAAGAGCGCGGGCGGCGAGGCAAGATGGCGGCAACCAAGAGGAAACGGCGTGGAGGCTTTGCAGTTCAGGCGAAGAAGC CAAAAAGAAACGAAATAGATGCGGAGCCGCCAGCTAAGCGGCACGCCACAGCAGAGGAGGTGGAGGAAGAAGAGAGGGACCGGA TCCCAGGCCCCGTTTGCAAGGGAAAGTGGAAAAATAAGGAACGGATTCTCATCTTTTCTTCCAGAGGAATAAATTTTAGAACAA GACATTTAATGCAGGACTTGAGAATGTTGATGCCTCATTCTAAAGCAGATACTAAAATGGATCGTAAGGATAAGCTATTTGTGA TTAACGAGGTTTGTGAAATGAAGAACTGTAATAAATGCATCTATTTTGAAGCTAAGAAAAAACAGGATCTCTATATGTGGTAAG AGAATGTATTAAGATTTTGGTTAAACTCATTTAAGTGGATTTGTTCTTTGTACCTTTTATGTTATAGACTCCTAGTGTTTCATG TTAAGGGTTGAGAATGAAGCAAACTTTTGATTTCACGAAACTTGATACCTTTAAAGAAAATTAAATGTATAAATATTATAAGCA TATTATTTATGGTGAATAGGTGGTAAGCATTGACTACATTTGCTAATTAGTGGAAAAAGCTTACTCCATATCTTTCAGGCTTTC AAATTCACCTCACGGACCATCTGCTAAATTCCTTGTTCAAAATAGTAAGTTGACTCAATAAATTTTTTTAGATGAGGAAATTAA AAGTAATCTTTTGAAATAGTTGTGCAAAAGTTACAACTATTTTTGTTTTTGTTGTAATTTTTCTAGTTCATACCCTCGCTGAAC TGAAGATGACTGGAAACTGTTTGAAAGGTTCTCGGCCCCTTTTGTCTTTTGACCCTGTAAGTTTCTCATTCAGTGTATGAGGTC TAATTTTCTTATCTGGCATGGTTGTTTTTAGTAGATATAGTTGTGTTATTCAATTTAGTTTCACCCCCACCTTGGTTTTATGGA TTATCAATTCTTTCAGGTACATTTATAATGAGGTTATAGCCAAGTTATAGAAACAAATGAGCAAACAGTTTTAAACAAGGCAGT CTACTGTTAAATAATATGCTTACCTTATTTTTATAGGCTTTTGATGAATTACCACATTATGCTTTGTTAAAAGAACTCTTAATT CAGGTAAATATCTTTAAAATTAGCTATCCAAAATATACATGATATATCTTGGAATAAGGAACTAACATACACTTTTTTAACTAG ATCTTTAGTACACCACGGTATCATCCCAAAAGCCAACCATTTGTGGACCACGTGTTTACTTTCACCATTTTGGATAATAGGATA TGGTTTCGGAACTTTCAGATCATAGAAGAAGATGCTGCTCTTGTAGAAATAGGACCTCGTTTTGTCTTAAATCTCATAAAGATT TTCCAGGGAAGTTTTGGAGGACCAACTTTATATGAAAATCCTCACTACCAGTCACCAAACATGGTAAGCGGTTGTGTCATTCAG TAGTCTTCAATGTACCAGAACCCTTTGGCCAAAATGATTCTGTGAAGTAATTGCTGTTTTATTACCTGTGAAACTGAATTTGGT TTTTGCTGCATAGAAACTTGGAAATTACTCCCTTTTTTCATGACACTGGCTGAAAGGATATATGGTTCATAACTGAAAGTCTTT GCCTTATATAAAATGTTTATTTTTATTTCAAAAGCATCTAATCTTTTTTTTTTTTTTTTAGCATCGGCGTGTCATAAGATCCAT CACAGCTGCAAAATACAGAGAGAAACAGCAAGTGAAAGATGTGCAAAAACTGAGAAAGAAAGAGCCGAAGACTCTTCTTCCACA TGATCCCACTGCAGATGTTTTTGTAACACCAGCTGAGGAGAAACCAATAGAAATACAGTGGGTAAAACCAGAGCCAAAAGTTGA TTTGAAAGCAAGAAAGAAACGGATTTACAAAAGGCAAAGAAAAATGAAACAGAGGATGGACAGTGGGAAAACAAAATAAGTCAA TGGAAACCTGATTTGTTTTTCAGTTACTTTATATTTATTTTGTATTCAATGTGTAAATACTTTTATTATCTAATACTATCTTAC GTCTAATTAGTGTAGCATTTACAAGAAAGAAAAATTAAGATCTTAAAATCAGTGATTATCTTTTTCTAAATAAAATATCACCAG AATTCATCAGTT
45
MDWKEVLRRR ATPNTCPNKKKSEQELKDEEMD FTKYYSE KGGRKNTNEFYKTIPRFYYRLPAEDEV LQKLREESRAVFLQ RKSRE LDNEE QNLWFLLDKRQTPPMIGEEAMI-.YENFLKVGEKAGAKCKQFFTAKVFAK LHTDSYGRISIMQFFNYVMRKV W HQTRIGLSLYDVAGQGYLRESD ENYI ELIPTLPQLDGLEKSFYSFYVCTAVRKFFFFLDP RTGKIKIQDILACSFLDDL LELRDEELSKESQET WFSAPSALRVYGQYLNLDKDHNG SKEELSRHGTATMT VFLDRVFQECLTYDGEMDYKTYLDFVLA LENRKEP LQYIFKL DIENKGY NVFS YFFRAIQELMKIHGQDPVSFQDV DEIFDMVKPKDP KISLQDLINSNQGDTV TTILIDLNGFWTYENREALVA DSENSADLDDT 46
AAAAATCCGGCTTGGTGAGCTTGGGTCGCCTCTGAAGGAGAACCATTTTCCATCTCTTTCATAGTTTTTTCCCCCAGTCAGCGT GGTAGCGGTATTCTCCGCGGCAGTGACAGTAATTGTTTTTGTCTCTTTAGCCAAGACTTCCGCCCTCGATCAAGATGGTGGTTG GACGGCCTTCCTAACCTTTACGGGGCCTGGCGGTGCTGACGCCTGAGCTGGTAGGGGTGGAGCAGGTAGGAAACAGCAAATGCA GAAGCTGCTGCGCGGGAGTCGGCCATGGACTGGAAAGAAGTTCTTCGTCGGCGCCTAGCGACGCCCAACACCTGTCCAAACAAA AAAAAAAGTGAACAAGAATTAAAAGATGAAGAAATGGATTTATTTACAAAATATTACTCCGAATGGAAAGGAGGTAGAAAAAAC ACAAATGAATTCTATAAGACCATTCCCCGGTTTTATTATAGGCTGCCTGCTGAAGATGAAGTCTTACTACAGAAATTAAGAGAG GAATCAAGAGCTGTCTTTCTACAAAGAAAAAGCAGAGAACTGTTAGATAATGAAGAATTACAGAACTTATGGTTTTTGCTGGAC AAACGCCAGACACCACCTATGATTGGAGAGGAAGCGATGATCAATTACGAAAACTTTTTGAAGGTTGGTGAAAAGGCTGGAGCA AAGTGCAAGCAATTTTTCACAGCAAAAGTCTTTGCTAAACTCCTTCATACAGATTCATATGGAAGAATTTCCATCATGCAGTTC TTTAATTATGTCATGAGAAAAGTTTGGCTTCATCAAACAAGAATAGGACTCAGTTTATATGATGTCGCTGGGCAGGGGTACCTT CGGGAATCTGATTTAGAAAACTACATATTGGAACTTATCCCTACGTTGCCACAATTAGATGGTCTGGAAAAATCTTTCTACTCC TTTTATGTTTGTACAGCAGTTAGGAAGTTCTTCTTCTTTTTAGATCCTTTAAGAACAGGAAAGATAAAAATTCAAGATATTTTA GCATGCAGCTTCCTAGATGATTTATTGGAGCTAAGGGATGAGGAACTGTCCAAGGAGAGTCAAGAAACAAATTGGTTTTCTGCT CCTTCTGCCCTAAGAGTTTATGGCCAGTACTTGAATCTTGATAAAGATCACAATGGCATGCTCAGTAAAGAAGAACTCTCACGC CATGGAACAGCTACCATGACCAATGTCTTCTTAGACCGTGTTTTCCAGGAGTGTCTCACTTATGATGGAGAAATGGACTATAAG ACCTACTTGGACTTTGTCCTTGCATTAGAAAACAGAAAGGAACCTGCAGCTCTACAATATATTTTCAAACTGCTTGATATTGAG AACAAAGGATACCTGAATGTCTTTTCACTTAATTATTTCTTTAGGGCCATACAGGAACTAATGAAAATCCATGGACAAGATCCT GTTTCATTTCAAGATGTCAAGGATGAAATCTTTGACATGGTAAAACCAAAGGATCCTTTGAAAATCTCTCTTCAGGATTTAATC AACAGTAATCAAGGAGACACAGTAACCACCATTCTAATCGATTTGAATGGCTTCTGGACTTACGAGAACAGAGAGGCTCTTGTT GCAAATGACAGTGAAAACTCTGCAGACCTTGATGATACATGATCTCTGAAAGACTAGACTGTCTTATATTATGAGATACTTGAA TGCTGCATGTAAAGCCTTTAAAGCAAAATCCTCAGAAATGGTCTAAATAAAACACTTGATATGCCTAGAGAACACAAAAAAAAA AAAAAAAAAAAAAAAAA 47
MP AKGKTRRQKFGYSWRKRNRNARRK RGIECSHIRHAWDHA SVRQN AEMGLAVDPNRAVPLRKRKVKAMEVDIEERP KELVRKPWLNDLEAEASLPEKKGNTLSRDLIDWRYMVENHGEDYKAMARDEK YYQDTPKQIRSKINVYKRFYPAEWQDFLD SLQKRKMEVE
48 GTTACACGAGGTCTGAGAGACAGAGGCAGCGTGTTTGAGCTGCTGGTGCGGTGGTCAGCGCGATGCCCAAGGCCAAGGGCAAAA CCCGGAGGCAGAAGTTTGGTTACAGTGTCAACCGAAAGCGTCTGAACCGGAATGCTCGACGGAAGGCAGCGCGCGGGATCGAAT. GCTCCCACATCCGACATGCCTGGGACCACGCTAAATCGGTACGGCAGAACCTGGCCGAGATGGGGTTGGCTGTGGACCCCAACA GGGCGGTGCCCCTCCGTAAGAGAAAGGTGAAGGCCATGGAGGTGGACATAGAGGAGAGGCCTAAAGAGCTTGTACGGAAGCCCT ATGTGCTGAATGACCTGGAGGCAGAAGCCAGCCTTCCAGAAAAGAAAGGAAATACTCTGTCTCGGGACCTCATTGACTATGTAC GCTACATGGTAGAGAACCACGGGGAGGACTATAAGGCCATGGCCCGTGATGAGAAGAATTACTATCAAGATACCCCAAAACAGA TTCGGAGTAAGATCAACGTCTATAAACGCTTTTACCCAGCAGAGTGGCAAGACTTCCTCGATTCTTTGCAGAAGAGGAAGATGG AGGTGGAGTGACTGGTTTAGATCACAGCTGCCCCAGGCTGAGGCGTCCCCCGGACCAGTGAAGCTGGAGCCAGGGTGTAAGGCA AGGAGGTGCTGTGTGGCTCCAGAGGAGCTGGCCAGGTCCCATGGAATCAGAAGGTTACACACACACGTGCACACTCCCCGCTCT GGGGAAGGAACTGTTCTCAGAGGCTCCAATTTATATTCATCTGGGGGTTCACGGAAAAGCCAGAACCTGCTGTTTTCAGGGTGG GTGATGTAMTATAGTGTGTACAT TA GCAMTATATTTTAAAAAAAAAAAAAAAAAAAAAAAAAAA
MMPEFQKSSVRIKNPTRVEEIICGLIKGGAAK QIITDFDMTLSRFSYKGKRCPTCHNIIDNCKLVTDECRKK LQLKEKYYAI EVDPVLTVEEKYPYMVE YTKSHG VQQA PKAKLKEIVAESDVMLKEGYENFFDKLQQHSIPVFIFSAGIGDVLEEVIRQAG WHPIWKWSNFMDFDETGVLKGFKGE IHVFNKHDGALR TEYFNQ KDNSNII LGDSQGDLRMADGVAVEHILKIGYLND RVDE LEKYMDSYDIVLVQDESLEVA SILQKIL
50
ATGATGCCAGAATTCCAGAAAAGTTCAGTTCGAATCAAGAACCCTACAAGAGTAGAAGAAATTATCTGTGGTCTTATCAAAGGA. GGAGCTGCCAAACTTCAGATAATAACGGACTTTGATATGACACTCAGTAGATTTTCATATAAAGGGAAAAGATGCCCAACATGT CATAATATCATTGACAACTGTAAGCTGGTTACAGATGAATGTAGAAAAAAGTTATTGCAACTAAAGGAAAAATACTACGCTATT GAAGTTGATCCTGTTCTTACTGTAGAAGAGAAGTACCCTTATATGGTGGAATGGTATACTAAATCACATGGTTTGCTTGTTCAG CAAGCTTTACCAAAAGCTAAACTTAAAGAAATTGTGGCAGAATCTGACGTTATGCTCAAAGAAGGATATGAGAATTTCTTTGAT AAGCTCCAACAACATAGCATCCCCGTGTTCATATTTTCGGCTGGAATCGGCGATGTACTAGAGGAAGTTATTCGTCAAGCTGGT GTTTATCATCCCAATGTCAAAGTTGTGTCCAATTTTATGGATTTTGATGAAACTGGGGTGCTCAAAGGATTTAAAGGAGAACTA ATTCATGTATTTAACAAACATGATGGTGCCTTGAGGAATACAGAATATTTCAATCAACTAAAAGACAATAGTAACATAATTCTT CTGGGAGACTCCCAAGGAGACTTAAGAATGGCAGATGGAGTGGCCAATGTTGAGCACATTCTGAAAATTGGATATCTAAATGAT AGAGTGGATGAGCTTTTAGAAAAGTACATGGACTCTTATGATATTGTTTTAGTACAAGATGAATCATTAGAAGTAGCCAACTCT ATTTTACAGAAGATTCTATAA 51*
MHTLVFLSTRQVLQCQPAACQALPL PRE FPL FKVAFMDKKTWRELVHT PFPL SFQQ LQECAHCSRAL QERPSTES MQAVILGLTARLHTSEPGASTQPLCRKHALRVLDMTG DDGVEQDPGTMSM DCTAAVARTCIAQQQGGAAEPGPAPIPVEVR VD RVNRASYAF REALRSSVGSPLRLCCRD RAEDLP R TVAL QLLDAGCLRRVDLRF NLGLRGLSVIIPHVARFQHLAS LRLHYVHGDSRQPSVDGEDNFRYF AQMGRFTCLRE SMGSS SGRLDQLLSTLQSPLESLELAFCAL PED RFLARSPHAA HLKKLDLSGNDLSGSQLAPFQG LQASAAT LH ELTECQ ADTQL ATLPILTQCAS RY GYGNP SMAGLKE LRDSVAQ AELRTWHPFPVDCYEGLPWPPPASV LEASINEEKFARVEAELHQ LLASGRAHVLWTTDIYGRLAADYFSL
• 52
CGGGGCTGGAGGCGGTGGCTGCGGTTGCGGGACCGGCACTATGCTGGGCCTTCCTACCACTTGTGTGTGGCTTGGTAGTGGCCT AGGGTCTCTCCTCCCTGCTGAAGTCCCTCTCCTGCAGGTGGCCGTCTGCCCGGCCCAGCACCATGCACACGCTTGTGTTCTTGA GCACACGGCAGGTGCTGCAGTGCCAGCCAGCTGCCTGCCAGGCCCTGCCCCTGCTGCCACGCGAACTCTTCCCCCTGCTGTTCA AGGTGGCCTTCATGGACAAGAAGACAGTGGTACTGCGCGAGTTGGTACACACGTGGCCCTTCCCGCTGCTCAGTTTCCAGCAGC TGCTACAGGAGTGTGCCCACTGCAGCCGTGCCCTCCTGCAGGAGCGGCCTAGCACTGAGAGCATGCAGGCTGTTATCCTGGGGC TGACTGCCCGGCTCCACACCTCAGAGCCTGGGGCCAGCACACAGCCCCTCTGCAGGAAGCATGCGCTGCGGGTGCTGGACATGA CGGGCCTCTTGGATGATGGTGTGGAACAGGATCCTGGCACCATGAGCATGTGGGACTGTACTGCTGCCGTAGCTCGCACATGCA TTGCCCAGCAGCAGGGTGGGGCCGCAGAGCCTGGGCCAGCCCCCATCCCCGTGGAGGTGCGCGTGGACCTGCGGGTGAACCGGG CCTCCTATGCGTTCCTGCGGGAGGCACTCCGAAGCAGCGTGGGCAGCCCGCTGCGGCTCTGCTGCCGGGACCTGCGAGCTGAGG ACCTGCCCATGCGCAACACTGTGGCCCTGCTGCAGCTTCTGGATGCAGGCTGCCTGCGCCGCGTGGACCTGCGCTTCAACAATC TGGGCCTGCGCGGCCTGTCTGTGATCATCCCACACGTGGCCCGCTTCCAGCACCTGGCCAGCCTGCGGCTCCACTATGTGCATG GGGATTCAAGGCAGCCCTCCGTGGATGGCGAGGACAACTTCCGCTACTTCCTTGCCCAGATGGGCCGCTTCACCTGTCTGCGTG AGCTCAGCATGGGCTCCTCTCTCCTTTCAGGGAGGCTGGACCAGCTGCTCAGCACCCTGCAGAGCCCCCTGGAGAGCCTGGAGT TGGCCTTCTGTGCTCTGCTGCCTGAGGACCTACGCTTCCTGGCACGGAGCCCACATGCTGCCCACCTCAAGAAGTTGGACCTGA GTGGTAACGACCTGTCTGGCAGCCAGCTGGCACCCTTCCAGGGTCTGTTGCAGGCATCAGCAGCCACACTGTTGCATCTGGAGC TGACTGAGTGTCAGCTCGCAGACACCCAGCTGTTGGCCACACTACCCATCCTGACTCAGTGCGCCAGTCTCCGGTACCTTGGCC TCTATGGCAACCCACTGTCCATGGCGGGCCTCAAGGAGCTGCTGCGGGACTCAGTGGCACAGGCTGAGCTGCGTACTGTGGTGC ACCCCTTCCCTGTGGACTGCTATGAGGGCTTGCCCTGGCCGCCGCCTGCCTCTGTCCTGCTGGAGGCCTCCATCAATGAGGAGA* AGTTTGCCCGCGTAGAAGCTGAGTTGCACCAGCTGCTTCTAGCCTCAGGCCGTGCCCATGTGCTCTGGACCACGGACATCTACG GGCGACTGGCTGCGGACTACTTCAGCCTATGATGAAGTAGCTCTGGGTGAGACACAGGCCGCCCTGCAGTCTCTTTAGGTAGGC AGGGCCTTTGCTGGGACCCCTGGTGGAGGCCTTCACAAAAGCACTGGTTACTGGTTTCCTGCTGGGTCTACCTTGCTTCTGGGC- ACACCTCAAGCCTCCCCTGCTTTCTGCAGTGCCCCACGCGGTTTTCCCTGCACTTGCTCCATAATTGGCTGATCATCTGTGGGC CCCGGGGCTGGATGTCAGGCCTCCATTGCCCTGCTCAGTTTGGCTGCATTTGGCTGCCGTCTGGGGTCCTGGTCCTTTGTGCAA ATGCTTTGGGATTCCAGTTGTGAGCTGAGAGAGATGATGGCCTCTCTGGGCCTTTCCTCTCCCTTTACTGAGAGCTCAGTGCTT CTGGGGTTGAAGTTGGACAGAGGCCTGCTTCAGGGAAGCTGGGAGTCCCCAGGCACTCACGCCTCTTACGTGTTCCCTACCCTG CCACCCAGCCACCCCACTGGGCTGGGCTCGGGCTGGAGGGGGTCATCAAGGTACACATGTGCCTGGAAGTTGAATTTGTGGCTG TTTTTTTTTCTGTCCACGTTGGTCACCCTTATCCTTATCTCTGCTGTCACCCCCAACATGGCCACCGGGCAACAACTGCCATCC AGCCTGTCGCCCCGCCCTTCGCGGGGCAGCCCCGTCGGCACTGCCGGCCAGTCCTTGCTCTTCCCACCTTTCGGAGGCCCAAGA
TCCTACTGTGGCCGGCCAGGGCCAGCGAGGGACCCCCCCCATGCAGAGCTGGAGGTTGGGGTGATGTCTTTTCGGAAGAGCTTC
AAGGGAGGTGTTGGGGCCTCCCCGGCCACCTTCCATTGCTACCCCAGGATTCCCGAGTGCAACGTTCCCGGCTCGCGCCCCACA
CACGGCTCAGCGCACACTGCGCGGCTTCCACCTTTACTGACGGAGCATGCGCGAGGCCGCACCGGCCAATCTCCGGCGCCCACG
. .TCATCCGCGCGCCCGGGGCCCTAGCAGTGGATCTCGTAGGCGACCGGCGGGGGCACGCGGAGTCCCGGCCCCGCCCCCTGTTCC GGGCCGCAGTCAGCGGGCGCCTCCGCCGGACCCTCGGCGAAGAGCGGCTTGGAGCGGTTGATGACGAACATCTCGTGGCCGGGC TCGTCGCGGAGCTCCTCTAGCTGTGCGAACGTACAGGGGCCGTCCAAGTAGTCGTTGACGAACAGCGCTCCCTCCCCCGGAGGC CCCCGCGCCTTTTTTCGCCTGCGGCGCCGGCGACAGATCATGGCGACCAGGAGCAGCGCCGTGAGCGCCAGCAGCGCGATGGCC GCCGCAATGGCCGTCTGTGTGGCCACGCCCAGGGCGCGGAAGGCCATGCTGCCCGCCTCGGGCCGGGGCTCGCTGCCGGCGGGG CGGGCGGCCGGAGGCGGCGGTTGCGCGGGCTGCTGCGGCTGCTGCCGGGACGCGTTGACCAGGAGCCGGAAGGGCACGCGGGCA GCGCCGCCGGCGTTGGAGGCCTCGCACTCGTACTTACCGGCGTGCGCCAGCGTGATGTTGCTGAGGAAGAGCATGCCGCTGCCC GTGTCGGATGCCGAGTGTCCGCCCAGGCCCAGCAACCCGCCTTCTAGCTGGGCCTGGGCTCGCGGCCGGCCCTCGCGAGGCTGG GGCACCTTTCTCCAGGTCACCAATGGCTGCGGGTAGCCGGAGGCTTGGCAGGCAACCCGCAGGTCCTCACCCAGGTTGGCTGTG AGCTCCAGCGGCTGCACGTGGACAGAGGGCGGAATGCAGATGAGGCTGCTGTGGGATACGTCCAGGAGACTCTGGAGCGCCAGG CGCGGGGGCTCTGCACACATGATCTTCCTGTCCCTGGAGGTGAGCAGCCGCTGGCCGCCCTCCTTGATCCAGGCCCCCAGCCAG TGCAGGGCGCAGTCACAGCGCCATGGGTTCTCTGTGGGAGAGCAGCGTTAGGCAGGTGGCTTGAGGGTGCTGCTAAAACAGCCT GTGCAGTTGGGGTTTTGCAGGCCAGGACAGAGGCCTCTTTCCCACCTCCCACAGCGTTTTCACACGGAGTCCAAGGCCCTGCCA CCCCTTCCTTGACCCCAAGCTCCTTGGGGCGGCAGGCCCTTCACCCTCGCCCCCCTCCCCTTTAGCTCTGTGATGCCTGCCTGT TACAGATCACTTCTCCGTCGGTCTCTGAGAAAGCACCTGCTCCTTAAGTCTTCCTGCAACAAGTGCCACTGTTTTTAGGAACCT GGGCGTCCACATAGACATCTCACCAGCACTGAAACCTCACAAGTCCTCTCAGCTTTGCCTTTGGATGCCCTCTCTTGGGAATGT CCCCAGTCCTGGTCAGCTGTCTCTCTCCTTTGCAATTTTGTCTGCCTCCCCTCAGCCTAAAAGTGTGCAGAACCCTCAATTCTG TTAAGTCACCCTGTGGAGTTCCTGTCTTCTGTTTTCCCCAGGCAGGGTGCCTGAGCTGTATCCCCCAGCACACCCACTCCCGCA GCCCTCCAGTGTGGCTGCAGGCGGTGGTGCAGCCTTCCAGACTGCTGCCCAGTTGCCTGATGTCAGAGCCCCTCCACACATGAG CCTGCTCCCTACTGCCAACACCGTGGCCCAGACAGAGACGCTTTCCGAGGAAGAGGTACCTGTGAGGCGCAGGACTTGCAGACT GGCCAGGGGCTGCAGGGCCTCTCGGCTGATGGTGCCCAGCTGGTTCCTGCTGAGGTCCAGCAGTGCTAGGGAGGACAGCCCCGC TAGAGCCTGGTCCTCCAGCAGCTCAATGCTGTTTTCTTGCAGGTGAAGCTCCTGCAGTCGCTGAAGTAAGGACAGCAGATCGTG AGGAAAAAGGGCGCCGAGGTTGGGGGCATGTCTCTCTTCTTACCAAGCTAGACTGGGTTGCCTTTTCTAACTATTCCAGCCCTA CAGGGCGAGGGGCCATAATGGAGTATCCCGCCCCTTTAGACCCCAGGCGCTCACCGGCAGGTGCAAGAAGGTGAAATCCAGCAG CCGCGCCAGCTGGTTGCCCGCCAGGTAGAGCACGCGCAGCTGGGCCAGGCCTACGAAGGCGCCGCTGCGCAAGCCGCGCAGCCG GTTGCTAGTGAGCGCCAGCTCCAGCAGGCGCGGCTGCGCGCGGAAGGCGCCGGCCTCCAGGGCGCGCAGGCTGTTGTTGTGCAG GTAGAGCCGGCGCAGAGCGGCGAGTGGCGCCAGGGCTCCCGGCTCTAGGCGGGCGATGTTGTTGTCCTGCAGGAACAGTGTCTG CAGGCCGGGGAAAGAGGAGGCGCTTACCCCGCTGCGGGGGTCTTCCTCTCCCTGGGGGCACCCCGTCCTCCCGCAGCTCCACAC GGTGCCCACCTGCGTCCCTGGCGGGATTCCCAGCGGGACGACGCGCAACCGCAGGGCGCCACACTCCACCGTGGCGCTGTAGCA GCGGCAGGCTGCTGGGCAGCCGGCGGCGCGGAGCGGCAGTAGTAGCAGCAGCAGCGGCAGCAGTTCGGGGGCCCTCAGGGCCAT CTCCCGAGGCCCGGTTCCTCACCGGCCCTTCCGCGGTTCAGCCGCAGACGCGTGCCCTCCTGAAACACAGGTTGGCAGGCCAGT CTCGGCAGTCGAGAGCCAGCCAATAGATGGAATGGAGGCCTGCACCTGCGTCTAACTTTTGACACTATAAATAGGTTCAAGAAA CTAATAAAACGTTCTGGTTTTCTCCTTTGAC
53
M QTSNYS VLS QFLL SYDLFV1.SFSE LQKTPVIQLVLFIIQDIAVLFNIIIIFLMFF-.TFVFQAGLV-.LLFHKFKGTIIL TAVYFALSISLH¥ VM LRWK SNSFIWTDGLQMLFVFQRLAAVLYCYFYKRTAVRLGDPHFYQDSLW RKEFMQVRR 54
ATGCTCCAGACCAGTAACTACAGCCTGGTGCTCTCTCTGCAGTTCCTGCTGCTGTCCTATGACCTCTTTGTCAATTCCTTCTCA GAACTGCTCCAAAAGACTCCTGTCATCCAGCTTGTGCTCTTCATCATCCAGGATATTGCAGTCCTCTTCAACATCATCATCATT TTCCTCATGTTCTTCAACACCTTCGTCTTCCAGGCTGGCCTGGTCAACCTCCTATTCCATAAGTTCAAAGGGACCATCATCCTG ACAGCTGTGTACTTTGCCCTCAGCATCTCCCTTCATGTCTGGGTCATGAACTTACGCTGGAAAAACTCCAACAGCTTCATATGG ACAGATGGACTTCAAATGCTGTTTGTATTCCAGAGACTAGCAGCAGTGTTGTACTGCTACTTCTATAAACGGACAGCCGTAAGA CTAGGCGATCCTCACTTCTACCAGGACTCTTTGTGGCTGCGCAAGGAGTTCATGCAAGTTCGAAGGTGA
55
MGGFQRGKYGTMAEGRSEDNLSATPPALRIILVGKTGCGKSATGNSILGQPVFESKLRAQSVTRTCQVKTGTMGRKVLWDTP SIFESQADTQELYKNIGDCY LSAPGPHVLLLVIQLGRFTAQDTVAIRKVKEVFGTGAMRHWILFTHKEDLGGQALDDYVA T DNCSLKDLVRECERRYCAF WGSVEEQRQQQAELLAVIERLGREREGSFHSNDLFLDAQLLQRTGAGACQEDYRQYQAKVEWQ VEKHKQELRENESNWAYKALLRVKHLM HYEIFVFLLLCSILFFI1F FIFHYI
56
GTTCCCAATCAGTTTCCAGCCAACACCAGGGTGTCCTAGTCCGCAGAGGTGTGGGGGACACACTCCATAATCTCTACTTTTCTT TTTGTGCAGCTGAGTCATGGAGCTTTCAGCCCCAGCACATGGCTCCTCCTTAACTGCGTCTGCTCAACCTCCCTCAGCCCTGTG AACAGCATCCCCGCACACAGACGCAGAGCAGGACTCTCTCTGCTGCCACTTCACCTTCCTGAGAGAGGACCAGCGGCCAGAGCC TCAGTGACTGCCACCCTGGAGGACAGGGCACAACAACCGTTTC.TGAAGAGAATGGGAGGATTCCAGAGGGGCAAATATGGAACT ATGGCTGAAGGTAGATCAGAAGATAACTTGTCTGCAACACCACCGGCATTGAGGATTATCCTAGTGGGCAAAACAGGCTGCGGG AAAAGTGCCACAGGGAACAGCATCCTTGGCCAGCCCGTGTTTGAGTCCAAGCTGAGGGCCCAGTCAGTGACCAGGACGTGCCAG GTGAAAACAGGAACATGGAACGGGAGGAAAGTCCTGGTGGTTGACACGCCCTCCATCTTTGAGTCACAGGCCGATACCCAAGAG CTGTACAAGAACATCGGGGACTGCTACCTGCTCTCTGCCCCGGGGCCCCACGTCCTGCTTCTGGTGATCCAGCTGGGGCGTTTC ACTGCTCAGGACACAGTGGCCATCAGGAAGGTGAAAGAGGTCTTTGGGACAGGGGCCATGAGACATGTGGTCATCCTCTTCACC CACAAAGAGGACTTAGGGGGCCAGGCCCTGGATGACTATGTAGCAAACACGGACMCTGCAGCCTGGAAGACCTGGTGCGGGAG TGTGAGAGAAGGTACTGTGCCTTCAACAACTGGGGCTCTGTGGAGGAGCAGAGGCAGCAGCAGGCAGAGCTCCTGGCTGTGATT GAGAGGCTGGGGAGGGAGCGAGAGGGCTCCTTCCACAGCAATGACCTCTTCTTGGATGCCCAGCTGCTCCAAAGAACTGGAGCT GGGGCCTGCCAGGAAGACTACAGGCAGTACCAGGCCAAAGTGGAATGGCAGGTGGAGAAGCACAAGCAAGAGCTGAGGGAGAAC GAGAGTAACTGGGCATACAAGGCGCTCCTCAGAGTCAAACACTTGATGCTTTTGCATTATGAGATTTTTGTTTTTCTATTGTTG TGCAGCATACTTTTTTTCATTATTTTTCTGTTCATCTTTCATTACATTTAAATCTCTGGACCCTGGAGCACTTCTAATGTATCA CCCCATGGAGTCATTGTTCTAATAATCACCAATTCAGACTCAGATCCTCGTGGTCTATGGAGCATGCTGCTTGCTGTCTGTGCA GCTCCCATTTCCCCTTCTTCCTGATAGACTTGGAGCTGTGTGCCTCCACTCCAAGGCTGCCTGCCTGCTGTAAACACTATTCCA CTCTGTCTGCCAACAACTGCTTCAGGAATGGGCCTGAGATCCCATGCAGGTCCCTGAGAAGTGAGTAAAAGTCCGCAGAGGTGG GGATGGAAGATCTCTCCTTAGATAGAACCTGTCTTCCTCCCTGGCATTGTGGGGTCTGGGCGTGACACTGGGACTCTCAGCAGC TTTGTGCTGCCAACCTGAGATTGAAGGCAGTGCCTCAGAGCAGCACAGAGAGTTGGGGCCCCCTGAGCCCTGAGCCACCAGCCC TGCAGCCTGCCCTATCTCCGCATTTCCAGTTGTATTAGCCAATAGATTTCCTACTTATTTAAGCTATTTGAGCTCCGGGTCTCT TCTACCTGCATTCTAAAACATTCAAAGTAATAAAAATTTCTCCACATT
57
ELGIPA LDPNDMVSMSVPDCLSIMTYVSQYYNHFCSPGQAGVSPPRKGAPCSPPSVAPTPVESEDVAQGEE SSGSLSEQGT GQTPSSTCAACQQHVHLVQRYADGRLYHRHCFRCRRCSSTLLPGAYENGPEEGTFVCAEHCARLGPGTRSGTRPGPFSQPKQQ HQQQLAEDAKDVPGGGPSSSAPAGAEADGPKASPEARPQIPTKPRVPGKLQE ASPPAGRPTPAPRKASESTTPAPPTPRPRSS LQQENLVEQAGSSSLWGRLHELPVPKPRGTPKPSEGTPAPRKDPPWITLVQAEPKKKPAPLPPSSSPGPPSQDSRQVENGGTE EVAQPSPTAS ESKPYNPFEEEEEDKEEEAPAAPSLATSPA GHPESTPKSLHPWYGITPTSSPKTKKRPAPRAPSASPLA HA SRLSHSEPPSATPSPA SVESLSSESASQTAGAEL EPPAVPKSSSEPAVHAPGTPGNPVSLSTNSSLASSGELVEPRVEQMPQ ASPGAPRTRGSSGPQPAKPCSGATPTPLL VGDRSPVPSPGSSSPQLQVKSSCKENPFNRKPSPAASPATKKATKGSKPVRPP APGHGFP IKRKVQADQYIPEEDIHGEMDTIERRLDA EHRGVLLEEKLRGGLNEGREDDMLVDWFKLIHEKHLLVRRESELIY VFKQQNLEQRQADVEYELRCLLNKPEKD TEEDRAREKVLMQELVT 1EQRAIINC DEDRQREEEEDKMLEAMIKKKEFQRE AEPEGKKKGKFKTMKMKL GNKRDAKSKSPRDKS
58 '
GGAGCTGGGGATCCCCGCTCTCCTGGACCCCAATGACATGGTCTCCATGAGCGTCCCTGACTGCCTCAGCATCATGACCTATGT GTCCCAGTATTACAACCACTTCTGCAGTCCTGGCCAAGCTGGTGTCTCGCCACCCAGAAAGGGCCTTGCACCCTGTTCCCCGCC GTCTGTAGCACCCACTCCAGTGGAATCAGAAGATGTGGCTCAGGGCGAGGAGCTCTCCTCAGGCAGCCTGTCAGAGCAGGGCAC CGGCCAGACCCCCAGCAGCACGTGCGCAGCCTGCCAGCAGCATGTGCACTTGGTGCAGCGCTACCTGGCTGACGGCAGGCTGTA CCATCGCCACTGCTTCCGGTGTCGGCGGTGCTCCAGCACCCTGCTCCCTGGGGCTTATGAGAATGGGCCTGAGGAGGGCACCTT TGTGTGTGCAGAACACTGTGCCAGGCTGGGCCCGGGGACACGGTCGGGGACCAGGCCTGGGCCCTTCTCACAGCCAAAGCAGCA GCACCAGCAGCAACTCGCAGAAGATGCCAAGGATGTTCCAGGAGGCGGCCCCAGCTCCAGTGCTCCTGCAGGGGCTGAGGCCGA TGGACCCAAGGCCAGCCCTGAGGCCCGGCCGCAGATCCCTACCAAGCCCCGGGTTCCTGGCAAACTACAGGAGCTGGCCAGCCC CCCTGCGGGCCGCCCCACCCCTGCCCCCAGGAAGGCCTCTGAGAGCACCACCCCAGCACCCCCCACGCCCCGGCCCCGCTCCAG TCTGCAGCAGGAGAACCTGGTGGAGCAGGCTGGCAGCAGCAGCCTGGTGAACGGGAGACTGCACGAACTGCCTGTCCCCAAGCC GAGGGGGACACCGAAGCCGTCCGAGGGGACACCAGCCCCCAGGAAGGACCCCCCATGGATCACGCTGGTGCAGGCAGAACCAAA GAAGAAGCCAGCCCCACTTCCCCCAAGCAGCAGCCCGGGGCCACCAAGCCAGGACAGCAGGCAGGTGGAGAATGGAGGCACCGA GGAGGTGGCCCAGCCGAGCCCAACGGCCAGCCTGGAGTCCAAACCCTATAACCCCTTTGAGGAGGAGGAGGAGGACAAGGAGGA AGAGGCTCCAGCTGCACCCAGCCTGGCCACCAGCCCTGCCCTGGGCCACCCGGAGTCCACACCCAAGTCCCTGCACCCCTGGTA CGGCATCACCCCTACCAGCAGCCCCAAGACAAAGAAGCGCCCTGCCCCGCGCGCACCCAGCGCGTCCCCACTGGCTCTCCACGC CTCCCGCCTCTCGCACTCGGAGCCGCCCTCGGCCACACCATCGCCAGCGCTCAGCGTGGAGAGCCTGTCGTCTGAGAGCGCCAG CCAGACTGCAGGTGCAGAGCTTCTGGAGCCGCCAGCTGTGCCCAAGAGCTCCTCAGAGCCTGCTGTCCATGCCCCTGGTACCCC TGGAAACCCTGTCAGCCTCTCTACCAACTCCTCCCTGGCCTCCTCTGGGGAACTAGTGGAGCCTAGAGTGGAACAAATGCCTCA AGCCAGCCCTGGCCTTGCCCCCAGGACCAGGGGCAGCTCAGGTCCCCAGCCAGCCAAGCCCTGCAGTGGCGCCACCCCAACGCC TCTCTTGTTGGTTGGAGACAGGAGCCCGGTGCCTTCCCCTGGAAGCTCGTCCCCACAGCTGCAGGTAAAGTCCTCCTGCAAGGA GAATCCTTTTAACCGGAAGCCATCACCTGCAGCGTCCCCAGCCACAAAGAAGGCCACCAAGGGATCCAAGCCAGTGAGGCCACC TGCCCCTGGACACGGCTTTCCACTCATCAAACGCAAGGTCCAGGCTGACCAGTACATCCCTGAGGAGGACATCCATGGAGAGAT GGATACCATTGAGCGCCGGCTGGATGCCCTGGAGCACCGTGGGGTGCTGCTGGAGGAGAAGCTGCGTGGCGGCCTGAATGAGGG CCGTGAGGATGACATGCTGGTGGACTGGTTCAAGCTCATCCACGAGAAGCACCTACTGGTGCGGCGAGAGTCCGAGCTCATCTA TGTCTTCAAGCAGCAGAACCTGGAGCAGCGCCAGGCTGATGTCGAGTATGAGCTCCGGTGCCTCCTCAATAAGCCAGAAAAGGA CTGGACGGAGGAGGACCGGGCCCGGGAGAAGGTGCTGATGCAGGAGCTTGTGACCCTCATTGAGCAGCGCAACGCTATCATCAA CTGCCTGGATGAGGACCGGCAGAGGGAGGAAGAGGAAGACAAGATGTTGGAAGCCATGATCAAGAAGAAAGAGTTCCAGAGGGA GGCTGAACCTGAGGGCAAGAAGAAGGGGAAGTTCAAGACCATGAAGATGTTGAAACTGGTAGGAAACAAACGTGATGCCAAGAG CAAGTCCCCCAGAGACAAGAGCTAACAGCACGAGAAGCCAGTTGGGGACTGCCCCCTCCTGGAGCAGCTCCTGGGCTGTGCTCT GTTTGAAGGGGGCGCCCTGCTCCCCTCAGATCAGTCAGGAGGAAGATGACTAAGGGGAGGGATCCTCTGGGTGATGGCCTCTTC CTCCTCAGGGACCTCTGACTGCTCTGGGCCAAAGAATCTCTTGTTTCTTCTCCGAGCCCCAGGCAGCGGTGATTCAGCCCTGCC CAACCTGATTCTGATGACTGCGGATGCTGTGACGGACCCAAGGGGCAAATAGGGTCCCAGGGTCCAGGGAGGGGCGCCTGCTGA
GCACTTCCGCCCCTCACCCTGCCCAGCCCCTGCCATGAGCTCTGGGCTGGGTCT.CCGCCTCCAGGGTTCTGCTCTTCCAGGCAG
GCCAGCAAGTGGCGCTGGGCCACACTGGCTTCTTCCTGCCCCATCCCTGGCTCTGAGTCTCTGTCTTCCTGTCCTGTGCAGGCG
CCCTTGGATCTCAGTTTCCCTCACTCAGGAACTCTGTTTCTGAAGTCTTCAGTTAAGTTTGAGTTTATGACTGAGTGGCCTGTA
• CTGTCAGACGTGAATGGGCCTGACGGGCAAATCCATCCCTCTCTCCCTCACAGTTCCAGGAGCGGCTTCCCTCGTCTCCCCTTA CTCCACAGGGAGCCTCCCTTGCCAGGACCAGGGCTGCGACGGCCATGCTGGGGCAGGTGAGTGCTCTGTTAGCTGCTCCCAGTG CTGTCCCCAGGCTGCAGTTCTGGTCCCTGGTTGTCAGGTAGGAAGGGTGCACTTGAAGCAGGTGCTCATCTCGGTTCCTTAACG TTTATAGTCTGACCCCTCACTTAGGCTTTCCTCTGCCACCCCGGTCCAGGGAAGAGGCTCGCTCCCGCCCATGGTCATCACTGG TCTGTCTGCTCTGTTGTCTGTTCTTTCCCTGACTCCCTCCCACCGAAGGCCTGATGGCTACTCACCCCTCTGGGATGGCTATGG GAGAGGAGGAGTGATGGGGACCGCCACCTTTTCTGCAGGAAATGTGCCCAGCAGCTCTTGGTCAAAGCACTGTTGCTATAAGCT ATCTCTGGGATGCCTCTAGGCCCCCTTCCCTCTACACACCTCTGGGAAAAGATTACACTGTATTAACTCTCGAGGAGTTTCCTC ACCAATAAACAGACAACCTCAACTGCCAGTGCCCTGCAGCCTCGGGCCACAGCGGCAGCCTTGTTTGCCTTCCCACCTGCCTCT GCCACACCTGGTGGCTGAACATCTCTGGTCGCCCAGAGGCCATGTTGGGGCCATCCTCCAAGAGGGATCTCTGCCCTCACCGCC TGCCACTGGGCAGGATCCCTTTCCTCTGCAGGGAGAGGTGGCTCCTCGGCCATGCAGCCCCTGGCAGGCTCCTTCTAAACATGC CTGTTGACCTGGAGCTGGCGCCACCAACTCCAGGGCCTTTCCAGGGCCAGACAGGTAACACGCATGAACCCGAGTGACAGCTCT GACGGGCTGTTTCGGTGTCAGGAGACAAAGCTGGCAGGGGCAGGGGTGAACTGGAGGCAAGTCAAGTCACCTGTGGCCTGTGGG GCTGAATGTGGGCCCGGTGTTGCCAGATCCTTTGTCATMGAAGCTAGAAATCCAGATTTTATGTGTGTGTAATTTGTAAATGC TGAAAGCTAGCCTGAATTTTTTTTTTTTTTTTGAGACAGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGCGATCTCA GCTCACTGCAGGCTCCGCCTCCTGGGTTCACGCCATCCTCCTGCCTCGGCCTCCTGAGCAGCTGGGACTACAGGCGCATGCTAC GACGCCTGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTGTTAACCAGGATGGTCTCGATCTCCTGACCTTGTG ATCCACCCACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCACGCCCGGCCACTAGCCTGAATTTCAATCAAGG GTTGGCTGATACTGTGTGTCCAGGGTGGACTGGATTTGTCCTGGGGGGTTCTCTGGTTTGCTGCCTCCTGACCACATGATGGGG CCTTCGAGGTCGAGGACAACTGTTCCCATTAGATTGCACCCTCTGCCCTCAGGTTCTTGAGGGTGTGTGGACACAGAGGCTTTC CATGGGATGTCCCTGAGCCGGCCCTTGATTGGGGCCTCACCATTTACAGGGCCGTTTTATTCTGCAAACCGAAACTTGGGTCAT GTGACCTGATGGGATTATGGGACTCCCTCCAGGTGCCCGAGACAAGGTTGATATTTCCAAAATATTTTGGTGATTTAGTGGGAC AAGCAAATGACAGAATACCGGAGAAGGCAGGGATCGTGGGTGTCAGGAGCCAGAGGGGAGGGGGACAGATGTGCTGTGTACAGG ACAAGGTGTCAGGTGACTCCTTCCCAGCAGGGCCTCGCAGATGCACAAGCACGGAGCTGGTGGGTTTTGCCCAAGAAAGGTCAC GCGGCACATGCAGGGATTGGAACTCCCAGGCCAGGGCTCTAGGTCGCTCCCACCTTTTCATGTTTCTTTCTGTGGCCATGGGTA TAGTGGAAAGACATAAAGCTAAAGCCAACTTTTAATCCTGAATGCACTGCTTGCCAGGTAAATGCCCTTGGTTGTGGTATCTTG TTGAGACTTAGTTTTCACAGAGGGATAATGAACCGTTGCAGAGGTTTATTGAGATCATTAACAGAGTGGAATTCAGCACCTGCC ACTGCACTCCAGCCTGGGCGACAGAGCAAGACTCAGTCTCAAAAAAAAAAAAAATTAGCTGGGCAGGGCATGGTGATGGTGCCT GTAATCCTAGCTACTTGGGAGGCTGAGGCATGAGAATTGCCTGAACCCAGGAGGTGGAGGTTGCAGTGAGCCGAGATCGTGCCA CTGTACTCCAGCCTGGGTGACAGCGCGAGACTCCGTCTCAAAAAAAGCTGGGTGTGGGGAACACCTGTGGTCCCAGCTATTCTG GAGACTGAGGCAGGAGGATTGCTTGAGCTCAGGAGTTCTGGCTGCAGTGAGCTATGATCATGCCACTGTATTACAGAATGGGTG ACAGAATGAGAGCGACACTGTCTCAAAAAAAAAAAAAAAAAAAGGCCGGGAGCGGTCGTTTGTGCCTGTAATCCCAACACTTTG GGAGGCCAGGGTGGGCGGATCACTTGAGGCCAGGAGTTCAAGACCAGCCTGGGCAACATGGTGAATCCCCATCTCTACTAAAAA AATTAACTGGACATGGTGGTGGACACTTGTAATCCCAGCTACTCAGGAGGCTGACACATGAGAATTGCTTGAACCCGGGAGGCG GAGGTTACAGTGAGCCGAGATAGCACCACTGCACTCCAACCTGGGCACAGAGTAAGGCTCTGTCTTT
59
MASEGPREPESEGIKLSADVKPFVPRFAGLVAWLESSEACVFPSSAATYYPFVQEPPVTEQKIYTEDMAFGASTFPPQYLSSE ITLHPYAYSPYTLDSTQNVYSVPGSQYLYNQPSCYRGFQTVKHRENTCPLPQEMKAFKKKTYDEKKTYDQQ FDSERADGTI
SSEI SARGSHHLSIYAENSLKSDGYHKRTDRKSRIIAIQWSTSKPEFEFTTLDFPELQGAENNMSEIQKQPK GPVHSVSTDI SL REWKPAAV SKGEIWKNNPNESVTA AATNSPSCTRELS TPMGYWRQTLSTELSAAPKNVTSMINLKTIASSADPKN VSIPSSEALSSDPSYNKEKHIIHPTQKSKASQGSDLEQNEASRKNKKKKEKSTSKYEVLTVQEPPR1EDAEEFPNLAVASERRD RIETPKFQSKQQPQDNFK WKKSQLPVQLDLGGMLTALEKKQHSQHAKQSSKPVWSVGAVPV SKECASGERGRRMSQMKTP HNPLDSSAP MKKGKQREIPKAKKPTSLKKIILKERQERKQR QENAVSPAFTSDDTQDGESGGDDQFPEQAELSGPEGMDELI STPSVEDKSEEPPGTE QRDTEASHLAPNHTTFPKIHSRRFRDYCSQMLSKEVDACVTDLLKELVRFQDRMYQKDPVKAKTKRR V GLREV KHLKLKK KCVIISPNCEKIQSKGG DDTLHTIIDYACEQNIPFVFALNRKA GRSLNKAVPVSWGIFSYDGAQ DQFHKMVELTVAARQAYKT LENVQQELVGEPRPQAPPSLLTQGPSCPAEDGPPALKEKEEPHYIEIWKKHLEAYSGCTLELEE SLEASTSQMM NL
60 CCAAGCCGACGGCCCGCTGCTGGCCTCCGTGACGCGGCCTCCTCCGCGCCTCGCGGCATGGCGTCGGAGGGGCCGCGGGAGCCC GAAAGCGAGGGCATCAAGTTATCAGCAGATGTCAAACCATTTGTCCCCAGATTTGCCGGGCTCAATGTGGCATGGTTAGAGTCC TCAGAAGCATGTGTCTTCCCCAGCTCTGCAGCCACATACTATCCGTTTGTTCAGGAACCACCAGTGACAGAGCAGAAAATATAT ACTGAAGACATGGCCTTTGGAGCTTCAACTTTTCCACCTCAGTATTTATCTTCTGAGATAACTCTTCATCCATATGCCTATTCT CCTTATACCCTTGACTCCACACAGAATGTTTACTCAGTGCCTGGCTCCCAGTATCTTTATAACCAACCCAGTTGTTACCGAGGT TTTCAAACAGTGAAGCATCGAAATGAGAACACATGCCCTCTCCCACAAGAAATGAAAGCTCTGTTTAAGAAGAAAACCTATGAT GAGAAAAAAACGTATGATCAGCAAAAGTTTGACAGTGAAAGGGCTGATGGAACTATATCATCTGAGATAAAATCAGCTAGAGGT TCACATCATTTGTCCATTTACGCTGAGAATAGTTTGAAATCAGATGGTTACCATAAGCGAACAGACAGGAAATCCAGAATCATT GCAAAAAATGTATCTACCTCCAAACCTGAGTTTGAATTTACCACACTGGACTTTCCTGAACTGCAAGGTGCAGAGAACAATATG TCAGAGATACAGAAGCAACCCAAGTGGGGACCTGTCCACTCTGTCTCTACCGACATTTCTCTTCTAAGAGAAGTAGTAAAACCA GCTGCAGTGTTATCAAAGGGTGAAATAGTGGTGAAAAATAACCCAAATGAATCTGTAACTGCTAATGCCGCTACCAATTCTCCT TCATGTACAAGAGAGTTATCTTGGACACCAATGGGTTATGTTGTTCGACAGACATTATCTACAGAACTGTCAGCAGCCCCTAAA AATGTTACTTCTATGATAAACTTAAAGACCATTGCTTCATCAGCAGATCCTAAAMTGTTAGTATACCATCTTCTGAAGCTTTA TCTTCGGATCCTTCCTACAACAAAGAAAAACACATTATTCATCCTACCCAAAAGTCTAAAGCATCACAAGGTAGTGACCTTGAA CAA TGMGCCTC GAMGMT GAAAAAGAAAGAAAAATCTACATCAAAATATGAAGTCCTGACAGTTCAAGAGCCTCCA AGGATTGAAGATGCCGAGGAATTTCCCAACCTGGCAGTTGCATCTGAMGAAGAGACAGAATAGAGACACCGAAATTTCAATCT AAGCAGCAGCCACAGGATAATTTTAAAAATAATGTAAAGAAGAGCCAGCTTCCAGTGCAGTTGGACTTGGGGGGCATGCTGACA GCCCTGGAGAAGAAGCAGCACTCTCAGCATGCAAAGCAGTCCTCCAAACCAGTGGTAGTCTCAGTTGGAGCAGTGCCAGTCCTT TCCAAAGAATGTGCATCAGGGGAGAGAGGCCGCCGCATGAGTCAAATGAAGACCCCGCACAATCCCTTGGACTCCAGCGCCCCA CTGATGAAGAAAGGGAAGCAGAGGGAGATCCCCAAGGCCAAGAAGCCAACCTCACTGAAGAAGATTATTTTGAAAGAACGGCAA GAGAGAAAGCAGCGTCTCCAAGAAAATGCTGTGAGTCCAGCTTTTACCAGTGATGACACACAAGATGGAGAGAGTGGTGGTGAT GACCAGTTTCCCGAGCAGGCAGAGCTGTCAGGGCCAGAGGGGATGGACGAACTGATCTCCACTCCTTCGGTTGAGGACAAGTCT GAAGAGCCACCAGGCACAGAGCTCCAGAGGGACACAGAGGCCTCCCACCTTGCTCCCAATCACACCACCTTCCCTAAGATCCAC AGCCGCAGATTCAGGGATTACTGCAGCCAGATGCTTAGTAAAGAAGTGGATGCTTGTGTTACCGACCTACTCAAAGAACTGGTC CGTTTCCAAGACCGTATGTACCAGAAAGATCCAGTCAAGGCCAAGACTAAACGTCGACTTGTGTTGGGGTTGAGGGAGGTTCTC AAACACCTGAAGCTCAAAAAACTGAAATGTGTCATTATTTCTCCCAACTGTGAGAAGATACAGTCAAAAGGTGGGCTGGATGAC ACTTTGCACACAATTATTGATTATGCCTGTGAGCAGAACATTCCCTTTGTGTTTGCTCTCAACCGCAAAGCTCTGGGGCGCAGT TTGAATAAGGCAGTTCCTGTCAGTGTGGTGGGGATCTTCAGCTATGATGGGGCCCAGGATCAGTTCCACAAGATGGTTGAGCTG ACAGTGGCGGCCCGACAGGCGTACAAGACCATGCTGGAGAATGTGCAGCAGGAGCTGGTGGGAGAGCCCAGGCCTCAGGCACCT CCCAGCCTACTCACACAGGGCCCCAGCTGCCCTGCAGAAGATGGCCCCCCAGCCCTGAAAGAAAAAGAAGAGCCACACTACATT GAAATCTGGAAAAAACATCTGGAAGCATACAGTGGATGTACCCTGGAGCTAGAAGAATCCTTGGAGGCTTCAACCTCTCAAATG ATGAATTTGAATTTATGAGAGTTCTTGCCTGTGTGTCTGTATTTTGGGTAAGGAGGGGAGGTCTGAAAAAGACTTTGGGGCTTT TTCTTCTGTTTTTCATGACAATGTAATTTGTGTAACTGTTGAATCTGGAAATTGATCAGCATTAAAGGGCACATGAAGCAGTGT CTGCAGGCGTTCAGTGCTGCGGAGCCTGTTAAAGGTCACTCAGATGTGCAGGTGTTAATCTTCTCTAAAAGCCTGGTGATACAG CTCTGGCTTTCTGAGCACACTACGGATCTGGAAAATACTGGAAAATGTGATACTTAGAATACTTTGGCTGCTAAGGAAACTTCC TCTCCATTGCAGAATAGCTGAGCCAAGTGAGTGAGTTTGCAGAAAGCAGGTGGTGAGCTCCTGCCTGCTGGAGGTTGCCATGGA GGGCCATTCCTGCCCGGCAACAGCACCGTCCTGCAGGGAGCCACTTGGCAGAAGGGTGCAGGGCTGCTGGTGTCAGAGCAAGAG GGCTACAGGGAAAGGGCCCTTTCTCAGGGGATGTAGCTTTTTTAAAAGATTTGGGAACACTTGGAGGATTTGCTAAAATGAGCC TCAGAAGGAAAATTGGTTTTCTAACCTGTGACTTTTTGAAATGAATTATTCCTTTCAGTCTTTATTTTTCAAAGAAACAATGTG TATTGAAGTACCTAGATTTGTTTGATAATCAACAAATCTTTCCTTTTTCAATGAACATATTCTGAATGTGGTTTCTGTCTTAGA CCAGGAGGACAGAGTTTGCTTTCATATTTTCCCTGTAAGTAAGAGGGCTTATTTATTTTAAATAAAGAGTAATTATTAAAAAAA AAAAAAAAAAAAA 62
CTCTTTGCTTTTGCATGGCTTGGCTTAGTATCCAAGGTATATTAGGGCCACTTGAAAGCATGAAGACCAGTTATATAGGGAACA GGTTTCTCTCAGTGGCACATTTTGCTTTTTCTGAGCCCCAAATACATTGCCTGGGCATGAACATTGTTACCGTAAATTGCACAT GGTCATGGACTGAATTATGTGACTTTAAAGGATGTAACTGCCCAACATTTGCAGATTCTGGGTGGTCTATGTGACCATTTGTCT CGTATCCAAAAACCCCGGGGCTATTGGAACCCTTCCAACACTTTTTCCTTTGTCATAGACAAGTTTATATATAACTTACCAAGA TGTTGGCTGTGCTGGTGTATTGCCAGACAGCTGTCTTTTGGTTCCCATTCCAAATGTGCTGCTGTCCTTCTTTGCATTTCACAA TATCAAAGAAACCACCACCCTTCTTCCTAACAGCATTTTATGCCTTTTATTCCACATTAAATGGGAATTGTGeCTACTTAGGAG TGCCCCTCCAATTAATTACATGTGTCCAAGAATAATCCAAGCTAGAGACACAAGGTGGGAAAACATTTCAAAAAAAAAAAGTCC TCTTAAGGCCAGTAATTTATCTGAAAAGGTATTTTATCACACCTTGACACCTTATATATGAGCCTATTAGGAGCTGCAGGTGGT TTCATAGGGTAAAATCCAAGAAAAGAGAAGGATGTGTGGGGTTTCTATTAGAAGATAATTTTGTTCTCATTTTACCTTTTCTTT TATGATCCTTCTCTGCTAGAACAGGTTAATTCTCCAAATTTGTTTTGTTTTGTTTTGTTATTTTTTAGGGAACTCTTTTGCAAA AGCAATGGTCGGATGTAAATAACATTTAAAGTATAGTGCACATAACTTCCCCGGACTGTTCCAATCTGATAATTTGTAAATGCT TTAGAGTTTTTTTAATTAACACTTGTGTTGCTAAATTCTATTTATGTAAGTCTGCTAAAGTTTTTTAGCCCACTTAAAACTTAA GACAACCATTTAAAATAATGGATGGGTTACTATGAGCAATTTCGCTTTCAGAACCCCCTTGTTTTAGTATATGAAAAAGGCTAA TGCGCATTAATGAGGTTGAAGAGACTATGAGAAATATGTATAGTGTATATTTTAAAACAGCTTTGCTTGTATTGTGAAGATTTA AAAACAAACTTGAGATTTTTAACGTAACTATTAACACAGTTTTAACATAAGTTATCCCACTGGGTTTAAGAGCATCTTGAATGT ATAATCCTTTTTGTAACCCAGGTTGGTTTCTACTTTTACCAGTCACCCAAACATATTTATGTTTTTAGTTTTATGTACTCATTT CCCTTTGTTTTCCTCAAACAGCATGATTTTTTTGCACATGTAGAAATTTTTTAAAAGAAAGAAATTAGTACATCATTTTCTCTG GATTTTCTTCACTTCCCTCTTCCTTTCTACTAACTCCTTCCTTAAAGGCCATATCACTCCATTTGCATTATTTGTGCAAATGCC AGGGTTGGTTTTTATTTTTATTTTTGCTATTTACCTAAAAAAAAAAAAAAAAA
63 '
MEVSRRKAPPRPPRPAAPLPLLAY AAAPGRGADEPV RSEQAIGAIAASQEDGVFVASGSCLDQDYS EHSLSRLYRDQA GNCTEPVS APPARPRPGSSFSK LLPYREGAAGLGGLLLTGWTFDRGACEVRPLGNLSRNSLRNGTEWSCHPQGSTAG YR AGRMRWYAVAATYVLPEPETASRCNPAASDHDTAIALKDTEGRS ATQELGRK CEGAGSLHFVDAF NGSIYFPYYPYN YTSGMTGWPSMARIAQSTEVLFQGQASLDCGHGHPDGRRL LSSSLVEALDVWAGVFSAAAGEGQERRSPTTTALCLFRMSEI QARAKRVSWDFKTAESHCKEGDQPERVQPIASSTLIHSDLTSVYGT¥VMNRTVLFLGTGDGQLLKVILGENLTSNCPEVIYEIK EETPVFYKVPDPVKNIYIYLTAGKEVRRIRVANCNKH SCSECLTATDPHCGWCHSLQRCTFQGDCVHSENLE WLDISSGAK KCPKIQIIRSSKEKTTV 1WGSFSPRHSKCWKWDSSRELCQNKSQPNRTCTCSIPTRATYKDVSVV1TO-FSFGS N SDRFN FTNCSSLKECPACVETGCAWCKSARRCIHPFTACDPSDYERQEQCPVAVEKTSGGGRPKENKGNRTNQALQVFYIKSIEPQKV STLGKSNVIVTGA FTRASNITMILKGTSTCDKDVIQVSHVLNDTHMKFSLPSSRKE KDVCIQFDGGNCSSVGSLSYIALPHC SLIFPATT ISGGQNITMMGR FDVIDN IISHELKGNINVSEYCVATYCGFLAPS KSSKVRTNVTVKRVQDTY DCGT QY REDPRFTGYRVESEVDTELEVKIQKENDMFNISKKDIEIT FHGENGQLNCSFENITRNQDLTTI CKIKGIKTASTIANSSKK VRVKLGNLELYVEQESVPST YF IV PVLLVIVIFAAVGVTRHKSKE SRKQSQQLELLESE RKEIRDGFAELQMDKLD D SFGTVPFLDYKHFALRTFFPESGGFTHIFTEDMHNRDANDKWESLTA DA ICNKSFLVTVIHTLEKQK FSVKDRCLFASFLT IALQTKVY TSILEVTRDLMEQCSMQPKLMLRRTES EK TWMSVCLSGFLRETVGEPFY VTTLNQKINKGPVDVI TCKALYTLNEDWLLWQVPEFSTVALWFEKIPENESAD¥CRNISVVDCDTIGQAKEKIFQAFLSKNGSPYGLQLNEIGLEL QMGTRQKE DIDSSSVILEDGITKLNTIGHYEISNGSTJKVFKKIANFTSDVEYSDDHCH I PDSEAFQDVQGKRHRGKHKF KVKEMYLTKLLSTKVAIHSV EKLFRSI SLPNS-^PFAIKYFFDF DAQAENKKITDPDVVHI KTNS P RF VNILK PQF VFDIKKTPHIDGCLSVIAQAFMDAFSLTEQQLGKEAPTNK LYAKDIPTYKEEVKSYYKAIRDLPPLSSSEMEEFLTQESKKHE NEFNEEVALTEIYKYIVKYFDEILNKLERERGLEEAQKQLLHVKVLFDEKKKCKM
64
GCGAGGAGGAAACGGTGCCGGAGCGCGCAGGGCTTGCTGCCGCCACCGCCGCTGCACAGGCTGGCGGAGCGAGCCTGCCGCGCG CCGCCCTCCCCGCTCTCCTTCCTGGGCGAGCTGCGGGGATGGGGCGGCCGCGGGAGCCCGAGCGCGCGCAGGAACCGCCGCCGC CGGCGCCCGCGTCTCCGTTGCCGCGCGCCTGAGCCGCCGTCGCCGGCGCGCGrrG f^rGrπGRGGGRRfGGGGOrAfirπGrATf; GGCCGGAACAACCGCTGGTACCTGGCGGTGGCCGCCACCTACGTGCTGCCTGAGCCGGAGACGGCGAGCCGCTGCAACCCCGCG GCATCCGACCACGACACGGCCATCGCGCTCAAGGACACGGAGGGGCGCAGCCTGGCCACGCAGGAGCTGGGGCGCCTCAAGCTG TGCGAGGGCGCGGGCAGCCTGCACTTCGTGGACGCCTTTCTCTGGAACGGCAGCATCTACTTCCCCTACTACCCCTACAACTAT ACGAGCGGCGCTGCCACCGGCTGGCCCAGCATGGCGCGCATCGCGCAGAGCACCGAGGTGCTGTTCCAGGGCCAGGCATCCCTC GACTGCGGCCACGGCCACCCCGACGGCCGCCGCCTGCTCCTCTCCTCCAGCCTAGTGGAGGCCCTGGACGTCTGGGCGGGAGTG TTCAGCGCGGCCGCTGGAGAGGGCCAGGAGCGGCGCTCCCCCACCACCACGGCGCTCTGCCTCTTCAGAATGAGTGAGATCCAG GCGCGCGCCAAGAGGGTCAGCTGGGACTTCAAGACGGCCGAGAGCCACTGCAAAGAAGGGGATCAACCTGAAAGAGTCCAACCA ATCGCATCATCTACCTTGATCCATTCCGACCTGACATCCGTTTATGGCACCGTGGTAATGAACAGGACTGTTTTATTCTTGGGG ACTGGAGATGGCCAGTTACTTAAGGTTATTCTTGGTGAGAATTTGACTTCAAATTGTCCAGAGGTTATCTATGAAATTAAAGAA GAGACACCTGTTTTCTACAAACTCGTTCCTGATCCTGTGAAGAATATCTACATTTATCTAACAGCTGGGAAAGAGGTGAGGAGA ATTCGTGTTGCAAACTGCAATAAACATAAATCCTGTTCGGAGTGTTTAACAGCCACAGACCCTCACTGCGGTTGGTGCGATTCG CTACAAAGGTGCACTTTTCAAGGAGATTGTGTACATTCAGAGAACTTAGAAAACTGGCTGGATATTTCGTCTGGAGCAAAAAAG TGCCCTAAAATTCAGATAATTCGAAGCAGTAAAGAAAAGACTACAGTGACTATGGTGGGAAGCTTCTCTCCAAGACACTCAAAG TGCATGGTGAAGAATGTGGACTCTAGCAGGGAGCTCTGCCAGAATAAAAGTCAGCCCAACCGGACCTGCACCTGTAGCATCCCA ACCAGAGCAACCTACAAAGATGTTTCAGTTGTCAACGTGATGTTCTCCTTCGGTTCTTGGAATTTATCAGACAGATTCAACTTT ACCAACTGCTCATCATTAAAAGAATGCCCAGCATGCGTAGAAACTGGCTGCGCGTGGTGTAAAAGTGCAAGAAGGTGTATCCAC CCCTTCACAGCTTGCGACCCTTCTGATTATGAGAGAAACCAGGAACAGTGTCCAGTGGCTGTCGAGAAGACATCAGGAGGAGGA AGACCCAAGGAGAACAAGGGGAACAGAACCAACCAGGCTTTACAGGTCTTCTACATTAAGTCCATTGAGCCACAGAAAGTATCG ACATTAGGGAAAAGCAACGTGATAGTAACGGGAGCAAACTTTACCCGGGCATCGAACATCACAATGATCCTGAAAGGAACCAGT ACCTGTGATAAGGATGTGATACAGGTTAGCCATGTGCTAAATGACACCCACATGAAATTCTCTCTTCCATCAAGCCGGAAAGAA ATGAAGGATGTGTGTATCCAGTTTGATGGTGGGAACTGCTCTTCTGTGGGATCCTTATCCTACATTGCTCTGCCACATTGTTCC CTTATATTTCCTGCTACCACCTGGATCAGTGGTGGTCAAAATATAACCATGATGGGCAGAAATTTTGATGTAATTGACAACTTA ATCATTTCACATGAATTAAAAGGAAACATAAATGTCTCTGAATATTGTGTGGCGACTTACTGCGGGTTTTTAGCCCCCAGTTTA AAGAGTTCAAAAGTGCGCACGAATGTCACTGTGAAGCTGAGAGTACAAGACACCTACTTGGATTGTGGAACCCTGCAGTATCGG GAGGACCCCAGATTCACGGGGTATCGGGTGGAATCCGAGGTGGACACAGAACTGGAAGTGAAAATTCAAAAAGAAAATGACAAC TTCAATATTTCCAAAAAAGACATTGAAATTACTCTCTTCCATGGGGAAAATGGGCAATTAAATTGCAGTTTTGAAAATATTACT AGAAATCAAGATCTTACCACCATCCTTTGCAAAATTAAAGGCATCAAGACTGCAAGCACCATTGCCAACTCTTCTAAGAAAGTT CGGGTCAAGCTGGGAAACCTGGAGCTCTACGTCGAGCAGGAGTCAGTTCCTTCCACATGGTATTTTCTGATTGTGCTCCCTGTC TTGCTAGTGATTGTCATTTTTGCGGCCGTGGGGGTGACCAGGCACAAATCGAAGGAGCTGAGTCGCAAACAGAGTCAACAACTA GAATTGCTGGAAAGCGAGCTCCGGAAAGAGATACGTGACGGCTTTGCTGAGCTGCAGATGGATAAATTGGATGTGGTTGATAGT TTTGGAACTGTTCCCTTCCTTGACTACAAACATTTTGCTCTGAGAACTTTCTTCCCTGAGTCAGGTGGCTTCACCCACATCTTC ACTGAAGATATGCATAACAGAGACGCCAACGACAAGAATGAAAGTCTCACAGCTTTGGATGCCCTAATCTGTAATAAAAGCTTT CTTGTTACTGTCATCCACACCCTTGAAAAGCAGAAGAACTTTTCTGTGAAGGACAGGTGTCTGTTTGCCTCCTTCCTAACCATT GCACTGCAAACCAAGCTGGTCTACCTGACCAGCATCCTAGAGGTGCTGACCAGGGACTTGATGGAACAGTGTAGTAACATGCAG CCGAAACTCATGCTGAGACGCACGGAGTCCGTCGTCGAAAAACTCCTCACAAACTGGATGTCCGTCTGCCTTTCTGGATTTCTC CGGGAGACTGTCGGAGAGCCCTTCTATTTGCTGGTGACGACTCTGAACCAGAAAATTAACAAGGGTCCCGTGGATGTAATCACT TGCAAAGCCCTGTACACACTTAATGAAGACTGGCTGTTGTGGCAGGTTCCGGAATTCAGTACTGTGGCATTAAACGTCGTCTTT GAAAAAATCCCGGAAAACGAGAGTGCAGATGTCTGTCGGAATATTTCAGTCAATGTTCTCGACTGTGACACCATTGGCCAAGCC AAAGAAAAGATTTTCCAAGCATTCTTAAGCAAAAATGGCTCTCCTTATGGACTTCAGCTTAATGAAATTGGTCTTGAGCTTCAA ATGGGCACACGACAGAAAGAACTTCTGGACATCGACAGTTCCTCCGTGATTCTTGAAGATGGAATCACCAAGCTAAACACCATT GGCCACTATGAGATATCAAATGGATCCACTATAAAAGTCTTTAAGAAGATAGCAAATTTTACTTCAGATGTGGAGTACTCGGAT GACCACTGCCATTTGATTTTACCAGATTCGGAAGCATTCCAAGATGTGCAAGGAAAGAGACATCGAGGGAAGCACAAGTTCAAA GTAAAAGAAATGTATCTGACAAAGCTGCTGTCGACCAAGGTGGCAATTCATTCTGTGCTTGAAAAACTTTTTAGAAGCATTTGG AGTTTACCCAACAGCAGAGCTCCATTTGCTATAAAATACTTTTTTGACTTTTTGGACGGCCAGGCTGAAAACAAAAAAATCACA GATCCTGACGTCGTACATATTTGGAAAACAAACAGCCTTCCTCTTCGCTTCTGGGTAAACATCCTGAAGAACCCTCAGTTTGTC TTTGACATTAAGAAGACACGACATATAGACGGCTGTTTGTCAGTGATTGCCCAGGCATTCATGGATGCATTTTCTCTCACAGAG CAGCAACTAGGGAAGGAAGCACCAACTAATAAGCTTCTCTATGCCAAGGATATCCCAACCTACAAAGAAGAAGTAAAATCTTAT TACAAAGCAATCAGGGATTTGCCTCCATTGTCATCCTCAGAAATGGAAGAATTTTTAACTCAGGAATCTAAGAAACATGAAAAT GAATTTAATGAAGAAGTGGCCTTGACAGAAATTTACAAATACATCGTAAAATATTTTGATGAGATTCTAAATAAACTAGAAAGA GAACGAGGGCTGGAAGAAGCTCAGAAACAACTCTTGCATGTAAAAGTCTTATTTGATGAAAAGAAGAAATGCAAGTGGATGTAA GCACTCTGGGGCCTGGCTTAATCTGGCAAAGTTCTTCAGACGACTTGGGAGCAAAATGGCTGCTTGAGCTACTCTGTGTCGTTA ATTTGTTGTTTGCACATAGGTTCCACTTTGGGCACTGTCTTTTTAAGAGACCAAGGCACATGCACAGCTTTTAGAAAGCAA 66
ACGCGTCCGAAGACATTAAGTAAAAAATTGGAACTATGATTTTTCTTTGTCATTTTTTAAAAAAGAATTATTTTATTAACCTGC TGGCATATAATCTGGAGTTCTTTTCACAACCTTACTTTTTCTGATTTGCTTTATTGAATGATTGAATACTCATTTCTTTCTAAA AATATGTTGTAAATTCTCCCTTGGCAAGATTTCTCCCTATGAGGGTAGTTATTATTTGAGTCTGCCAAGTGGTTACCATGGGGC AAGGTGCCATGATGTATTCTTGGGTGCATTGGTTTTTTGCGCATTGTAAATTTAAGACACTTATAGTAAGTGGACTCATTCATA GATGAGTTTCAGAACCTTT.TACGTTCTCGGTAGAGGCTTCTGTCGGACAGGCAGAAGAGTGTATTCCTCACTTTTTTTTTTGTC TTCAAATTCCAGTAAGGCATAGCACTTTTAAGAAATTAGAATTTTTCTATCATCTATGCAAATGATATTTATGTTAATATTAAA TATCTTATGTTACACTGGGAGTAATTTGAGGTGCAATTATTTTTATTACTACTTTGAATAGAGGACCATTATCCTTCTTTCTTC AGAAMCTAAGAAGTAAGTGTAACTTTTAAAGTAAGTATATATCAGTGAGAGTAGGCTTGTTTTACAACTATTTCTAGCCAGTG AGTTGTGTTTTCATGTCTCATCAAAAGACAATACCACATTGCATCATTTTACAAAATATGTTGTCATTTTCATTTCAGTTGTAA CATAGGAAAATAGATATTTCCTAGATGATTTCTGAGTTTCTTACTGCAMGMCAGTTATAAATTGGTATACATGTGTCTCTGT AATAGGGATAATATTGATATATCTGTTGCTACATATTTAAGAATCATTCTATCTTATGTTGTCTTGAGGCCAAGATTTACCACG TTTGCCCAGTGTATTGAATTGGTGGTAGAAGGTAGTTCCATGTTCCATTTGTAGATCTTTAAGATTTTATCTTTGATAACTTTA ATAGAATGTGGCTCAGTTCTGGTCCTTCAAGCCTGTATGGTTTGGATTTTCAGTAGGGGACAGTTGATGTGGAGTCAATCTCTT TGGTACACAGGAAGCTTTATAAAATTTCATTCACGAATCTCTTATTTTGGGAAGCTGTTTTGCATATGAGAAGAACACTGTTGA AATAAGGAACTAAAGCTTTATATATTGATCAAGGTGATTCTGAAAGTTTTAΆTTTTTAATGTTGTAATGTTATGTTATTGTTAA TTGTACTTTATTATGTATTCAATAGAAAATCATGATTTATTAATAAAAGCTTAAATTCTCATCTAAAAAAAAAAAAAAAAA
67
MGRGWGFLFGLLGAVWLLSSGHGEEQPPETAAQRCFCQVSGYLDDCTCDVETIDRFMYR FPR QKLLESDYFRYYV RP CPF NDISQCGRRDCAVKPCQSDEVPDGIKSASYKYSEEA LIEECEQAERLGAVDESLSEETQKAVLQ TKHDDSSDNFCEA DDIQSPEAEYVDLLLNPERYTGYKGPDAWKI VIYEENCFKPQTIKRPLNPLASGQGTSEENTFYSWLEGLCVEKRAFYR IS GLHASI VH SARYLLQET EKKWGHNITEFQQRFDGI TEGEGPRRLKNLYF Y IE RA SKV PFFERPDFQ FTGNKIQ- DEENKM L EI HEIKSFPLHFDENSFFAGDKKEAHKLKEDFRLHFRNISRIMDCVGCFKCRLWGKLQTQGLGTALKILFSEKL IAMPESGPSYEFHLTRQEIVSLFNAFGRISTSVKELENFRN QNIH 68
GCACGAGCCCCGGGCTGCCGGCGCGGGCGCCGCGGCACGTCCACAGGCTGGGTCGCGAGGTGGCGATCGCTGAGAGGCAGGAGG GCCGAGGCGGGCCTGGGAGGCGGCCCGGAGGTGGGGCGCCGCTGGGGCCGGCCCGCACGGGCTTCATCTGAGGGCGCACGGCCC GCGACCGAGCGTGCGGACTGGCCTCCCAAGCGTGGGGCGACAAGCTGCCGGAGCTGCAATGGGCCGCGGCTGGGGATTCTTGTT TGGCCTCCTGGGCGCCGTGTGGCTGCTCAGCTCGGGCCACGGAGAGGAGCAGCCCCCGGAGACAGCGGCACAGAGGTGCTTCTG CCAGGTTAGTGGTTACTTGGATGATTGTACCTGTGATGTTGAAACCATTGATAGATTTAATAACTACAGGCTTTTCCCAAGACT ACAAAAACTTCTTGAAAGTGACTACTTTAGGTATTACAAGGTAAACCTGAAGAGGCCGTGTCCTTTCTGGAATGACATCAGCCA GTGTGGAAGAAGGGACTGTGCTGTCAAACCATGTCAATCTGATGAAGTTCCTGATGGAATTAAATCTGCGAGCTACAAGTATTC TGAAGAAGCCAATAATCTCATTGAAGAATGTGAACAAGCTGAACGACTTGGAGCAGTGGATGAATCTCTGAGTGAGGAAACACA GAAGGCTGTTCTTCAGTGGACCAAGCATGATGATTCTTCAGATAACTTCTGTGAAGCTGATGACATTCAGTCCCCTGAAGCTGA ATATGTAGATTTGCTTCTTAATCCTGAGCGCTACACTGGTTACAAGGGACCAGATGCTTGGAAAATATGGAATGTCATCTACGA AGAAAACTGTTTTAAGCCACAGACAATTAAAAGACCTTTAAATCCTTTGGCTTCTGGTCAAGGGACAAGTGAAGAGAACACTTT TTACAGTTGGCTAGAAGGTCTCTGTGTAGAAAAAAGAGCATTCTACAGACTTATATCTGGCCTACATGCAAGCATTAATGTGCA TTTGAGTGCAAGATATCTTTTACAAGAGACCTGGTTAGAAAAGAAATGGGGACACAACATTACAGAATTTCAACAGCGATTTGA TGGAATTTTGACTGAAGGAGAAGGTCCAAGAAGGCTTAAGAACTTGTATTTTCTCTACTTAATAGAACTAAGGGCTTTATCCAA AGTGTTACCATTCTTCGAGCGCCCAGATTTTCAACTCTTTACTGGAAATAAAATTCAGGATGAGGAAAACAAAATGTTACTTCT GGAAATACTTCATGAAATCMGTCATTTCCTTTGCATTTTGATGAGAATTCATTTTTTGCTGGGGATAAAAAAGAAGCACACAA ACTAAAGGAGGACTTTCGACTGCATTTTAGAAATATTTCAAGAATTATGGATTGTGTTGGTTGTTTTAAATGTCGTCTGTGGGG AAAGCTTCAGACTCAGGGTTTGGGCACTGCTCTGAAGATCTTATTTTCTGAGAAATTGATAGCAAATATGCCAGAAAGTGGACC TAGTTATGAATTCCATCTAACCAGACAAGAAATAGTATCATTATTCAACGCATTTGGAAGAATTTCTACAAGTGTGAAAGAATT AGAAAACTTCAGGAACTTGTTACAGAATATTCATTAAAGAAAACAAGCTGATATGTGCCTGTTTCTGGACAATGGAGGCGAAAG AGTGGAATTTCATTCAAAGGCATAATAGCAATGACAGTCTTAAGCCAAACATTTTATATAAAGTTGCTTTTGTAAAGGAGAATT ATATTGTTTTAAGTAAACACATTTTTAAAAATTGTGTTAAGTCTATGTATAATACTACTGTGAGTAAAAGTAATACTTTAATAA TGTGGTACAAATTTTAAAGTTTAATATTGAATAAAAGGAGGATTATCAAATTCATATATGATAAAAGTGAATGTTCTAAGTCTC TCAAACTAGCGTTTTATGTAATAATATGTAATATAAATAAAACTATGGTAAATGTGACAAGCATTTAATAGGAAAATGCTAAGG AGGCCTCATAAATGACCCATAATTACCAACGTAGAATTTTTCAGTACATTTAGGGTTGCTGGATTTAGCAAATAAAAATAAAGA TTGCCCAGTTAGATTTGAATTTCAGATAAACAATTAGTTTTTTAATATTTTACATGGAATATTTGGAAAATACTTATACTAAAA AATTATTTGTTTGAAATTCACATTTAACTGGGAGTCTTGTATTTTATCTGGCAATCCTAAAATACATTGGTATGAAACAAATCA CTTTTAGAAGTATATTGCTATTTTGATTGGGTTGTTTTTGTGTGTAGAAACGTACAATAACAACTGAAAGGCACAGGAGATTTC TAAACATTGTGAAAAGTTGAATAGATTATATATTTATTCTCATAATACTTTCACTAATACTAAATAAAATTTGGGGAACACTTT TTATTTTTATATAATTTCCAATTTACAGAAAAGTTTCAAAAATAGTACAMGAGCTCTCTTACCCAGATTCACTAATTGTTCAT ACGTGCTTTATCTTTCATGCTTTCTCTGTACACACACACACACACACAAATTTTTCCTCAATCATTTGAAAGTCAGTTATAGGC ATCATGCCCCTTAAACCCTAAATACTTCAGTGTGTAATACTGAATAATTACTAAAAATGATTTTCTCAGAAAAAAAAACTCCCA CAATTCTGGAACTATAATACTGTAAGCCTTAGAATAAATAATACTTTCAAGTTCCAATCTAAAGTTCTTTTTGAGTTTTGTTGC CCGTTTTATGCTTGATGTGTATAGTAATAGGGTAGGCTATTTATTTTATTAAAATTTTTTTTAGAGACAAGGTTTTGCTGTGTT GCCCAAGCTGGAACTTGAACGACTGGGCTGAAGTGATCTTCCCACCTCAGCCTCCCAAGTAGCTGGGAATACAGGTGTCTGCCA CCATACCCAGTTTCATTTTTGTTTTTTATACCCGAAGTTCATTTCCTTTGTCTCCCTAAAACTGAACTGTAATTT.TGGGAGGTT TTCATTAGTGGAAGCTCTTCATTTATAAAGCTATTTGAAGGGGTTTAGGAATTTATATCACATGGTAATTGTAGAGAAAAAGAA GCTATATACCTCAAAATCGTGCCCTCTTTACATATGTCTTATCAGGTATAACATGTTGAAATGTCACATTAGTAGTAAAGTGGG GTTTATTTATATAGTGGTTAAGAAATGTCAGTTTACACTGCTGTATACTTCTTCTTCTGTGTCCCTAAGGCCTGGTACAGTGCC AAGCACATACTTGGTATCCAATAAATATTTGTTGGATGAAAAAAAAAAAAAAAAAAAA
70
GGCACGAGGAGATGGCGGCAGCGGCGCTGGGGAGGGCGAGGCGGAGGCGGCAAAACGGGCGGTCGAGCAGAACGTGTAGCCGCG TCCCCTCCAGTCCGCTCCGGGCAGCTGCTGATGCAAGGAATCCCCTGGGCTCCCGTCCACTCCACTGCTGACCAGCCCATTCGC CTGTGCTGAGTCTTCCTGCAGGCCTTTCCTTGCCTCTGTGGGACCCTGTGGGGGTCCATCCGGCTGGAGAAGAAAAGCCTCTCA TGCTAACGTTGCAGACCCCAGAGGGTCCTGTGTGGGTGTGGAGATGGCCAATGAGAATCACGGCAGCCCCCGGGAGGAAGCGTC CCTGCTGAGTCACTCCCCAGGTACCTCCAATCAGAGCCAGCCCTGTTCTCCAAAGCCAATCCGCCTGGTTCAGGACCTCCCAGA GGAGCTGGTGCATGCAGGCTGGGAGAAGTGCTGGAGCCGGAGGGAGAATCGTCCCTACTACTTCAACCGATTCACCAACCAGTC CCTGTGGGAGATGCCCGTGCTGGGGCAGCACGATGTGATTTCGGACCCTTTGGGGCTGAATGCGACCCCACTGCCCCAAGACTC AAGCTTGGTGGAAACTCCCCCGGCTGAGAACAAGCCCAGAAAGCGGCAGCTCTCGGAAGAGCAGCCAAGCGGCAATGGTGTGAA GAAGCCCAAGATTGAAATCCCAGTGACACCCACAGGCCAGTCGGTGCCCAGCTCCCCCAGTATCCCAGGAACCCCAACGCTGAA GATGTGGGGTACGTCCCCTGAAGATAAACAGCAGGCAGCTCTCCTACGACCCACTGAGGTCTACTGGGACCTGGACATCCAGAC CAATGCTGTCATCAAGCACCGGGGGCCTTCAGAGGTGCTGCCCCCGCATCCCGAAGTGGAACTGCTCCGCTCTCAGGTCATCCT GAAGCTTCGGCAGCACTATCGGGAGCTGTGCCAGCAGCGAGAGGGCATTGAGCCTCCACGGGAGTCT.TTCAACCGCTGGATGCT GGAGCGCAAGGTGGTAGACAAAGGATCTGACCCCCTGTTGCCCAGCAACTGTGAACCAGTCGTGTCACCTTCCATGTTTCGTGA AATCATGAACGACATTCCTATCAGGTTATCCCGAATCAAGTTCCGGGAGGAAGCCAAGCGCCTGCTCTTTAAATATGCGGAGGC CGCCAGGCGGCTCATCGAGTCCAGGAGTGCATCCCCTGACAGTAGGAAGGTGGTCAAATGGAATGTGGAAGACACCTTTAGCTG GCTTCGGAAGGACCACTCAGCCTCCAAGGAGGACTACATGGATCGCCTGGAGCATCTGCGGAGGCAGTGTGGCCCCCACGTCTC GGCCGCAGCCAAGGACTCCGTGGAAGGCATCTGCAGTAAGATCTACCACATCTCCCTGGAGTACGTCAAACGGATCCGAGAGAA 'GCACCTTGCCATCCTCAAGGAAAACAACATCTCAGAGGAGGTGGAGGCCCCTGAGGTGGAGCCCCGCCTAGTGTACTGCTACCC AGTCCGGCTGGCTGTGTCTGCACCGCCCATGCCCAGCGTGGAGATGCACATGGAGAACAACGTGGTCTGCATCCGGTATAAGGG AGAGATGGTCAAGGTCAGCCGCAACTACTTCAGCAAGCTGTGGCTCCTTTACCGCTACAGCTGCATTGATGACTCTGCCTTTGA GAGGTTCCTGCCCCGGGTCTGGTGTCTTCTCCGACGGTACCAGATGATGTTCGGCGTGGGCCTCTACGAGGGGACTGGCCTGCA GGGATCGCTGCCTGTGCATGTCTTTGAGGCCCTCCACCGACTCTTTGGCGTCAGCTTCGAGTGCTTCGCCTCACCCCTCAACTG CTACTTCCGCCAGTACTGTTCTGCCTTCCCCGACACAGACGGCTACTTTGGCTCCCGCGGGCCCTGCCTAGACTTTGCTCCACT GAGTGGTTCATTTGAGGCCAACCCTCCCTTCTGCGAGGAGCTCATGGATGCCATGGTCTCTCACTTTGAGAGACTGCTTGAGAG CTCACCGGAGCCCCTGTCCTTCATCGTGTTCATCCCTGAGTGGCGGGAACCCCCAACACCAGCGCTCACCCGCATGGAGCAGAG CCGCTTCAAACGCCACCAGTTGATCCTGCCTGCCTTTGAGCATGAGTACCGCAGTGGCTCCCAGCACATCTGCAAGAAGGAGGA AATGCACTACAAGGCCGTCCACAACACGGCTGTGCTCTTCCTACAGAACGACCCTGGCTTTGCCAAGTGGGCGCCGACGCCTGA ACGGCTGCAGGAGCTGAGTGCTGCCTACCGGCAGTCAGGCCGCAGCCACAGCTCTGGTTCTTCCTCATCGTCCTCCTCGGAGGC CAAGGACCGGGACTCGGGCCGTGAGCAGGGTCCTAGCCGCGAGCCTCACCCCACTTAACATATCCTGCGGGGAGGAGGAGCCCC AGGGGTGCTAGTCTGGACTGCTGGGACTCGGGCCCCTGGGGCCTCAGAGGGACCCCGGCTGCCACTGACATATGAAGATTATGG TTCTGCCAGGGCTCCCCTCCCTGCCTGTCCCCAAGTCCTCACCTCAAACTCCCTCCAAGTCCCATGTATATAGGTCCTGATGCC TTCCCAACCCCGCCCCTCACCCTGTTGCCACCTTGTTTCATTTGTAAAAGGAAATACAGAAACCCCCCCAAAAAAAAAAAAAAA AAAAAAAAAAAA 72 TATCATGCATGTGGGAAGGTGGGTGTGGTGAGAAAAGTTTTAAGGCAAGAGTAGATGGCCATGTTCAACTTTACAAAATTTCTT GGAAAACTGGCAGTATTTTGAACTGCATCTTCTTTGGTACCGGAACCTGCAGAAACAGTGTGAGAAATTAAGTCCTGGTTCACT GCGCAGTAGCAAAGATGGTCAAGGCCATGGAAAAAGCAGAAATTTACCAAGAAAGCTGATACCCATGTATAGTTCCCACTCATC TCAAATACATCTGCTATCTTTTTAAGCTAAGTCCTAGACATATCGGGGATAACATGGGGGTTGATTAGTGACCACAGTTATCAG AAGCAGAGAAATGTAATTCCATATTTTATTTGAAACTTATTCCATATTTTAATTGGATATTGAGTGATTGGGTTATCAAACACC CACAAACTTTAATTTTGTTAAATTTATATGGCTTTGAAATAGAAGTATAAGTTGCTACCATTTTTTGATAACATTGAAAGATAG TATTTTACCATCTTTAATCATCTTGGAAAATACAAGTCCTGTGAACAACCACTCTTTCACCTAGCAGCATGAGGCCAAAAGTAA AGGCTTTAAATTATAACATATGGGATTCTTAGTAGTATGTTTTTTTCTTGAAACTCAGTGGCTCTATCTAACCTTACTATCTCC TCACTCTTTCTCTAAGACTAAACTCTAGGCTCTTAAAAATCTGCCCACACCAATCTTAGAAGCTCTGAAAAGAATTTGTCTTTA AATATCTTTTAATAGTAACATGTATTTTATGGACCAAATTGACATTTTCGACTATTTTTTCCAAAAAAGTCAGGTGAATTTCAG CACACTGAGTTGGGAATTTCTTATCCCAGAAGACCAACCAATTTCATATTTATTTAAGATTGATTCCATACTCCGTTTTCAAGG AGAATCCCTGCAGTCTCCTTAAAGGTAGAACAAATACTTTCTATTTTTTTTTTCACCATTGTGGGATTGGACTTTAAGAGGTGA CTCTAAAAAAACAGAGAACAAATATGTCTCAGTTGTATTAAGCACGGACCCATATTATCATATTCACTTAAAAAAATGATTTCC TGTGCACCTTTTGGCAACTTCTCTTTTCAATGTAGGGAAAAACTTAGTCACCCTGAAAACCCACAAAATAAATAAAACTTGTAG ATGTGGGCAGAAGGTTTGGGGGTGGACATTGTATGTGTTTAAATTAAACCCTGTATCACTGAGAAGCTGTTGTATGGGTCAGAG
AAAATGAATGCTTAGAAGCTGTTCACATCTTCAAGAGCAGAAGCAAACCACATGTCTCAGCTATATTATTATTTATTTTTTATG
CATAAAGTGAATCATTTCTTCTGTATTAATTTCCAAAGGGTTTTACCCTCTATTTAAATGCTTTGAAAAACAGTGCATTGACAA
TGGGTTGATATTTTTCTTTAAAAGAAAAATATAATTATGAAAGCCAAGATAATCTGAAGCCTGTTTTATTTTAAAACTTTTTAT
• GTTCTGTGGTTGATGTTGTTTGTTTGTTTGTTTCTATTTTGTTGGTTTTTTACTTTGTTTTTTGTTTTGTTTTGTTTTGTTTTG CATACTACATGCAGTTCTTTAACCAATGTCTGTTTGGCTAATGTAATTAAAGTTGTTAATTTATATGAGTGCATTTCAACTATG TCAATGGTTTCTTAATATTTATTGTGTAGAAGTACTGGTAATTTTTTTATTTACAATATGTTTAAAGAGATAACAGTTTGATAT GTTTTCATGTGTTTATAGCAGAAGTTATTTATTTCTATGGCATTCCAGCGGATATTTTGGTGTTTGCGAGGCATGCAGTCAATA TTTTGTACAGTTAGTGGACAGTATTCAGCAACGCCTGATAGCTTCTTTGGCCTTATGTTAAATAAAAAGACCTGTTTGGGATGT
73 MREIVHIQAGQCGNQIGAKF EVISDEHGIDPSGNYVGDSDLQLERISVYYWEASSHKYVPRAILVDLEPGTMDSVRSGAFGHL FRPDNFIFGQSGAG MAKGHYTEGAE VDSVLDVVRKECENCDCLQGFQLTHSLGGGTGSG GTL ISKVREEYPDRIMTFS WPSPKVSDTWEPYNATLSIHQLVEWTDETYCIDNEALYDICFRTLKLATPTYGDL HLVSATMSGVTTSLRFPGQLNADLRK LAVMVPFPRLHFFMPGFAPLTRRGSQQYRALTVPELTQQ FDAKMMAACDPRHGRYLTVATVFRGRMSMKEVDEQ LAiQSK NSSYFVEWIP 1WKVAVCDIPPRGLK SSTFIGNSTAIQELFKR1SEQFTMFRR-AFLHMTGEGMDEMEFTEAES MDLVS EYQQYQDATAEEEGEMYEDDEEESEAQGPK
74
ATGCGGGAGATCGTGCACATCCAGGCCGGCCAGTGCGGCAACCAGATCGGGGCCAAGTTCTGGGAAGTCATCAGTGATGAGCAT GGCATCGACCCCAGCGGCAACTACGTGGGCGACTCGGACTTGCAGCTGGAGCGGATCAGCGTCTACTACAACGAGGCCTCTTCT CACAAGTACGTGCCTCGAGCCATTCTGGTGGACCTGGAACCCGGAACCATGGACAGTGTCCGCTCAGGGGCCTTTGGACATCTC TTCAGGCCTGACAATTTCATCTTTGGTCAGAGTGGGGCCGGCAACAACTGGGCCAAGGGTCACTACACGGAGGGGGCGGAGCTG GTGGATTCGGTCCTGGATGTGGTGCGGAAGGAGTGTGAAAACTGCGACTGCCTGCAGGGCTTCCAGCTGACCCACTCGCTGGGG GGGGGGACGGGCTCCGGCATGGGCACGTTGCTCATCAGCAAGGTGCGTGAGGAGTATCCCGACCGCATCATGAACACCTTCAGC GTCGTGCC.CTCACCCAAGGTGTCAGACACGGTGGTGGAACCCTACAACGCCACGCTGTCCATCCACCAGCTGGTGGAAAACACG GATGAAACCTACTGCATCGACAACGAGGCGCTCTACGACATCTGCTTCCGCACCCTCAAGCTGGCCACGCCCACCTACGGGGAC CTCAACCACCTGGTATCGGCCACCATGAGCGGAGTCACCACCTCCTTGCGCTTCCCGGGCCAGCTCAACGCTGACCTGCGCAAG CTGGCCGTCAACATGGTGCCCTTCCCGCGCCTGCACTTCTTCATGCCCGGCTTCGCCCCCCTCACCAGGCGGGGCAGCCAGCAG TACCGGGCCCTGACCGTGCCCGAGCTCACCCAGCAGATGTTCGATGCCAAGAACATGATGGCCGCCTGCGACCCGCGCCACGGC CGCTACCTGACGGTGGCCACCGTGTTCCGGGGCCGCATGTCCATGAAGGAGGTGGACGAGCAGATGCTGGCCATCCAGAGCAAG AACAGCAGCTACTTCGTGGAGTGGATCCCCAACAACGTGAAGGTGGCCGTGTGTGACATCCCGCCCCGCGGCCTCAAGATGTCC TCCACCTTCATCGGGAACAGCACGGCCATCCAGGAGCTGTTCAAGCGCATCTCCGAGCAGTTCACGGCCATGTTCCGGCGCAAG GCCTTCCTGCAGTGGTACACGGGCGAGGGCATGGACGAGATGGAGTTCACCGAGGCCGAGAGCAACATGAACGACCTGGTGTCC GAGTACCAGCAGTACCAGGACGCCACGGCCGAGGAAGAGGGCGAGATGTACGAAGACGACGAGGAGGAGTCGGAGGCCCAGGGC CCCAAGTGAAACTGCTCGCAGCTGGAGTGAGAGGCAGGTGGCGGCCGGGGCCGAAGCCAGCAGTGTCTAAACCCCCGGAGCCAT CTTGCTGCCGACACCCTGCTTTCCCCATCGCCCTAGGGCTCCCTTGCCGCCCTCCTGCAGTATTTATGGCCTCGTCCTCCCCCA CCTAGGCCACGTGTGAGCTGCTCCTGTCTCTGTCTTATTGCAGCTCCAGGCCTGACGTTTTACGGTTTTGTTTTTTACTGGTTT GTGTTTATATTTTCGGGGATACTTAATAAATCTATTGCTGTCAGATACCCTT
75
MAEGETESPGPKKCGPYISSVTSQSVNLMIRGWLFFIGVFLALVLN LQIQRNVTLFPPD¥IASIFSSA VPPCCGTASAVI GLLYPCIDRH GEPHKFKRE SSVMRCVAVFVGINHASAKVDFDNNIQLS TLAALSIGL TFDRSRSGFGLGVGIAFLATW TQLLVYNGVYQYTSPDFLYVRSW PCIFFAGGITMGNIGRQLAMYECKVIAENLIRNEEGKKY LYRRAR
76
ACTCACTATAGGGCTCGAGCGGCCGCCCGGGCAGGTGGGATTTCGGGTAGGTCCTACTTTAGGACAAGATGTGGTACCGTTGAA GCGTCAGTCTTTGATTCACAGACAGTTGAGCTTTTCAGCTGGGAAGCCTTTCCATTTTTTTTTTTTTAACGGCTTTCTGAACCT. ATGAAACCATGGCAGAAGGAGAGACAGAGTCACCTGGGCCCAAAAAGTGTGGCCCATATATTTCATCTGTCACTAGCCAGAGTG TGAACTTGATGATTCGAGGAGTAGTGCTATTTTTTATTGGAGTATTTCTTGCATTAGTGTTAAATTTACTTCAGATTCAGAGAA ATGTGACGCTCTTTCCACCTGATGTGATTGCAAGCATCTTTTCTTCTGCATGGTGGGTACCCCCATGCTGTGGCACGGCTTCAG CTGTGATTGGGTTATTATACCCCTGCATTGACAGACATCTAGGAGAACCACATAAATTTAAAAGAGAGTGGTCCAGTGTAATGC GGTGTGTAGCAGTCTTTGTTGGTATAAATCATGCCAGTGCTAAAGTGGATTTCGATAAGAACATACAGTTGTCTCTCACACTGG CTGCACTATCCATTGGACTGTGGTGGACTTTTGATAGATCTAGAAGTGGTTTTGGCCTTGGAGTAGGAATTGCCTTCTTGGCAA CTGTGGTCACTCAACTGCTAGTATATAATGGTGTTTACCAATATACATCTCCAGATTTCCTCTATGTTCGTTCTTGGTTACCAT GTATATTTTTTGCTGGAGGCATAACAATGGGAAACATTGGTCGACAACTGGCAATGTACGAATGTAAAGTTATCGCAGAAAATC TCATCAGGAATGAAGAAGGCAAAAAATATCTTTTGTACAGAAAAGCAAGATGAAAAGGATGTGAAATGGTAGATATACCAACAA AACTTCAGACTGTAAAATTGCCAGGATGCAGTTTTCCCCTTGAATGGCGTGTGTGTATATATGGATAAATATATATATACACAC ACACATATTACTGCAATCTGTGATTGCTTCATCTGTAAATCAGTTGTAAACCTTTACATATTTGACTTAAATAACTGTAAGATA TATATGTACTACATTAAAAAGTGTTGATTAATAGATGAAATTTTTAAATTAATTTTTTAAAACATGCCATACATTGTATCACAA TGTTAATGTGCCAAGATATTGTTCCTGTCATGCAGAGTATAAGAATGCTTTGAACAATTTGTAGGACTTAGTGGAAATAAAATA AGAGGGAAAGGCCAAAAACAAACAAACAAAAGGCATATGGGGAGCTGGGTATTTTCTCTTTAGGCTTACTGTTGTGGCCTTTTT ATTTTTCCTAATCCACGCCGGTATGGGGTTTGGGGGGCCCCAATTGTTGG 77 ASKLLRAVILGPPGSGKGTVCQRIAQNFG QHLSSGHFLRENIKASTEVGEMAKQYIEKSL VPDHVITRMMSELENRRGQH WL DGFPRTLGQAEALDKICEVDLVISLNIPFET KDRLSRRWIHPPSGRVY LDFNPPHVHGIDDVTGEPLVQQEDDKPEAVA ARLRQYKDVAKPVIELYKSRGV HQFSGTETNKIWPYVYTLFSNKITPIQSKEAY
78 CGGCGCTGGGCTGAGGGGAGGGGTTGTCTTAAAAGTCTCTCCTTCCCCCTGTAGGGGCGGCCGGCGAGTCCCAGTGAGAGCGGA GGGTGCCAGAGGTAGGGGGCCGAGAAACAAAGTTCCCGGGGCTTCCTCCGGGGCCGCGGTCGGGGCTGCGCGTTTGACCGCCCC CCTCCTCGCGAAGCAATGGCTTCCAAACTCCTGCGCGCGGTCATCCTCGGGCCGCCCGGCTCGGGCAAGGGCACCGTGTGCCAG AGGATCGCCCAGAACTTTGGTCTCCAGCATCTCTCCAGCGGCCACTTCTTGCGGGAGAACATCAAGGCCAGCACCGAAGTTGGT GAGATGGCAAAGCAGTATATAGAGAAAAGTCTTTTGGTTCCAGACCATGTGATCACACGCCTAATGATGTCCGAGTTGGAGAAC AGGCGTGGACAGCACTGGCTCCTTGATGGTTTTCCTAGGACATTAGGACAAGCCGAAGCCCTGGACAAAATCTGTGAAGTGGAT CTAGTGATCAGTTTGAATATTCCATTTGAAACACTTAAAGATCGTCTCAGCCGCCGTTGGATTCACCCTCCTAGCGGAAGGGTA TATAACCTGGACTTCAATCCACCTCATGTACATGGTATTGATGACGTCACTGGTGAACCGTTAGTCCAGCAGGAGGATGATAAA CCCGAAGCAGTTGCTGCCAGGCTAAGACAGTACAAAGACGTGGCAAAGCCAGTCATTGAATTATACAAGAGCCGAGGAGTGCTC CACCAATTTTCCGGAACGGAGACGAACAAAATCTGGCCCTACGTTTACACACTTTTCTCAAACAAGATCACACCTATTCAGTCC AAAGAAGCATATTGACCCTGCCCAATGGAAGAACCAGGAAGATGTGGTCATTCATTCAATAGTGTGTGTAGTATTGGTGCTGTG TCCAAATTAGAAGCTAGCTGAGGTAGCTTGCAGCATCTTTTCTAGTTGAAATGGTGAACTGATAGGAAAACAAATGAGTAGAAA GAGTTCATGAAGAGGCCCTCCTCTGCCTTTCAAAAGGCTGGTCACCTACACATGTTTAAGGTGTCTCTGCACATGTCTCAAGCC CATCACAAGAAAGCAAGTACAGTGTGGATTTCAAATGGTGTGTAACTTCAGCTCCAGCTGGTTTTTGACAGCTGTTGCTGTGGT AATATTTTTGACATGTGATGGTGATAGTCTCTGGTTCTCCCCATCCCCACAAAGGCTGTTGAACCACAGCACCAGGAAGCCTGA GAATGAATCCTGAGGGCTCTAGCCCAGGCTTTGTCCCAGGCTTTCTGGTGTGTGCCCTCCTGGTAACAGTGAAATTGAAGCTAC' TTACTCATAGTGGTTGTTTCTCTGGTCTTGAGTGACTGTGTCCACAGTTCATTTTTTTCCGGTAGGAATAACTCCTTTTCTACA TCCACGCTCCATAGAGTCTCTCCTTTTCAGACATCCTGGGATGAAAGAATTTGGCTTTTTTTTTTCTTTTTTTTTTGGACATCT GTTTTCACTCTTAGGCTTTTAAACAATAGTTATTGCTTTTATCCCTCTCAGATTCTAATAACTGAGAGCGATGGGGCTATATTG AATCTCTGTATGCACTGAGAACTGAGCTATGAAGAGAATCTTATTAAACTGCTGGTCTGACTTTATGGATTGACACTGTTCCTT TCTTTTATTGTGAAAAAAAAAAAAAAA
79
MGSVAASAGVPRGCDILIVYSPDAEEWCQYLQTLF SSRQVRSQKILTHRLGPEASFSAED SLFLSTRC VL SAE VQHFH KPS P QRAFHPPHRWR CGVRDSEEF DFFPDWAHWQE TCDDEPETYVAAVKKAISEDSGCDSVTDTEPEDEKWSYS
• KQQNLPTVTSPGN IWVQPDRIRCGAETTVYVIVRCKLDDRVGTEAEFSPEDSPSVRMEAKVENEYTISVKAPHLSSGNVSLKI
YSGDLWCETVISYYTDMEEIGNL SNA PVEFMCQAFKIVPY TETLDKLLTESLKN IPASGLH FGINQLEEEDMMTNQR
DEELPTLLHFAAKYGLKNLTALLLTCPGA QAYSVA KHGHYPNTIAEKHGFRDLRQFIDEYVETVDMLKSHIKEELMHGEEAD
AWES HLSTDLLMKCSLNPGCDEDLYESMAAFVPAATEELYVEMLQASTSNPIPGDGFSRATKDSMIRKFLEGNSMGMTNLE RDQCHLGQEEDVYHTVDDDEAFSVDLASRPPVPVPRPETTAPGAHQLPDNEPYIFKVFAEKSQERPGNFYVSSESIRKGPPVRP
WRDRPQSSIYDPFAGMKTPGQRQLITLQEQV LGIVNVDEAVLHFKEWQLNQKRRSESFRFQQENLKRLRDSITRRQREKQKSG
KQTD EITVPIRHSQH PA VEFGVYESGPRKSVIPPRTE RRGDWKTDSTSSTASSTSNRSSTRSL SVSSGMEGDNEDNEVP
EVTRSRSPGPPQVDGTPTMS ERPPRVPPRAASQRPPTRETFHPPPPVPPRGR •
80 AGACCCCCCAGGGTGCCTCCGAGAGCTGCCTCACAGAGGACTCCGACCAGGGAGACCTTCCATCCTCCTCCACCTGTTCCACCC AGAGGACGCTGATTCCACCTCCTAAAACCTGCCTACTTCAGGACTTTAAGACTCACAGTCTTCAGCCTGTTAATGATGTCTTCA TGTTGAGTTTTATAGCATGACTGTTGACCTTAAGATCCATTCTCATTGCTGATAATGCTGCAGCCCTGCTGGTTTGGGCTTGCT CGAAGATTTTATTAAGGCACGAAGAAGTGAAAAACTAAGGGCTTCATTCACCATCACCAAGTATATCGAACCATATACTTGTTT GCCAAAAGGGTGGAAGGACTTTAATTCGGAAATACTTTACCTCTTAATTTGGCCATATTCAGGAGGCCTAAAAGGATTGATCCN TAATGTTATTTCACCGTGGTTTTTATTGAATGG
82
TTTGTGTGGTCTTTTTTTTTTTTTCTCAGTGTTTTCAATTCCTCCTTGGTTGAATCCATGGATGCAAAACCCACAGATATGAAG GGCTGGCTATATATGCATTGATGATTGTCCTATTATATTAGTTATAAAGTGTCATTTAATATGTAGTGAAAGTTATGGTACAGT GGAAAGAGTAGTTGAAAACATAAACATTTGGGCCTTTCAAGAAAGGTAGCTTGGTGAAGTTTTTCACCTTCAAACTATGTCCCA GTCAGGG
84
GCTTGAGATCTCCAGCCTTACCGCGGCTCGAAATGGCCCCAACTGCTCCTGCACCACTGGTGTCTCCTGCANCTGCACCGGCTC CTGCAAGTGCAAAGAGTGCAAATGACCTCCTGCAAGAAGAGCTGCTGMCTGCTGCCCCGTGGTGTGCAAGTGTGCCACGGTGT GTCTGCAAAGGGACGTTGGAGAACTGCAGCTGCTGTNCTGATGTGGGAACAAGCTCTTCTCCCAGATGTTAATAGAACAAGCTG CACAACCTGGGATTTTTTTTCAATACGATACTTGAGCCATTTTCTGCATTTCTTTTTATTGTTAAATATGTGAGTGACAATAAA ACAATTTTGACTTTGAATCTTAAAAA
85
MPLGHIMRLD EKIALEYIVPC HEVGFCY DNFLGEWGDCVLERV QLHCTGALRDGQLAGPRAGVS RHLRGDQIT IGGN EEGCEAISFLLSLIDR VLYCGSR GKYYV ERSKAMVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNK WDAK HGGILRIF PEGKSFIADVEP1FDRLLFF SDRR PHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED-
86
GAGTCTGGCCGCAGTCGCGGCAGTGGTGGCTTCCCATCCCCAAAAGGCGCCCTCCGACTCCTTGCGCCGCACTGCTCGCCGGGC CAGTCCGGAAACGGGTCGTGGAGCTCCGCACCACTCCCGCTGGTTCCCGAAGGCAGATCCCTTCTCCCGAGAGTTGCGAGAAAC TTTCCCTTGTCCCCGACGCTGCAGCGGCTCGGGTACCGTGGCAGCCGCAGGTTTCTGAACCCCGGGCCACGCTCCCCGCGCCTC GGCTTCGCGCTCGTGTAGATCGTTCCCTCTCTGGTTGCACGCTGGGGATCCCGGACCTCGATTCTGCGGGCGAGATGCCCCTGG GACACATCATGAGGCTGGACCTGGAGAAAATTGCCCTGGAGTACATCGTGCCCTGTCTGCACGAGGTGGGCTTCTGCTACCTGG ACAACTTCCTGGGCGAGGTGGTGGGCGACTGCGTCCTGGAGCGCGTCAAGCAGCTGCACTGCACCGGGGCCCTGCGGGACGGCC AGCTGGCGGGGCCGCGCGCCGGCGTCTCCAAGCGACACCTGCGGGGCGACCAGATCACGTGGATCGGGGGCAACGAGGAGGGCT GCGAGGCCATCAGCTTCCTCCTGTCCCTCATCGACAGGCTGGTCCTCTACTGCGGGAGCCGGCTGGGCAAATACTACGTCAAGG AGAGGTCTAAGGCAATGGTGGCTTGCTATCCGGGAAATGGAACAGGTTATGTTCGCCACGTGGACAACCCCAACGGTGATGGTC GCTGCATCACCTGCATCTACTATCTGAACAAGAATTGGGATGCCAAGCTACATGGTGGGATCCTGCGGATATTTCCAGAGGGGA AATCATTCATAGCAGATGTGGAGCCCATTTTTGACAGACTCCTGTTCTTCTGGTCAGATCGTAGGAACCCACACGAAGTGCAGC CCTCTTACGCAACCAGATATGCTATGACTGTCTGGTACTTTGATGCTGAAGAAAGGGCAGAAGCCAAAAAGAAATTCAGGAATT TAACTAGGAAAACTGAATCTGCCCTCACTGAAGACTGACCGTGCTCTGAAATCTGCTGGCCTTGTTCATTTTAGTAACGGTTCC TGAATTCTCTTAAATTCTTTGAGATCCAAAGATGGCCTCTTCAGTGACAACAATCTCCCTGCTACTTCTTGCATCCTTCACATC CCTGTCTTGTGTGTGGTACTTCATGTTTTCTTGCCAAGACTGTGTTGATCTTCAGATACTCTCTTTGCCAGATGAAGTTATTTG CTAACTCCAGAAATTCCTGCAGACATCCTACTCGGCCAGCGGTTTACCTGATAGATTCGGTAATACTATCAAGAGAAGAGCCTA GGAGCACAGCGAGGGAATGAACCTTACTTGCACTTTATGTATACTTCCTGATTTGAAAGGAGGAGGTTTGAAAAGAAAAAAATG GAGGTGGTAGATGCCACAGAGAGGCATCACGGAAGCCTTAACAGCAGGAAACAGAGAAATTTGTGTCATCTGAACAATTTCCAG ATGTTCTTAATCCAGGGCTGTTGGGGTTTCTGGAGAATTATCACAACCTAATGACATTAATACCTCTAGAAAGGGCTGCTGTCA TAGTGAACAATTTATAAGTGTCCCATGGGGCAGACACTCCTTTTTTCCCAGTCCTGCAACCTGGATTTTCTGCCTCAGCTCCAT TTTGCTGAAMTAATGACTTTCTGAATAAAGATGGCAACACMTTTTTTCTCCATTTTCAGTTCTTACCTGGG CCTAATTCC CCAGAAGCTAAAAAACTAGACATTAGTTGTTTTGGTTGCTTTGTTGGAATGGAATTTAAATTTAAATGAAAGGAAAMTATATC CCTGGTAGTTTTGTGTTAACCACTGATAACTGTGGAAAGAGCTAGGTCTACTGATATACAATAAACATGTGTGCATCTTGAACA ATTTGAGAGGGGAGGTGGAGTTGGAAATGTGGGTGTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTAGTTTTCCTTTTTAAT GAGCTCACCCTTTAACACAAAAAAAGCAGGGTGATGTATTTTAAAAAAGGAAGTGGAAATAAAAAAATCTCAAAGCTATTTGAG TTCTCGTCTGTCCCTAGCAGTCTTTCTTCAGCTCACTTGGCTCTCTAGATCCACTGTGGTTGGCAGTATGACCAGAATCATGGA ACTTGCTAGAACTGTGGAAGCTTCTACTCCTGCAGTAAGCACAGATCGCACTGCCTCAATAACTTGGTATTGAGCACGTATTTT GCAAAAGCTACTTTTCCTAGTTTTCAGTATTACTTTCATGTTTTAAAAATCCCTTTAATTTCTTGCTTGAAAATCCCATGAACA TTAAAGAGCCAGAAATATTTTCCTTTGTTATGTACGGATATATATATATATATAGTCTTCCAAGATAGAAGTTTACTTTTTCCT CTTCTGGTTTTGGAAAATTTCCAGATAAGACATGTCACCATTAATTCTCAACGACTGCTCTATTTTGTTGTACGGTAATAGTTA TCACCTTCTAAATTACTATGTAATTTACTCACTTATTATGTTTATTGTCTTGTATCCTTTCTCTGGAGTGTAAGCACAATGAAG ACAGGAATTTTGTATATTTTTAACCAATGCAACATACTCTCAGCACCTAAAATAGTGCCGGGAACATAGTAAGGGCTCAGTAAA TACTTGTTG TAMCTCAGTCTCCTACATTAGCATTCTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAG
87 MERRRLWGSIQSRYIS SWTSPRRLVELAGQSLLKDEALAIMLE LPRELFPPLFMAAFDGRHSQTLAMVQA PFTCLPLG VLMKGQHLH ETFKAVDG DVLAQEVRPRRWKLQVLDLRKNSHQDF TV SGNRASLYSFPEPEAAQPMTKKRKVDGLSTEA EQPF1PVEVVDLFLKEGACDELFSYLIEKVKRKK1WLRLCCKKLKIFAMPMQDIKMILKMVQLDSIEDLEVTCTWKLPTLAKF SPYLGQMINLRRLLLSHIHASSYISPEKEEQYIAQFTSQFLSLQCLQALYVDSLFFLRGRLDQLLRHVMNPLETLSITNCRLSE GDVMHLSQSPSVSQLSVLSLSGVMLTDVSPEPLQALLERASATLQDLVFDECGITDDQLLALLPS SHCSQLTTLSFYGNSISI SALQS LQHLIG SNLTHVLYPVP ESYEDIHGTLH ERAYLHAR RE CELGRPSMVW SANPCPHCGDRTFYDPEPI CP CFMPN • * •
GCTTCAGGGTACAGCTCCCCCGCAGCCAGAAGCCGGGCCTGCAGCCCCTCAGCACCGCTCCGGGACACCCCACCCGCTTCCCAG GCGTGACCTGTCAACAGCAACTTCGCGGTGTGGTGAACTCTCTGAGGAAAAACCATTTTGATTATTACTCTCAGACGTGCGTGG CMCMGTGACTGAGACCTAGAMTCCAAGCGTTGGAGGTCCTGAGGCCAGCCTMGTCGCTTCAAAATGGAACGAAGGCGTTT GTGGGGTTCCATTCAGAGCCGATACATCAGCATGAGTGTGTGGACAAGCCCACGGAGACTTGTGGAGCTGGCAGGGCAGAGCCT GCTGAAGGATGAGGCCCTGGCCATTGCCGCCCTGGAGTTGCTGCCCAGGGAGCTCTTCCCGCCACTCTTCATGGCAGCCTTTGA CGGGAGACACAGCCAGACCCTGAAGGCAATGGTGCAGGCCTGGCCCTTCACCTGCCTCCCTCTGGGAGTGCTGATGAAGGGACA ACATCTTCACCTGGAGACCTTCAAAGCTGTGCTTGATGGACTTGATGTGCTCCTTGCCCAGGAGGTTCGCCCCAGGAGGTGGAA ACTTCAAGTGCTGGATTTACGGAAGAACTCTCATCAGGACTTCTGGACTGTATGGTCTGGAAACAGGGCCAGTCTGTACTCATT TCCAGAGCCAGAAGCAGCTCAGCCCATGACAAAGAAGCGAAAAGTAGATGGTTTGAGCACAGAGGCAGAGCAGCCCTTCATTCC AGTAGAGGTGCTCGTAGACCTGTTCCTCAAGGAAGGTGCCTGTGATGAATTGTTCTCCTACCTCATTGAGAAAGTGAAGCGAAA GAAAAATGTACTACGCCTGTGCTGTAAGAAGCTGAAGATTTTTGCAATGCCCATGCAGGATATCAAGATGATCCTGAAAATGGT GCAGCTGGACTCTATTGAAGATTTGGAAGTGACTTGTACCTGGAAGCTACCCACCTTGGCGAAATTTTCTCCTTACCTGGGCCA GATGATTAATCTGCGTAGACTCCTCCTCTCCCACATCCATGCATCTTCCTACATTTCCCCGGAGAAGGAAGAGCAGTATATCGC CCAGTTCACCTCTCAGTTCCTCAGTCTGCAGTGCCTGCAGGCTCTCTATGTGGACTCTTTATTTTTCCTTAGAGGCCGCCTGGA TCAGTTGCTCAGGCACGTGATGAACCCCTTGGAAACCCTCTCAATAACTAACTGCCGGCTTTCGGAAGGGGATGTGATGCATCT GTCCCAGAGTCCCAGCGTCAGTCAGCTAAGTGTCCTGAGTCTAAGTGGGGTCATGCTGACCGATGTAAGTCCCGAGCCCCTCCA AGCTCTGCTGGAGAGAGCCTCTGCCACCCTCCAGGACCTGGTCTTTGATGAGTGTGGGATCACGGATGATCAGCTCCTTGCCCT CCTGCCTTCCCTGAGCCACTGCTCCCAGCTTACAACCTTAAGCTTCTACGGGAATTCCATCTCCATATCTGCCTTGCAGAGTCT CCTGCAGGACCTCATCGGGCTGAGCAATCTGACCCACGTGCTGTATCCTGTCCCCCTGGAGAGTTATGAGGACATCCATGGTAC CCTCCACCTGGAGAGGCTTGCCTATCTGCATGCCAGGCTCAGGGAGTTGCTGTGTGAGTTGGGGCGGCCCAGCATGGTCTGGCT TAGTGCCAACCCCTGTCCTCACTGTGGGGACAGAACCTTCTATGACCCGGAGCCCATCCTGTGCCCCTGTTTCATGCCTAACTA GCTGGGTGCACATATCAAATGCTTCATTCTGCATACTTGGACACTAAAGCCAGGATGTGCATGCATCTTGAAGCAACAAAGCAG CCACAGTTTCAGACAAATGTTCAGTGTGAGTGAGGAAAACATGTTCAGTGAGGAAAAAACATTCAGACAAATGTTCAGTGAGGA AAAAAAGGGGAAGTTGGGGATAGGCAGATGTTGACTTGAGGAGTTAATGTGATCTTTGGGGAGATACATCTTATAGAGTTAGAA ATAGAATCTGAATTTCTAAAGGGAGATTCTGGCTTGGGAAGTACATGTAGGAGTTAATCCCTGTGTAGACTGTTGTAAAGAAAC TGTTGAAAATAAAGAGAAGCAATGTGAAGCAAAAAAAAAAAAAAAAAA
89 MA DSGGPGGPSPSERDRQYCELCGKMENL RCSRCRSSFYCCKEHQRQDWKKHKLVCQGSEGALGHGVGPHQHSGPAPPAAVP PPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADPAAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANYPPSNT PGDA SPGGGLRPNGQTKPLPA LA EYIVPC NKHGICWDDFLGKETGQQIGDEVRA HDTG FTDGQLVSQKSDSSKDIR GDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMVACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDA KVSGGILRIFPEGKAQFADIEPKFDR LFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVE NKPSDS VGKDVF
90
TTAGGGGCAGAAAAACATTTGTAATAATTAATGGCTTTGAGAGACACAAGGCTTTGTTTGCCCCAGAGTATTAGTTAACCCACC TAGTGCTCCTAATCATACAATATTAAGGATTGGGAGGGACATTCATTGCCTCACTCTCTATTTGTTTCACCTTCTGTAAAATTG GTAGAATAATAGTACCCACTTCATAGCATTGTATGATGATTAAATTGGTTAATATTTTTAAAATGCTTAGAACACAGATTGGGC ACATAACAGCAAGCACCACATGTGTTTATAAGATAAATTCCTTTGTGTTGCCTTCCGTTAAAGTTTAAATAAGTAAATAAATAA ATAAATACTTGCATGACATTTTGAAGTCTCTCTATAACATCTGAGTAAGTGGCGGCTGCGACAATGCTACTGGAGTTCCAGAAT CGTGTTGGTGACAAGATTGTTCACCAGCATATGGTGTGGTGAAAACTCACTAATTTGGAATTAGTTCAGATTATTAAGCCTGAA TAGGTGAAAATCCTGAAATCAAGGATCTTTGGAACTATTTGAAATCAGTATTTTATATTTTCCTGTTGTATTCATTAAAGTGTT GCAAGTGTTCTATTTGATGGATTAAGTATATTTAGGATATACATGTTCAATTTGTGATTTTGTATACTTAATTGGAACAAGAAA GCTAATAAAGGTTTTGATATGGACATCTATTCTTTTAAGTAAACTTCAATGAAAATATATGAGTAGAGCATATAGAGATGTAAA TAATTTGTGGACACACCACAGACTGAAATAGCAAATTTAAAAGAAATTGTTGGAAGAATCAAGTGTTTGTGGAATGAGTCCTCC TAGTAAAGTTCCTGCTCTTGTGAATAATTAAGCCTCATGTATAATTACTATAGCAAAAGGAAGCCTAAGAAGTATTAGACTCTA CTTGTATTTAAATTACATTTTACATAATTTATGTGTATGAAAAATGTTTTAAATGCTTATTTTCGTAAGCCATGAGATAGCTCC TTTATATTTTAAGAATTTCTGAATTAATTTGCTTGGATTTTATTAGTGCAAATGGCAGAGCTAGCAATTCCTTTTTCTGTGTTC CCATTCCATCCTATTCATCCCTCTTTTAGGAAACTCTGAACTCTGGATTGTCCTTGTTTACATACCTGCCTCCTGCATTGGACT ATGTGTCTCTGAGTGTAGTATGACTAATTCATTTGTTTGTCAAGGACTCTCAATGCATTTGTTGAACAGCCTAATTAGTAATGT CTGCAACAATGACATTTTACTGTATTTAATAAAGCTCTGGGAAAGTAGGATACACATAAGACAGGTCTAGGTCTAAATTCTTTA CAGAAACTTGGATTTTTAGTTCGGTTTGAAATTTGAAGATGTGAGTATATTTATCTCAGTTTCCCAAAGGACAAGCTAATTGGA ATTATCATCCTCTTTCACTTGATTGGATCCCCAGAATGCCATTTACGCATGCAGCAGGATTTTATAACAGTTTTAAATTCTGTA TATTTGATGAAGAGGTTTTATATTTTTGGATTCAAGCCTCTTTTTAAACTTCTACAATATGGTTTACAATAATTCCTTATATCC
* TGCTTTTGAAATACATATTACAACTTTTTAAGTTTGGAAGGCTATATTTCAAGGACTGAAGTTACAGTATACTCAAGTGATACA
CAAGCCTAGCACCCCACTTTCCACATAGTGTTCGATAAAGATTGATAAACTCGAAATCACAGACCTTTTAATTCTTAAGACAAA
TAGCAGCAGAAAGAAACATCTTTGGCTTATTTCTGGTAAGGTTTTTATGCTCTGTAAAACAAAGAATTGTATTCATCCGCGCAG
CACAGATTCTATTAAAAATAAATGTGAGAGTCGTTAATGTAGTACTGCTCATTTACCATCAAAATTCACTTTTCAGGAATAATC CCATCAGTTTAAATTGGATATTGGAATGAGCATTGATTACATTTAACTTGGTAGCCCAAAATTTCTTCATGGGGTTTTGAACTC GGCGGGATTTCAAAGGTTTTAAAAATGAGTTTTTGATTTTTTTTAAAACCCTCAAATTTCATTACCTTTAAACTAGGTCGAAAC GGGGCGCAAGAGATTGGATTAAGACCATAGTAATACTTATTTTGTTCTTAACCATTTCAGGGCTTCTTGAAATAGAGGCTGTAT GGTGTAATGGAAAAAACAGCCTTGGAATCTGGGAGCCTGATTCCTGGATTCAGTCCCAGTTTTGCGTGACCTTGGGCAAGTTAC TTTACTTCTCTGAATTTCCGTTTCCTCCTCTGCAAAATGAGGATCGCAATAGCCACCTTGCAACCTTGACTGGAGCGAGCCTCG CACACCCCGCGCCGGCCTGGAGGAAGAGCAGCCATGATTACGCCGCCTTCGCTCCGCTACCCGCTTGCGGCTGGCGCCCTCCTC CAGCAGGTGTAGGCGCTGCCGCGCTGCCCCACGCCTTTCCGCCGCTCGCGGGCCTGCGCCTCGGCGTCCCCGAGGAGGCCGCTG CGGGCTGAGGTAGCGCACCGGCCTCTCGGCGTCCCAGTCCGGTCCCGGGCGGAGGGAAAGCGGGCGACCCACCTCCGAGGCAGA
AGCCGAGGCCCGGCCCCGCCGAGTGCGGAGGAGCGCAGGCAGCCCCCGCCCCTCGGCCCTCCCCCCGGCCCTCCCGGCCCTCCC
TCCGCCCCCTCCGCCCTCGCGCGCCGCCCGCCCGGGTCGCCGCGGGGCCGTGGTGTACGTGCAGAGCGCGCAGAGCGAGTGGCG CCCGTATGCCCTGCGCTCCTCCACAGCCTGGGCCGGGCCGCCCGGGACGCTGAGGCGGCGGCGGCGGCCGAGGGGGCCGGTCTT GCGCTCCCCAGGCCCGCGCGCCTGAGCCCAGGTTGCCATTCGCCGCACAGGCCCTATTCTCTCAGCCCTCGGCGGCGATGAGGC GCTGAGGCGGCTGCCGGCGCTGCGCCGGAGCTTAGGACTCGGAAGCGGCCGGGCCGAGGGCGTGGGGTGCCGGCCTCCCTGAGG CGAGGGTAGCGGGTGCATGGCGCAGTAACGGCCCCTATCTCTCTCCCCGCTCCCCAGCCTCGGGCGAGGCCGTCCGGCCGCTAC CCCTCCTGCTCGGCCGCCGCAGTCGCCGTCGCCGCCGCCGCCGCCGCCATGGCCAATGACAGCGGCGGGCCCGGCGGGCCGAGC CCGAGCGAGCGAGACCGGCAGTACTGCGAGCTGTGCGGGAAGATGGAGAACCTGCTGCGCTGCAGCCGCTGCCGCAGCTCCTTC TACTGCTGCAAGGAGCACCAGCGTCAGGACTGGAAGAAGCACAAGCTCGTGTGCCAGGGCAGCGAGGGCGCCCTCGGCCACGGA GTGGGCCCACACCAGCATTCCGGCCCCGCGCCGCCGGCTGCAGTGCCGCCGCCCAGGGCCGGGGCCCGGGAGCCCAGGAAGGCA GCGGCGCGCCGGGACAACGCCTCCGGGGACGCGGCCAAGGGAAAAGTAAAGGCCAAGCCCCCGGCCGACCCAGCGGCGGCCGCG TCGCCGTGTCGTGCGGCCGCCGGCGGCCAGGGCTCGGCGGTGGCTGCCGAAGCCGAGCCCGGCAAGGAGGAGCCGCCGGCCCGC TCATCGCTGTTCCAGGAGAAGGCGAACCTGTACCCCCCAAGCAACACGCCCGGGGATGCGCTGAGCCCCGGCGGCGGCCTGCGG CCCAACGGGCAGACGAAGCCCCTGCCGGCGCTGAAGCTGGCGCTCGAGTACATCGTGCCGTGCATGAACAAGCACGGCATCTGT GTGGTGGACGACTTCCTCGGCAAGGAGACCGGACAGCAGATCGGCGACGAGGTGCGCGCCCTGCACGACACCGGGAAGTTCACG GACGGGCAGCTGGTCAGCCAGAAGAGTGACTCGTCCAAGGACATCCGAGGCGATAAGATCACCTGGATCGAGGGCAAGGAGCCC GGCTGCGAAACCATTGGGCTGCTCATGAGCAGCATGGACGACCTGATACGCCACTGTAACGGGAAGCTGGGCAGCTACAAAATC AATGGCCGGACGAAAGCCATGGTTGCTTGTTATCCGGGCAATGGAACGGGTTATGTACGTCATGTTGATAATCCAAATGGAGAT GGAAGATGTGTGACATGTATATATTATCTTAATAAAGACTGGGATGCCAAGGTAAGTGGAGGTATACTTCGAATTTTTCCAGAA GGCAAAGCCCAGTTTGCTGACATTGAACCCAAATTTGATAGACTGCTGTTTTTCTGGTCTGACCGTCGCAACCCTCATGAAGTA CAACCAGCATATGCTACAAGGTACGCAATAACTGTTTGGTATTTTGATGCAGATGAGAGAGCACGAGCTAAAGTAAAATATCTA ACAGGTGAAAAAGGTGTGAGGGTTGAACTCAATAAACCTTCAGATTCGGTCGGTAAAGACGTCTTCTAGAGCCTTTGATCCAGC AATACCCCACTTCACCTACAATATTGTTAACTATTTGTTAACTTGTGAATACGAATAAATGGGATAAAGAAAAATAGACAACCA GTTCGCATTTTAATAAGGAAACAGAAACAACTTTTTGTGTTGCATCAAACAGAAGATTTTGACTGCTGTGACTTTGTACTGCAT GATCAACTTCAAATCTGTGATTGCTTACAGGAGGAAGATAAGCTACTAATTGAAAATGGTTTTTACATCTGGATATGAAATAAG TGCCCTGTGTAGAATTTTTTTCATTCTTATATTTTGCCAGATCTGTTATCTAGCTGAGTTCATTTCATCTCTCCCTTTTTTATA TCAAGTTTGAATTTGGGATAATTTTTCTATATTAGGTACAATTTATCTAAACTGAATTGAGAAAAAATTACAGTATTATTCCTC AAAATAACATCAATCTATTTTTGTAAACCTGTTCATACTATTAAATTTTGCCCTAAAAGACCTCTTAATAATGATTGTTGCCAG TGACTGATGATTAATTTTATTTTACTTAAAATAAGAAAAGGAGCACTTTAATTACAACTGAAAAATCAGATTGTTTTGCAGTCC TTCCTTACACTAATTTGAACTCTTAAAGATTGCTGCTTTTTTTTTGACATTGTCAATAACGAAACCTAATTGTAAMCAGTCAC CATTTACTACCAATAACTTTTAGTTAATGTTTTACAAGG
91 MLRTAMGLRS LAAPWGALPPRPPLLLLLLLL LLQPPPPTWALSPRISLPLGSEERPFLRFEAEHISNYTALLLSRDGRTLYV GAREALFA SSNLSFLPGGEYQELLWGADAEKKQQCSFKGKDPQRDCQ YIKI LPLSGSH FTCGTAAFSPMCTYIMEWFT ARDEKGNVL EDGKGRCPFDPNFKSTA WDGELYTGTVSSFQGNDPAISRSQSLRPTKTESSLM QDPAFVASAYIPES GS QGDDDKIYFFFSETGQEFEFFENTIVSRIARICKGDEGGERVLQQR TSFLKAQLLCSRPDDGFPFNVLQDVFTLSPSPQD R DTLFYGVFTSQWHRGTTEGSAVCVFTMKDVQRVFSGLYKEWRETQQWYTVTHPVPTPRPGACITNSARERKIWSSLQLPDRVL NFLKDHFLMDGQVRSR LLQPQARY RVAVHRVPGLHHTYDVLFLGTGDGRLHKAVSVGPRVHIIEE QIFSSGQPVQNLLLD THRGL YAASHSGVVQVPMANCS YRSCGDC ARDPYCA SGSSCKHVS YQPQLATRPWIQDIEGASAKDLCSASS SPSF VPTGEKPCEQVQFQPNTVNT ACP SNLATR WLR-.GAPVWASASCHVLPTGDLLLVGTQQLGEFQCWSLEEGFQQLVASYCP EWEDGVADQTDEGGSVPVIISTSRVSAPAGGKAS GADRSY KEFLVMCTLFVLAVLLPVLFL YRHR SMKVF KQGECASV HPKTCPVV PPETRPLNGLGPPSTP DHRGYQS SDSPPGARVFTESEKRPLSIQDSFVEVSPVCPRPRVRLGSEIRDSW 92
GCTCTGCCCAAGCCGAGGCTGCGGGGCCGGCGCCGGCGGGAGGACTGCGGTGCCCCGCGGAGGGGCTGAGTTTGCCAGGGCCCA CTTGACCCTGTTTCCCACCTCCCGCCCCCCAGGTCCGGAGGCGGGGGCCCCCGGGGCGACTCGGGGGCGGACCGCGGGGCGGAG CTGCCGCCCGTGAGTCCGGCCGAGCCACCTGAGCCCGAGCCGCGGGACACCGTCGCTCCTGCTCTCCGAATGCTGCGCACCGCG ATGGGCCTGAGGAGCTGGCTCGCCGCCCCATGGGGCGCGCTGCCGCCTCGGCCACCGCTGCTGCTGCTCCTGCTGCTGCTGCTC" CTGCTGCAGCCGCCGCCTCCGACCTGGGCGCTCAGCCCCCGGATCAGCCTGCCTCTGGGCTCTGAAGAGCGGCCATTCCTCAGA TTCGAAGCTGAACACATCTCCAACTACACAGCCCTTCTGCTGAGCAGGGATGGCAGGACCCTGTACGTGGGTGCTCGAGAGGCC CTCTTTGCACTCAGTAGCAACCTCAGCTTCCTGCCAGGCGGGGAGTACCAGGAGCTGCTTTGGGGTGCAGACGCAGAGAAGAAA CAGCAGTGCAGCTTCAAGGGCAAGGACCCACAGCGCGACTGTCAAAACTACATCAAGATCCTCCTGCCGCTGAGCGGCAGTCAC CTGTTCACCTGTGGCACAGCAGCCTTCAGCCCCATGTGTACCTACATCAACATGGAGAACTTCACCCTGGCAAGGGACGAGAAG GGGAATGTCCTCCTGGAAGATGGCAAGGGCCGTTGTCCCTTCGACCCGAATTTCAAGTCCACTGCCCTGGTGGTTGATGGCGAG CTCTACACTGGAACAGTCAGCAGCTTCCAAGGGAATGACCCGGCCATCTCGCGGAGCCAAAGCCTTCGCCCCACCAAGACCGAG AGCTCCCTCAACTGGCTGCAAGACCCAGCTTTTGTGGCCTCAGCCTACATTCCTGAGAGCCTGGGCAGCTTGCAAGGCGATGAT GACAAGATCTACTTTTTCTTCAGCGAGACTGGCCAGGAATTTGAGTTCTTTGAGAACACCATTGTGTCCCGCATTGCCCGCATC TGCAAGGGCGATGAGGGTGGAGAGCGGGTGCTACAGCAGCGCTGGACCTCCTTCCTCAAGGCCCAGCTGCTGTGCTCACGGCCC GACGATGGCTTCCCCTTCAACGTGCTGCAGGATGTCTTCACGCTGAGCCCCAGCCCCCAGGACTGGCGTGACACCCTTTTCTAT GGGGTCTTCACTTCCCAGTGGCACAGGGGAACTACAGAAGGCTCTGCCGTCTGTGTCTTCACAATGAAGGATGTGCAGAGAGTC TTCAGCGGCCTCTACAAGGAGGTGAACCGTGAGACACAGCAGTGGTACACCGTGACCCACCCGGTGCCCACACCCCGGCCTGGA GCGTGCATCACCAACAGTGCCCGGGAAAGGAAGATCAACTCATCCCTGCAGCTCCCAGACCGCGTGCTGAACTTCCTCAAGGAC CACTTCCTGATGGACGGGCAGGTCCGAAGCCGCATGCTGCTGCTGCAGCCCCAGGCTCGCTACCAGCGCGTGGCTGTACACCGC GTCCCTGGCCTGCACCACACCTACGATGTCCTCTTCCTGGGCACTGGTGACGGCCGGCTCCACMGGCAGTGAGCGTGGGCCCC
CGGGTGCACATCATTGAGGAGCTGCAGATCTTCTCATCGGGACAGCCCGTGCAGAATCTGCTCCTGGACACCCACAGGGGGCTG
*• CTGTATGCGGCCTCACACTCGGGCGTAGTCCAGGTGCCCATGGCCAACTGCAGCCTGTACAGGAGCTGTGGGGACTGCCTCCTC
GCCCGGGACCCCTACTGTGCTTGGAGCGGCTCCAGCTGCAAGCACGTCAGCCTCTACCAGCCTCAGCTGGCCACCAGGCCGTGG
ATCCAGGACATCGAGGGAGCCAGCGCCAAGGACCTTTGCAGCGCGTCTTCGGTTGTGTCCCCGTCTTTTGTACCAACAGGGGAG AAGCCATGTGAGCAAGTCCAGTTCCAGCCCAACACAGTGAACACTTTGGCCTGCCCGCTCCTCTCCAACCTGGCGACCCGACTC TGGCTACGCAACGGGGCCCCCGTCAATGCCTCGGCCTCCTGCCACGTGCTACCCACTGGGGACCTGCTGCTGGTGGGCACCCAA CAGCTGGGGGAGTTCCAGTGCTGGTCACTAGAGGAGGGCTTCCAGCAGCTGGTAGCCAGCTACTGCCCAGAGGTGGTGGAGGAC GGGGTGGCAGACCAAACAGATGAGGGTGGCAGTGTACCCGTCATTATCAGCACATCGCGTGTGAGTGCACCAGCTGGTGGCAAG GCCAGCTGGGGTGCAGACAGGTCCTACTGGAAGGAGTTCCTGGTGATGTGCACGCTCTTTGTGCTGGCCGTGCTGCTCCCAGTT TTATTCTTGCTCTACCGGCACCGGAACAGCATGAAAGTCTTCCTGAAGCAGGGGGAATGTGCCAGCGTGCACCCCAAGACCTGC CCTGTGGTGCTGCCCCCTGAGACCCGCCCACTCAACGGCCTAGGGCCCCCTAGCACCCCGCTCGATCACCGAGGGTACCAGTCC CTGTCAGACAGCCCCCCGGGGTCCCGAGTCTTCACTGAGTCAGAGAAGAGGCCACTCAGCATCCAAGACAGCTTCGTGGAGGTA TCCCCAGTGTGCCCCCGGCCCCGGGTCCGCCTTGGCTCGGAGATCCGTGACTCTGTGGTGTGAGAGCTGACTTCCAGAGGACGC TGCCCTGGCTTCAGGGGCTGTGAATGCTCGGAGAGGGTCAACTGGACCTCCCCTCCGCTCTGCTCTTCGTGGAACACGACCGTG GTGCCCGGCCCTTGGGAGCCTTGGGGCCAGCTGGCCTGCTGCTCTCCAGTCAAGTAGCGAAGCTCCTACCACCCAGACACCCAA ACAGCCGTGGCCCCAGAGGTCCTGGCCAAATATGGGGGCCTGCCTAGGTTGGTGGAACAGTGCTCCTTATGTAAACTGAGCCCT TTGTTTAAAAAACAATTCCAAATGTGAAACTAGAATGAGAGGGAAGAGATAGCATGGCATGCAGCACACACGGCTGCTCCAGTT CATGGCCTCCCAGGGGTGCTGGGGATGCATCCAAAGTGGTTGTCTGAGACAGAGTTGGAAACCCTCACCAACTGGCCTCTTCAC CTTCCACATTATCCCGCTGCCACCGGCTGCCCTGTCTCACTGCAGATTCAGGACCAGCTTGGGCTGCGTGCGTTCTGCCTTGCC AGTCAGCCGAGGATGTAGTTGTTGCTGCCGTCGTCCCACCACCTCAGGGACCAGAGGGCTAGGTTGGCACTGCGGCCCTCACCA GGTCCTGGGCTCGGACCCAACTCCTGGACCTTTCCAGCCTGTATCAGGCTGTGGCCACACGAGAGGACAGCGCGAGCTCAGGAG AGATTTCGTGACAATGTACGCCTTTCCCTCAGAATTCAGGGAAGAGACTGTCGCCTGCCTTCCTCCGTTGTTGCGTGAGAACeC GTGTGCCCCTTCCCACCATATCCACCCTCGCTCCATCTTTGAACTCAAACACGAGGAACTAACTGCACCCTGGTCCTCTCCCCA GTCCCCAGTTCACCCTCCATCCCTCACCTTCCTCCACTCTAAGGGATATCAACACTGCCCAGCACAGGGGCCCTGAATTTATGT GGTTTTTATACATTTTTTAATAAGATGCACTTTATGTCATTTTTTAATAAAGTCTGAAGAATTACTGTTT
92a
GGCACGAGGCCGCTTGCGGGTGAGCTCTGCCCAAGCCGAGGCTGCGGGGCCCGTGCTCCGGCGAACGCCCACTCGAGACGGGTT- CGGCTCCGACGCCCCGCGGCGCCGGCGGGAGGACTGCGGTGCCCCGCGGAGGGGCTGAGTTTGCCAGCCGCGGCCGCCCTCCTG ACGCCACGGGGCGCCTCCCCGACTCAAACGGTGGGCCCACTTGACCCTGTTTCCCACCTCCCGCCCCCCAGGTCCGGAGGCGCC CGGGTGAACTGGGACAAAGGGTGGAGGGCGGGGGGTCCAGGCCTCCGCGGGGCCCCCGGGGCGACTCGGGGGCGGACCGCGGGG
CGGAGCTGCCGCCCCCCCGGGGGCCCCGCTGAGCCCCCGCCTGGCGCCCCGCCTCGACGGCGGGGTGAGTCCGGCCGAGCCACC
TGAGCCCGAGCCGCGGGACACCGTCGCTCCCACTCAGGCCGGCTCGGTGGACTCGGGCTCGGCGCCCTGTGGCAGCGAGGTGCT
CTCCGAATGCTGCGCACCGCGATGGGCCTGAGGAGCTGGCTCGCCGACGAGAGGCTTACGACGCGTGGCGCTACCCGGACTCCT
.CGA€CGAGCGGCCCCCATGGGGCGCGCTGCCGCCTCGGCCACCGCTGCTGCTGCTCCTGCTGGGGGTACCCCGCGCGACGGCGG AGCCGGTGGCGACGACGACGAGGACGACCTGCTGCTCCTGCTGCAGCCGCCGCCTCCGACCTGGGCGCTCAGCCCCCGGACGAC GAGGACGACGTCGGCGGCGGAGGCTGGACCCGCGAGTCGGGGGCGATCAGGCTGCCTCTGGGCTCTGAAGAGCGGCCATTCCTC AGATTCGAAGCTAGTCGGACGGAGACCCGAGACTTCTCGCCGGTAAGGAGTCTAAGCTTCCTGAACACATCTCCAACTACACAG CCCTTCTGCTGAGCAGGGATGGCAGGGACTTGTGTAGAGGTTGATGTGTCGGGAAGACGACTCGTCCCTACCGTCCACCCTGTA CGTGGGTGCTCGAGAGGCCCTCTTTGCACTCAGTAGCAACCTTGGGACATGCACCCACGAGCTCTCCGGGAGAAACGTGAGTCA TCGTTGGACAGCTTCCTGCCAGGCGGGGAGTACCAGGAGCTGCTTTGGGGTGCAGACGGTCGAAGGACGGTCCGCCCCTCATGG TCCTCGACGAAACCCCACGTCTGCCAGAGAAGAAACAGCAGTGCAGCTTCAAGGGCAAGGACCCACAGCGCGACGTCTCTTCTT TGTCGTCACGTCGAAGTTCCCGTTCCTGGGTGTCGCGCTGTGTCAAAACTACATCAAGATCCTCCTGCCGCTCAGCGGCAGTCA CCTGTTACAGTTTTGATGTAGTTCTAGGAGGACGGCGAGTCGCCGTCAGTGGACAACACCTGTGGCACAGCAGCCTTCAGCCCC ATGTGTACCTACAT.CAACATGGGTGGACACCGTGTCGTCGGAAGTCGGGGTACACATGGATGTAGTTGTACCAGAACTTCACCC TGGCAAGGGACGAGAAGGGGAATGTCCTCCTGGAAGATTCTTGAAGTGGGACCGTTCCCTGCTCTTCCCCTTACAGGAGGACCT 5 TCTAGGCAAGGGCCGTTGTCCCTTCGACCCGAATTTCAAGTCCACTGCCCTGGTCCGTTCCCGGCAACAGGGAAGCTGGGCTTA AAGTTCAGGTGACGGGACCAGGTTGATGGCGAGCTCTACACTGGAACAGTCAGCAGCTTCCAAGGGAATGCCAACTACCGCTCG AGATGTGACCTTGTCAGTCGTCGAAGGTTCCCTTACACCCGGCCATCTCGCGGAGCCAAAGCCTTCGCCCCACCAAGACCGAGA GCTGGGCCGGTAGAGCGCCTCGGTTTCGGAAGCGGGGTGGTTCTGGCTGTCGTCCCTCAACTGGCTGCAAGACCCAGCTTTTGT GGCCTCAGCCTACATTCCAGGGAGTTGACCGACGTTCTGGGTCGAAAACACCGGAGTCGGATGTAAGGTGAGAGCCTGGGCAGC
10 TTGCAAGGCGATGATGACAAGATCTACTTTTTCTACTCTCGGACCCGTCGAACGTTCCGCTACTACTGTTCTAGATGAAAAAGA TCAGCGAGACTGGCCAGGAATTTGAGTTCTTTGAGAACACCATTGTGTCCAGTCGCTCTGACCGGTCCTTAAACTCAAGAAACT CTTGTGGTAACACAGGCGCATTGCCCGCATCTGCAAGGGCGATGAGGGTGGAGAGCGGGTGCTACAGCGTAACGGGCGTAGACG TTCCCGCTACTCCCACCTCTCGCCCACGATGTGCAGCGCTGGACCTCCTTCCTCAAGGCCCAGCTGCTGTGCTCACGGCCCGCG TCGCGACCTGGAGGAAGGAGTTCCGGGTCGACGACACGAGTGCCGGGCACGATGGCTTCCCCTTCAACGTGCTGCAGGATGTCT
15 TCACGCTGAGCCCCTGCTACCGAAGGGGAAGTTGCACGACGTCCTACAGAAGTGCGACTCGGGGAGCCCCCAGGACTGGCGTGA
. CACCCTTTTCTATGGGGTCTTCACTTCCCATCGGGGGTCCTGACCGCACTGTGGGAAAAGATACCCCAGAAGTGAAGGGTGTGG
CACAGGGGAACTACAGAAGGCTCTGCCGTCTGTGTCTTCACAATGACACCGTGTCCCCTTGATGTCTTCCGAGACGGCAGACAC
AGAAGTGTTACTAGGATGTGCAGAGAGTCTTCAGCGGCCTCTACAAGGAGGTGAACCGTGAGTCCTACACGTCTCTCAGAAGTC
GCCGGAGATGTTCCTCCACTTGGCACTCACACAGCAGTGGTACACCGTGACCCACCCGGTGCCCACACCCCGGCCTGGTGTGTC
20 GTCACCATGTGGCACTGGGTGGGCCACGGGTGTGGGGCCGGACCAGCGTGCATCACCAACAGTGCCCGGGAAAGGAAGATCAAC TCATCCCTGCTCGCACGTAGTGGTTGTCACGGGCCCTTTCCTTCTAGTTGAGTAGGGACGAGCTCCCAGACCGCGTGCTGAACT TCCTCAAGGACCACTTCCTGATGGACTCGAGGGTCTGGCGCACGACTTGAAGGAGTTCCTGGTGAAGGACTACCTGGGGCAGGT CCGAAGCCGCATGCTGCTGCTGCAGCCCCAGGCTCGCTACCACCCGTCCAGGCTTCGGCGTACGACGACGACGTCGGGGTCCGA GCGATGGTGCGCGTGGCTGTACACCGCGTCCCTGGCCTGCACCACACCTACGATGTCCCGCGCACCGACATGTGGCGCAGGGAC
25 CGGACGTGGTGTGGATGCTACAGGTCTTCCTGGGCACTGGTGACGGCCGGCTCCACAAGGCAGTGAGCGTGGGCAGAAGGACCC GTGACCACTGCCGGCCGAGGTGTTCCGTCACTCGCACCCGCCCCGGGTGCACATCATTGAGGAGCTGCAGATCTTCTCATCGGG ACAGCCGGGGCCCACGTGTAGTAACTCCTCGACGTCTAGAAGAGTAGCCCTGTCGGCGTGCAGAATCTGCTCCTGGACACCCAC AGGGGGCTGCTGTATGCGGCCTGCACGTCTTAGACGAGGACCTGTGGGTGTCCGCCGACGACATACGCCGGACACACTCGGGCG TAGTCCAGGTGCCCATGGCCAACTGCAGCCTGTACCGGGTGTGAGCCCGCATCAGGTCCACGGGTACCGGTTGACGTCGGACAT
30 GGCCAGCTGTGGGGACTGCCTCCTCGCCCGGGACCCCTACTGTGCTTGGAGCGGTCGACACCCCTGACGGAGGAGCGGGCCCTG GGGATGACACGAACCTCGCCCTCCAGCTGTAAGCACGTCAGCCTCTACCAGCCTCAGCTGGCCACCAGGCGAGGTCGACATTCG TGCAGTCGGAGATGGTCGGAGTCGACCGGTGGTCCGCGTGGATCCAGGACATCGAGGGAGCCAGCGCCAAGGACCTTTGCAGCG CGGCACCTAGGTCCTGTAGCTCCCTCGGTCGCGGTTCCTGGAAACGTCGCGCTCTTCGGTTGTGTCCCCGTCTTTTGTACCAAC AGGGGAGAAGCCATGTGAAGAAGCCAACACAGGGGCAGAAAACATGGTTGTCCCCTCTTCGGTACACTGCAAGTCCAGTTCCAG
35 CCCAACACAGTGAACACTTTGGCCTGCCCGCTCCCGTTCAGGTCAAGGTCGGGTTGTGTCACTTGTGAAACCGGACGGGCGAGG TCTCCAACCTGGCGACCCGACTCTGGCTACGCAACGGGGCCCCCGTCAATAGAGGTTGGACCGCTGGGCTGAGACCGATGCGTT GCCCCGGGGGCAGTTAGCCTCGGCCTCCTGCCACGTGCTACCCACTGGGGACCTGCTGCTGGTGGGCGGAGCCGGAGGACGGTG CACGATGGGTGACCCCTGGACGACGACCACCCCACCCAACAGCTGGGGGAGTTCCAGTGCTGGTCACTAGAGGAGGGCTTCCGT GGGTTGTCGACCCCCTCAAGGTCACGACCAGTGATCTCCTCCCGAAGGAGCAGCTGGTAGCCAGCTACTGCCCAGAGGTGGTGG
40 AGGACGGGGTGGCATCGTCGACCATCGGTCGATGACGGGTCTCCACCACCTCCTGCCCCACCGTGACCAAACAGATGAGGGTGG CAGTGTACCCGTCATTATCAGCACATCGCGCTGGTTTGTCTACTCCCACCGTCACATGGGCAGTAATAGTCGTGTAGCGCTGTG AGTGCACCAGCTGGTGGCAAGGCCAGCTGGGGTGCAGACAGGTCCTACACTCACGTGGTCGACCACCGTTCCGGTCGACCCCAC GTCTGTCCAGGAACTGGAAGGAGTTCCTGGTGATGTGCACGCTCTTTGTGCTGGCCGTGCTGTGACCTTCCTCAAGGACCACTA CACGTGCGAGAAACACGACCGGCACGACCTCCCAGTTTTATTCTTGCTCTACCGGCACCGGAACAGCATGAAAGTCTTGAGGGT
45 CAAAATAAGAACGAGATGGCCGTGGCCTTGTCGTACTTTCAGAACCTGAAGCAGGGGGAATGTGCCAGCGTGCACCCCAAGACC TGCCCTGTGGGGACTTCGTCCCCCTTACACGGTCGCACGTGGGGTTCTGGACGGGACACCTGCTGCCCCCTGAGACCCGCCCAC TCAACGGCCTAGGGCCCCCTAGCACCACGACGGGGGACTCTGGGCGGGTGAGTTGCCGGATCCCGGGGGATCGTGGCCACTCGA TCACCGAGGGTACCAGTCCCTGTCAGACAGCCCCCCGGGGGCGGTGAGCTAGTGGCTCCCATGGTCAGGGACAGTCTGTCGGGG GGCCCCCGCCGAGTCTTCACTGAGTCAGAGAAGAGGCCACTCAGCATCCAAGACAGCTGGCTCAGAAGTGACTCAGTCTCTTCT
50. CCGGTGAGTCGTAGGTTCTGTCGATCGTGGAGGTATCCCCAGTGTGCCCCCGGCCCCGGGTCCGCCTTGGCTCGAGCACCTCCA TAGGGGTCACACGGGGGCCGGGGCCCAGGCGGAACCGAGCGAGATCCGTGACTCTGTGGTGTGAGAGCTGACTTCCAGAGGACG CTGCCCCTCTAGGCACTGAGACACCACACTCTCGACTGAAGGTCTCCTGCGACGGGTGGCTTCAGGGGCTGTGAATGCTCGGAG AGGGTCAACTGGACCTCCCCTCACCGAAGTCCCCGACACTTACGAGCCTCTCCCAGTTGACCTGGAGGGGAGCGCTCTGCTCTT
CGTGGMCACGACCGTGGTGCCCGGCCCTTGGGAGCCTGCGAGACGAGAAGCACCTTGTGCTGGCACCACGGGGCGGGAACCCT
CGGATGGAGCCAGCTGGCCTGCTGCTCTCCAGTCAAGTAGCGAAGCTCCTAGCAACCTCGGTCGACCGGACGACGAGAGGTCAG TTCATCGCTTCGAGGATGGTCCCAGACACCCAAACAGCCGTGGCCCCAGAGGTCCTGGCCAAATATGGGGGGGTCTGTGGGTTT GTCGGCACCGGGGTCTCCAGGACCGGTTTATACCCCGCCTGCCTAGGTTGGTGGAACAGTGCTCCTTATGTAAACTGAGCCCTT
TGCGGACGGATCCAACCACCTTGTCACGAGGAATACATTTGACTCGGGAAACTTTAGAAAACAATTCCAAATGTGAAACTAGAA
• TGAGAGGGAAGAGATAGCAAATCTTTTGTTAAGGTTTACACTTTGATCTTACTCTCCCTTCTCTATCGATGGCATGCAGCACAC
ACGGCTGCTCCAGTTCATGGCCTCCCAGGGGTGCTACCGTACGTCGTGTGTGCCGACGAGGTCAAGTACCGGAGGGTCCCCACG
TGGGGATGCATCCAAAGTGGTTGTCTGAGACAGAGTTGGAAACCCTCACCACCCCTACGTAGGTTTCACCAACAGACTCTGTCT CAACCTTTGGGAGTGGAACTGGCCTCTTCACCTTCCACATTATCCCGCTGCCACCGGCTGCCCTGTTTGACCGGAGAAGTGGAA GGTGTAATAGGGCGACGGTGGCCGACGGGACACTCACTGCAGATTCAGGACCAGCTTGGGCTGCGTGCGTTCTGCCTTGCCAGA GTGACGTCTAAGTCCTGGTCGAACCCGACGCACGCAAGACGGAACGGTGTCAGCCGAGGATGTAGTTGTTGCTGCCGTCGTCCC ACCACCTCAGGGACCAGTCGGCTCCTACATCAACAACGACGGCAGCAGGGTGGTGGAGTCCCTGCAGAGGGCTAGGTTGGCACT GCGGCCCTCACCAGGTCCTGGGCTCGGACCGTCTCCCGATCCMCCGTGACGCCGGGAGTGGTCCAGGACCCGAGCCTGGCAAC TCCTGGACCTTTCCAGCCTGTATCAGGCTGTGGCCACACGAGAGGAGTTGAGGACCTGGAAAGGTCGGACATAGTCCGACACCG GTGTGCTCTCCTCAGCGCGAGCTCAGGAGAGATTTCGTGACAATGTACGCCTTTCCCTCAGAGTCGCGCTCGAGTCCTCTCTAA AGCACTGTTACATGCGGAAAGGGAGTCTATTCAGGGAAGAGACTGTCGCCTGCCTTCCTCCGTTGTTGCGTGAGAACCTAAGTC CCTTCTCTGACAGCGGACGGAAGGAGGCAACAACGCACTCTTGGCGTGTGCCCCTTCCCACCATATCCACCCTCGCTCCATCTT TGAACTCAAAGCACACGGGGAAGGGTGGTATAGGTGGGAGCGAGGTAGAAACTTGAGTTTCACGAGGAACTAACTGCACCCTGG TCCTCTCCCCAGTCCCCAGTTCACCCGTGCTCCTTGATTGACGTGGGACCAGGAGAGGGGTCAGGGGTCAAGTGGGTCCATCCC TCACCTTCCTCCACTCTAAGGGATATCAACACTGCCCAGCACAGGTAGGGAGTGGAAGGAGGTGAGATTCCCTATAGTTGTGAC GGGTCGTGAGGGGCCCTGAATTTATGTGGTTTTTATATATTTTTTAATAAGATGCACTTCCCCGGGACTTAAATACACCAAAAA TATATAAAAAATTATTCTACGTGATTATGTCATTTTTTAATAAAGTCTGAAGAATTACTGTTTAAAAAAAAAAAAATACAGTAA AAAATTATTTCAGACTTCTTAATGACAAATTTTTTTTTTTAAAAAAACTTTTTTTG 93
MVGYDPKPDGRNNTKFQVAVAGSVSGLVTRALISPFDVIKIRFQLQHER SRSDPSAKYHGI QASRQILQEEGPTAFWKGHVP AQI S1GYGAVQFLSFEMLTELVHRGS¥YDAREFSVHFVCGGLAACMATLTVHPVDVLRTRFAAQGEPKVYNT RHAVGTMYRS EGPQVFYKGLAPTLIAIFPYAGLQFSCYSSLKHLYKWAIPAEGKKNENLQNLLCGSGAGVISKTLTYP DLFKKRLQVGGFEHA RAAFGQVRRYKGLMDCAKQV QKEGALGFFKGLSPSL KTυVLSTGFMFFSYEFFCNVFHCMNRTASQR 94
ATGGTTGGCTATGACCCCAAACCAGATGGCAGGAATAACACCAAGTTCCAGGTGGCAGTGGCTGGGTCTGTGTCTGGACTTGTT
. ACTCGGGCGCTGATCAGTCCCTTCGACGTCATCAAGATCCGTTTCCAGCTTCAGCATGAGCGCCTGTCTCGCAGTGACCCCAGC
GCAAAGTACCATGGCATCCTCCAGGCCTCTAGGCAGATTCTGCAGGAGGAGGGTCCGACAGCTTTCTGGAAAGGACACGTCCCA
GCTCAGATTCTCTCCATAGGCTATGGAGCTGTCCAATTCTTGTCATTTGAAATGCTGACGGAGCTGGTCCACAGAGGCAGCGTG TACGACGCCCGGGAATTCTCAGTGCACTTTGTATGTGGTGGCCTGGCTGCCTGTATGGCCACCCTCACTGTGCACCCCGTGGAT GTTCTGCGCACCCGCTTTGCAGCTCAGGGTGAGCCCAAGGTCTATAATACGCTGCGCCACGCCGTGGGGACCATGTATAGGAGC GAAGGCCCCCAGGTTTTCTACAAAGGCTTGGCTCCCACCTTGATCGCCATCTTCCCCTACGCCGGGCTGCAGTTCTCTTGCTAC AGCTCCTTGAAGCACCTGTACAAGTGGGCCATACCAGCCGAAGGAAAGAAAAATGAGAACCTCCAAAACCTGCTTTGTGGCAGT GGAGCTGGTGTCATCAGCAAGACCCTGACATATCCGCTGGACCTCTTCAAGAAGCGGCTACAGGTTGGAGGGTTTGAGCATGCC AGAGCTGCCTTTGGCCAGGTACGGAGATACAAGGGCCTCATGGACTGTGCCAAGCAGGTGCTACAAAAGGAAGGCGCCCTGGGC TTCTTCAAGGGCCTGTCCC.CCAGCTTGCTGAAGGCTGCCCTCTCCACAGGCTTCATGTTCTTCTCGTATGAATTCTTCTGTAAT . GTCTTCCACTGCATGAACAGGACAGCCAGCCAGCGCTGA
95 '
MELALRRSPVPRWLLLLPLLLGLNAGAVID PTEEGKEWDWTVRKDAYMFMLYYATNSCK FSE PLVM LQGGPGGSSTG FGNFEEIGPLDSD KPRKTTWLQ SLLFVDNPVGTGFSYWGSGAYAKD A VASDMMVL KTFFSCHKEFQTVPFYIFSESY GGK AAGIG ELYKAIQRGTIKCNFAGVALGDS ISPVDSVLSWGPYLYS SLLEDKGLAEVSKVAEQV NAWKGLYREATEL WGKAEMIIEQNTDG FY I TKSTPTSTMESS EFTQSHLVC CQRHVRHLQRDALSQLM GPIRKKLKIIPEDQS GGQATN VFVMEEDF KPVISIVDELLEAGIIWTVYNGQLDLIVDTMGQEAWVRKLK PELPKFSQLKWRALYSDPKSLETSAFVKSYKN LAFY ILKAGHMVPSDQGDMALKffiRLVTQQE 96
CCTGTTGCTGATGCTGCCGTGCGGTACTTGTCATGGAGCTGGCACTGCGGCGCTCTCCCGTCCCGCGGTGGTTGCTGCTGCTGC CGCTGCTGCTGGGCCTGAACGCAGGAGCTGTCATTGACTGGCCCACAGAGGAGGGCAAGGAAGTATGGGATTATGTGACGGTCC GCAAGGATGCCTACATGTTCTGGTGGCTCTATTATGCCACCAACTCCTGCAAGAACTTCTCAGAACTGCCCCTGGTCATGTGGC TTCAGGGCGGTCCAGGCGGTTCTAGCACTGGATTTGGAAACTTTGAGGAAATTGGGCCCCTTGACAGTGATCTCAAACCACGGA AAACCACCTGGCTCCAGGCTGCCAGTCTCCTATTTGTGGATAATCCCGTGGGCACTGGGTTCAGTTATGTGAATGGTAGTGGTG CCTATGCCAAGGACCTGGCTATGGTGGCTTCAGACATGATGGTTCTCCTGAAGACCTTCTTCAGTTGCCACAAAGAATTCCAGA CAGTTCCATTCTACATTTTCTCAGAGTCCTATGGAGGAAAAATGGCAGCTGGCATTGGTCTAGAGCTTTATAAGGCCATTCAGC GAGGGACCATCAAGTGCAACTTTGCGGGGGTTGCCTTGGGTGATTCCTGGATCTCCCCCGTGGATTCGGTGCTCTCCTGGGGAC CTTACCTGTACAGCATGTCTCTTCTCGAAGACAAAGGTCTGGCAGAGGTGTCTAAGGTTGCAGAGCAAGTACTGAATGCCGTAA ATAAGGGGCTCTACAGAGAGGCCACAGAGCTGTGGGGGAAAGCAGAAATGATCATTGAACAGAACACAGATGGGGTGAACTTCT ATAACATCTTAACTAAAAGCACTCCCACGTCTACAATGGAGTCGAGTCTAGAATTCACACAGAGCCACCTAGTTTGTCTTTGTC AGCGCCACGTGAGACACCTACAACGAGATGCCTTAAGCCAGCTCATGAATGGCCCCATCAGAAAGAAGCTCAAAATTATTCCTG AGGATCAATCCTGGGGAGGCCAGGCTACCAACGTCTTTGTGAACATGGAGGAGGACTTCATGAAGCCAGTCATTAGCATTGTGG ACGAGTTGCTGGAGGCAGGGATCAACGTGACGGTGTATAATGGACAGCTGGATCTCATCGTAGATACCATGGGTCAGGAGGCCT GGGTGCGGAAACTGAAGTGGCCAGAACTGCCTAAATTCAGTCAGCTGAAGTGGAAGGCCCTGTACAGTGACCCTAAATCTTTGG AAACATCTGCTTTTGTCAAGTCCTACAAGAACCTTGCTTTCTACTGGATTCTGAAAGCTGGTCATATGGTTCCTTCTGACCAAG GGGACATGGCTCTGAAGATGATGAGACTGGTGACTCAGCAAGAATAGGATGGATGGGGCTGGAGATGAGCTGGTTTGGCCTTGG GGCACAGAGCTGAGCTGAGGCCGCTGAAGCTGTAGGAAGCGCCATTCTTCCCTGTATCTAACTGGGGCTGTGATCAAGAAGGTT CTGACCAGCTTCTGCAGAGGATAAAATCATTGTCTCTGGAGGCAATTTGGAAATTATTTCTGCTTCTTAAAAAAACCTAAGATT TTTTAAAAAATTGATTTGTTTTGATCAAAATAAAGGATGATAATAGATATTATTTTTTCTTATGACAGAAGCAAATGATGTGAT TTATAGAAAAACTGGGAAATACAGGTACCCAAAGAGTAAATCAACATCTGTATACCCCCTTCCCAGGGGTAAGCACTGTTACCA ATTTAGCATATGTCCTTGCAGAATTTTTTTTTCTATATATACATATATATTTTTTACCAAAATGAATCATTACTCTATGTTGTT TTACTATTTGTTTGACATATCAGTATATCTGAAACACCTTTTCATGTCAATAAATGTTCTTCTCTAACATTAA 98
AATAGTTCATTAATTAGTCTTTATTATGTGAAAAGACTTTTCTAAAATTCTTCCATAATAATTGAAGATATAAATTACAATAAT TAAAATTTACAAAAGAATAAAAGCATTAAAATAAAGTGTGAAAAATTTAAAAAGGGTAAAGATGAAAATTATTTAATTTTTAAT CTCAAAAATCCGAAAGTGATTTTATCAATGTCCTAAGAAAATTAAAATGAAAACAAACTTAATAATGTAAAGAAAGGAGGTTTC TGCCGGGCTGGGGGCGGGAGCTACGGCTTCTCTGGGGACGCGGAAGCGAGAAGCAGGGACCTTGGGGCGCGCCCGGTTTTCCGG GACGGTGCCCCGGCCCCCAGCCCACGCCTCCGGCCGCTGGCATGGTGCTGCTTGCTGGGACCCGGCCGCAGGGTGGCTGGGAGC GCTGCATGACCCCGCCACCGCCGTCCCCACTCCTAGGCGCACAGGTCGAGGAGGACCGCGCTGACTACAAAGAGTTCCAGGGCC CCACACCTGCAGCATAGCCTGGGACGACTCTGTACCCTTTCCAGGACGAGGAGGAGCACGGCGTCGAGGGCTTGGAGAGCGTCC CGGAGGAGGGCGTCCAGGAGGCATGGGGCTGCTGCGGACGCTGGTGCGGCGAGGGGTGAGCGTTGAGAAGGCGCAGGAGACTGA CCACAATGGCTGGACCAGCCTTAATGTCGCCTGCTACCACGGCTTTGTGGATATACCGTGGTGGCCTTAGCTGAGTAACCCCAC ACTGACGTCAACTGGCAGGACAGGGAGGGGAACGCAGCCCTAAATACAGCTGCACAGGCAGGAGCTGCCTCTGGCCCCATGGGC ACCGTTGCCTTGGACACTGGCTCTCAGCCTTGTGCTTCCTGGTCAGCATCACGTGGGCTGGTTCATTTGAGCTTTAACACAGAT CTGGTGGAAACACAGGCTGCCAGGCCCTGCCCCTGGAGTCTTTCTTTGAATAGGCCTGGGGTGGGGCCCAAGAATGAGCAGAAG AACAGGTTTCCTGGTGAGGCTGATGCCGCTGGCCCAGGGTTCTCACGTTGAGGACCGAGAGCTTTGAGGTTTTCATACCTGATG ATGTCCAGGAACCCTTCTCAGTAGGCACTGAAGACCATCAGCAGAATCACAGACCCCAGGAGAGATGTCGTCAGACAGACACAG AGGCATCACCGAATTAAAGTGAAAATGAAGAAAGGAGCTGAGCATCTGTTTCATGACTTTCGTGGCTGTTTTACTAAAGAGGCT ATCCTGGCCCAGTCAGGGCACGCTATCATCACCAACTACTTGTTGAACTACGTTCAGGGTCTTGACCTTGAAGGAGGGACGCGT TCGGGTTGAAAGCCGCCATGCAGGGTCGAACGGATCGCATCGGAGCCCTGAGCTAGCAGGGGCGGGTGTCCACGCGAGGGCCCC CGCCGTGGGATGTCGCCAGAGGAGTGGCCACTTATACGTCCGCCTCATGCAGAGGCTCCTGGAGCGCCCCTGCCGGGAGCTGTT GGGGAAAAAGTACCAGCTTGAGCTGCCGCCGCTCCCCGAGAGGCCGCAAAAGCCCGAGGGCTCCAAGAACTGCCTGCAGAGGCT CAGGGACTGCGAGCTGTCCGCGCTGACGCCGCGCTCCATGCGGGGCCCAGAGGACCGGGGCGCCCTGGACCACATGGTCAGGAT GACCACGAGCCTCTAACAGCCCCGCCGGGGCCCTCGCGTGCCAGACTATGTGCCCCGAGAGCACCTTGTGCTGG
99
MAPMGIRLSP GVAVFC G GVLYH YSGF AGRFS FG GGEPGGGAAGPAAAADGGTVDLREM AVSV AAVRGGDEVRRV
RES V HEKSKGKTREGAEDKMTSGDVLSNRKMFYLLKTAFPSVQINTEEHVDAADQEVILWDHKIPEDILKEVTTPKEVPAES ¥TWIDPLDATQEYTEDLRKWTTMVCVAWGKPMLGVIHKPFSEYTA AMVDGGSNVKARSSYNEKTPRIWSRSHSGMVKQV ALQTFGNQTTIIPAGGAGYKVLALLDVPDKSQEKADLYIHVTYIKKWDICAGNAILKALGGHMTTLSGEEISYTGSDG1EGGLL AS1RMNHQAVRKLPDLEKTGHK
100
CACCTCGCGGCCGTAGGCTAACGTGGAAGTCGGACCAGCCGGCCGGCGGAAGAACCTAGAGCGCGCTGCCTGGCGAGTCAGGCG CGCGGGGCGGCGTTGGTGGTCTTCGCGGCGTAACTCGGCCTTTCCTGGGAGGGAGTGATGGGGCGCACCGGGGCCGGGGAGCGG GCGCCAGTGTAGCCCGCGCGGCGCCTGGCCCGGAGCGCGGCGGCTGCGGCGGCGGCGGCGGCGGGCGCTGGAGGCCTGTGAGAG CCGCAGCCCGGAGCGCCCGGCTTCCCACGCCATGGCCCCCATGGGCATCCGCCTTTCCCCACTGGGGGTGGCAGTGTTTTGTCT GCTGGGGCTCGGCGTGCTCTACCACCTCTACTCGGGCTTCTTGGCCGGCCGCTTCAGCCTCTTCGGCCTGGGCGGCGAGCCTGG CGGCGGCGCGGGGGGGCCCGCGGCCGCGGCCGATGGGGGCACCGTGGACTTGCGCGAGATGCTGGCTGTGTCAGTGCTGGCCGC AGTCCGCGGCGGCGACGAGGTGAGGCGCGTCCGCGAGAGCAACGTCCTCCACGAGAAGTCCAAGGGGAAGACGCGCGAGGGAGC CGAGGACAAGATGACCAGCGGCGACGTGCTGTCCAACCGCAAGATGTTCTACCTGCTCAAGACCGCCTTCCCCAGCGTCCAGAT TAATACTGAGGAACACGTGGATGCAGCTGATCAGGAGGTTATCTTGTGGGATCATAAGATTCCTGAGGATATCCTAAAGGAAGT AACTACTCCTAAAGAGGTACCAGCAGAAAGTGTTACTGTCTGGATTGACCCACTTGATGCTACACAGGAATATACAGAGGATCT- TCGAAAGTACGTCACTACTATGGTGTGTGTGGCTGTAAATGGTAAACCCATGCTAGGAGTTATACATAAGCCATTTTCCGAATA TACAGCTTGGGCAATGGTAGATGGTGGTTCAAATGTGAAAGCCCGCTCTTCCTACAATGAGAAGAGCCCAAGGATCGTTGTGTC TCGTTCCCATTCAGGGATGGTCAAACAGGTCGCTCTTCAGACTTTTGGAAACCAGACTACAATTATCCCAGCTGGTGGTGCTGG TTATAAAGTTTTAGCACTTTTGGATGTGCCTGATAAGAGTCAAGAAAAAGCTGATTTATACATCCATGTGACATACATCAAAAA GTGGGATATATGTGCTGGTAATGCCATCTTAAAAG.CCCTAGGGGGGCATATGACTACCCTGAGTGGTGAAGAAATCAGTTACAC TGGTTCAGACGGCATTGAAGGGGGACTCCTTGCTAGCATCAGAATGAACCACCAGGCCCTGGTCAGAAAACTCCCAGATCTAGA AAAGACAGGACATAAATGAGCATAACTGATTACAGGGTACAGTTCTTCACAGCTGAAATGGTTAGCCTGAGATGCTGGAAGCTT CAAAGGATTGGTGGAGACTATGCATGGTTAAGGCCATCCCGAACTTTTTAAAGTATTTATGAAGCATCAGAGACTTATTTTCCC TGTAATAGAATGCAAAATCAGGGAAAATGGGTTGCTTTGTGTCTCAAGTATTGTCTTTATTTTTGAGACTATTTTCATACAGTT GTCATACACAAGGCGCATATATATATTTGTGMTTAAAATCTGTAGCTGAGTCTAAAAAAAAAAAAAAAAAA
102 TTTTTTTTTATTTGGATTCTATTTATTTAAAATTAAATTCTTTGCAAAATTGAACTTCTCAACTAAAACGTGTCCATGTCAGAA TTTTAACTGTTAGCAGGTAGTTTGTGGCAAAGATGGCTAAATAATGAAGCAAATTAGAAfCTGTGTGTATACTAATGAGCTGCT TTTTTTCTGTTGAGACTATCATTATTTGTCTTATTACCCAAGAGGCAATTACCTGAATTTGGATGTCTGAATTATAACTTATGC AGGAATAGTTCTGTAAATACATTTAAATAAACTGTAAAGATATTTAATAAATATAGTATTTATACTAATCTGTGTGCTTCTTTT GGTTTGAATAGTAACTAAATGAGACACCAGCCCTTGACATTGAGTTTGTTGGTCACTATCAGGTCCTCATTTCCAAGCCTCCTA GTCATTCTAGCACTGATTATATGCTGCTACTTTAACTGGCTCCAGCTGCTTCACTACATCAGTTTAGCTTCCTCAGAAATTCAT CAAAATGGACGGACAATTAAATGTAAATTATAGAACTTTTTCCCAGCTGAGGCTTTGCACCTTCCGTATAGTATAGAGGGAAGC TACAAAAA • • •
103
MPIVDFH QK PAAAAAPFLDKSHSSSPGSPKTAELFFTERTPWFHQFPQIPVAPDLSSRGTRRKDFLSTRRI GAAKVPVVSF YHSRGVLLKASERASGGSKAVQPGRKEKETPRHRKPRFSRRKNR
104
AATATTGCAGAGCAACTTGAAAGGGGGAGCTGGCCGCGTAGGAGGTGAGAGCCAGCCGCAAAAATCCGTTCGGCGGCATTTTCT CTTCAAACCCGCCCGGTCGGATGTGGCATTTGAAGAAAGAAGGCGTGGGTCAATAATCAACCCGCACTTTCTCCTCCAAACTGC TGACGCGACTCTCACCGCCTTCTCAGCTAAGCCAGCTGCCGGGAAGGCCAGCTCTCCGTAAGAACCTGCCAGGGGAAGGGATTC TCTGGGCCAAGGGGACCGAGGGCTCCCGAGCAAGGGCTGGGGCGCCCTGAAAGCATACCTTTCCACTGGCGCCAAGACCCTGCC GGGCAAAACGCGGGGACCAGACCTGAGGAGCCGTGGGAGCCCAGGGAGATCTGGGGCGGGAGCTTCGTTCCGGCCAGGGCCTCT ATCCGCCCCGATACGTGGCTCCTGGGCCGCGGGCCTCAGCGGGCAGAAGTGGGGCTCCGACCTCAAGATGAAGGTCCAGCGTCC TGGCATGCAGATGGTCGGTGCCCCAGCCTCAAGCCGCTCTGCTTAAATCCAAAGGACTGGCTTTGGAGCAAGCGTAGGCGAGAT TATTTTAAAATAATAATTTATGCTGGCGGAAGGTTTTTATTTGTTGGTTTGCTATTGGTGTTTTGTTTTTTAAGCGAAAATGCC GATTGTTGATTTCCACCTCCAGAAATTACCAGCCGCCGCCGCTGCGCCCTTTCTAGACAAATCCCACAGCAGTTCACCCGGCTC CCCCAAAACCGCAGAGCTTTTCTTTACTGAGAGGACCCCTTGGTTCCACCAATTCCCCCAAATCCCCGTGGCTCCCGATCTCTC ATCCAGGGGGACTAGAAGAAAAGATTTTCTCAGCACTAGAAGAATACTTGGAGCAGCAAAGGTGCCCGTGGTGTCTTTCTACCA TTCAAGGGGTGTCCTCCTGMGGCGTCTGAGAGGGCCTCTGGCGGTTCCAAGGCTGTGCAGCCGGGGAGGAAGGAAAAGGAAAC GCCAAGACATAGAAAACCACGCTTTTCCCGTAGGAAGAACCGATGATGAGCCCTGATGAAAGAAGGAAGAAGACCCGCTGTCTG CGAAGGCCTAAAGGTTAGAAATACAGCAATTTTTCTCATGCCGAAGGAAAGGCAAAATGGTCTAAGAAACTGCAAGAGTGTGAT ACAAGTTTTCCTCAACAGCGAGCTGGGACTGGCGACAATTTCTTAACTCACAGCCTCCGCAGTCGCCTTAGTCGACAAAGAGAG CAGCCCACGTAGCGGCCGCCGCGCCCGTGCCCGTGGCCTTTACTTGCTTTTGCCCTGAAGTTCAGTGTAGTGGTTTGTTTGGGG CTTGCAGGAAGAAACAAACACACTCCCTCTGACTCTCCACAACCCATCTTTGCCTTCTGCAACCGCTTCTCCTGCCCATCGCTG GTTTTGGGGTAGGCTCTTTGTCTGCCTGAGGCCCCGCACTCGCAGGGCAAGAAGCTTAAAGGAATCCAACTCCAAACTCCTCCG AAGTTAAATATTGACCAGAACCTCTTTCAACAGGCCGCGGTTGCCAGGAACCGTGGAGGGCCAACTCCTCCCAACCGCCCTGGT GCAAAGTCCCACGCGGCGAAGAGTTTTGGAGCAGCGCTTACCTAGAAAGATGTTTAAATTCTGAACCAGGAATTGTCTCCAACT CCAGGCGCTCAGGGAATCGCCTTTTCCGGTGTCCAGGCGCTCTGCAGACAAATAAACAGCAGAAGGTGAATGGCGGCTGCGAGG GAAGGGAGTTGGAGGCCGGGAGTGGGAAGCGAGGCTCATGCGGGCGCCAAGGTGGCCCTGGGGGTGACGCGAACATCAGGGAGT CACCAGGGCACTCGTCCGTGTGGCGCACTCATTGCTCGAAATGTTCCAGTCTACAAATGGTCCGAAGATGGTGATTTATTTTTG TAAAATAAATACATACTCCATCTCCACACCC
106
TTTTTTTTCCTAGTTTCATTAAAGATGGAGTTCATATTTGTTTCTCATATTAATTTTTAAGACAAAAAAAAGCAGAACTGTTTT CACCCATTAAGTTAAAAACTGGAATTTTACCTTTCCAAACTTATTTCCTACCTTGCCCCTTTTCATGTTAATACCATGAACTAT TCAGTAATTCTCTTCAAGCTCCATAATTTCCTACTTTCTACTTTTGCTCATTATTTCCATTCCAAGGGAAAGTTCTGTGTGCGT GTCTATTTCTATGTTCAAATTACACCTGTAAGATCCAACTCACAGGGCCATTGCCCTCTAGGGGTCTCTCCTGGATCCACTTCA ACAGGAGGTAATTTTATCTNCACCGGATACCATTTCCTCCTTGGACACTTACCTCTTTTA GGGGACTCCCGAGGGTTGAGGGG GNG 108
GCTTACCTGGAAAACTGTAACAATCTCCAGGTTGACCTTTCTGTCTCCCTCTAAACACATCACATTGGCTAAAATTATCTTTTG TTAATAAGGATTATATTACATATAAAAGTATTTAAATATTTTAATGACTCTTACCCTTAGGATAGGGTCTGAACTCCTTAGCAG GCTTCATGATATATTAACCTTGTTGACCTCTTTGGTCTCTCTCAGTACTTCTCAATTCATACTTTGCTCTTCAGCCACAGTAAG TTAGTTTTAGTTCCCTGAGTATGTTATCAGCTCTCTGGATTCTGGGCTTTGCTCATATTTCCTCTATTCAAAATACTCTTATAC TTCATGTCTTTCTTGCCACACCCCCCACCCCTTCCCACCAGCATATGTGTATGTATCACAATTACTCATCCTTCAGATCAGATT CAGTTTAAATGGCATTTCTTTGGGAAGCATTTCCTGATTCTCTACCTCCCAGGCTGGGTTGATTGCATGTATAGCACCTTCTAC TGTAGTACCCTTTTCATGGCATTTACTTACCATAGCCTATTTGTTATTGCCCTCAAGCTCCATTAGGGCAAATTGTTTTTTCAT TGTTTTAAAGTCAGCACCTAAATCTCCCTGGCC
110 TCTCTACAMT NCTATAACAAAACTTTTTAGGAAAGTACCACAAATATGTTAAACAGAAGAAGCAAATCTCAAATAATGTGCA AAAGCTGTGAGTTTCTTCTTACATAAAACTGGTACCTAAGCAAGTGAGGGTTCATTTTATTTTTCACTCACCAATCCCCATATC ATTATACAGTAACACCATACAGCCAAAACGGCCATGATATTCCTCCCTTCTCAGCCAAAATTGGGCAAGAGAGAATGACCCTTG TAGGGGAAAAGAAACCTCTACGATAAACTGAAATGCCACCATCAGGGTTTGTTGAAACTGTAGGNACAGGGTCTACGNCTCACT TAGCTGCTAATGAGTTTCTATGGTTCCAGNTGGGGTAGTTCAAAGTA 112
TAAAAAGCATTAGGCATATAAATGTATAAATATATTTTATCATGTACAGTACAAAAATGGAACCTTATGCATGGGCCTTAGGAA TACAGGCTAGTATTTCAGCACAGACTTCCCTGCTTGAGTTCTTGCTGATGCTTGCACCGTGACAGTGGGCACCAACACAGACGT GCCACCCAACCCCCTGCACACACCACCGGCCACCAGGGGCCCCCTTGTGCGCCTTGGCTTTATAACTCCTCTGGGGGTGATATT GGTGGTGATCACAGCTCCTAGCATAATGAGAGTTCCATTTGGTATTGTCACACGTCTCCTGCCTCGCTTGGGTTGCCATGTTTG AGCGATGGCCCTGTTGATTTCACCCTGCCTTTTACTGAATCTGTAAATTGTTGTGCAATTGTGGTTATAGTAGACTGTAGCACA TTGCCTTTTCTAAACTGCTACATGTTTATAATCTTCATTTTTAAAGTATGTGTAATTTTTTTAAGTATGTATTCTATTCATATG GTCTGCTTGTCAGTGAGCCAGACTTGCTTACTATATTCCTTTATAATAATGCTAGCCACTTCCTGGATTCTTTAGTAATGTGCT GCATGCAAGAACTTTCCAGTAGCAGTGAAGGAGGGCTGCCTCTCCAAGCTTCCTAAGGGATGCTGCCCTGTGTGGGGATGCATT GCAGAGGCACTAGTAGCATGGGGGCTAGAGTGGGGAGCGAGATGTAAAAGGGTGGGGGGATAGGAGAATTCCAGAGTGCTTCCA GCATTAGGGTCCTGAGAACTTCTGAGTTCAGAGAAACATGCAAAGTGACTAACAAAATAGCTACTTACCTTTGCAGTTCTACAG ACCCTGGGAGCTGCTTTGGGAGTGAGAAAGGCAACCCTCCAATGTGTTTCAACTTTAAAATGTTGAATTCTTTTCAGACATGGT ATCTCATTTATTCTCCTTTTCTAGCGTTTGTTGAATTTCAGGCAGAATGTCTTACAGACTGTCCTAGAACCAGATTATCATTTA ATCTGAAACAGCTGAGGAAGGGACAGAGAAGGTACAAGGGCAAGGCAGCACAAAACAGATCAGGAGAATGAAGAGGGAATGCTT TGGTTTTTTGTTTTGTTTTGTTTTTTCTTTTTCAAGTAACTAAAACAACATCTACATGTAGAGTGTTGTGGAGAGCTGAGACCA GGGTAAAGTCAAGTGCAGCATCAGTACTGCGAGACCCACCAGCCCCTGGAGAGGGTCAGCCGAGAATCTGGTAGTGAAGCCTGT CTAGGGTCCCGGCACCCTCACCCTCAGCCACCTGCAGAGAGGCCAGGGCCCCAGAGACTAGCCTGGTTCTGAAGTGGGCAGGGG TGCTGCCAGAGCCCTCTGCCCCTTATGTTGAGACCCTGCTTTCAGGACAGGCCAGCCGTTGGCCACCATGTCACATTCTGAGTG AGTGTCACAGGTCCCTAACAATAATTTTCTGATCTGGAGCATATCAGCAGAATGCTTAGCCTCAAGGGGCCTGGAAGCTGTAAT GTTTGATTTATGATGAGAACTATCCGAGGCCACCCTTGGCCTCTAAATAAGCTGCTCTAGGGAGCCGCCTACTTTTTGATGAGA AATTAGAAGAGTACCTAATGTTGAAAACATGACATGCGCTCTTGGGATCTGCTGTTCTCTCCAGGGCTCCAGAACCTGATACCT GTTACCAAAGCTAGGAAAGAGCTTTATCACAAGCCTTCACTGTCCTGGCATGAGAACTGGCTGCCAGGCTCAGTGTACCCCATT AACTGTGAATGAATCTGAGCTTGGTTTCCTTTATTGCTTCCTCTGCAATATGATTGCTGAAACACATTTTAAAAATTCAGAAGC TTGTCACTCCTGTTAATGGGAGGATCAGTCACACATGTGTAGTACAAGGCGGACTTTGTGTTTGTTTTTGGTGTTAATTTTTAG CATTGTGTGTGTTGCTTCCCCACCCTGAGGAGAGGACACCATGGCTTACTACTCAGGACAAGTATGCCCCGCTCAGGGTGTGAT TTCAGGTGGCTTCCAAACTTGTACGCAGTTTAAAGATGGTGGGGACAGACTTTGCCTCTACCTAGTGAACCCCACTTAAAGAAT AAGGAGCATTTGAATCTCTTGGAAAAGGCCATGAAGAATAAAGCAGTCAAAAAGAAGTCCTCCATGTTGGTGCCAAGGACTTGC GAGGGGAAATAAAAATGTTATCCAGCCTGACCAACATGGAGAAACCCCGTCTCCATTAAAAATACAAAATTAGCCTGGCATGGT GGCGCATGCCTGTAATCCCAGCTACTCTGGAGGCTGAGGCAGGAGAATCGCTTGAACCCAGGAGGCGGAGGTCGCAGTGAGCCG AGATCATGCCAGTGCACTCCAGCCTGGGTAACAAGAGTGAAACTCCGTGTCAAAAAAAAAAAAAAAAAATGTTACTCATCCTCT CTGAAAGCAAAAAGGAAACCCTAACAGCTCTGAACTCTGGTTTTATTTTTCTTGCTGTATTTGGGTGAACATTGTATGATTAGG CATAATGTTAAAAAAAAAAAATTTTTTTTTGGTAGAAATGCAATCACCAGTAAAGAGGTACGAAAAAGCTAGCCTCTCTCAGAG ACCGGGGAGGCAGAGTACTACTAGAGGAAGTGAAGTTCTGATGGAATCATGCCTGTCAAATGAGGTCTTGAAGCGGATGCCCAA ATAAAAGAGTATATTTTATCTAAATCTTAAGTGGGTAACATTTTATGCAGTTTAAATGAATGGAATATTTTCCTCTTGTTTAGT TGTATCTGTTTGTATTTTTCTTTGATGAATGATTGGTCATGAGGCCTCTTGCCACACTCCAGAAATACGTGTGCGGCTGCTTTT AAGAACTATGTGTCTGGTCACTTATTTCTCTAAAATTATCTCATTGCCTGGCAATCAGTCTTCTCTTGTATACTTGTCCTAGCA CATTATGTACATGGGAAATGTAAACAAATGTGAAGGAGGACCAGAAAAATTAGTTAATATTTAAAAAAATGTATTGTGCATTTT GGCTTCACATGTTTAACTTTTTTTAAGAAAAAAGTTGCATGAATGGAAAAAAAAATCTGTATACAGTATCTGTAAAAACTATCT TATCTGTTTCAATTCCTTGCTCATATCCCATATAATCTAGAACTAAATATGGTGTGTGGCCATATTTAAACACCTGAGAGTCAA GCAGTTGAGACTTTGATTTGAAGCACCTCATCCTTCTTTCAATGCGAACACTATCATATGGCATTCTTACTGAGGATTTTGTCT AACCATATGTTGCCATGAATTAACTCTGCCGCCTTTCTTAAGGATCAAAACCAGTTTGATTTGGGAATCTTCCCCTTTCCAAAT GAAATAGAGATGCAGTACTTAACTTTCCTTGGTGTTTGTAGATATTGCCTTGTGTATTCCACTTAAAACCGTAATCTAGTTTGT AAAAGAGATGGTGACGCATGTAAATAAAGCATCAGTGACACTCT 113
MGTDSRAAKALLARARTLHLQTGNLLNWGRLRKKCPSTHSEE HDCIQKT NEWSSQINPDLVREFPDVLECTVSHAVEKINPD EREE KVSAK FIVESNSSSSTRSAVDMACSVLGVAQLDSVIIASPPIEDGVNLS EHLQPYWEELENLVQSKKIVAIGTSDLD KTQLEQ YQ AQVKPNSNQV-.LASCCVMPPDLTAFAKQFDIQLLTH-.DPKELLSEASFQEA QESIPDIQAHE VPLWL RYSV IVKSRGIIKSKGYII-QAKRRGS 114
GGCACGAGGCTGCGGCCGCAGTAGCCGGAGCCGGAGCCGCAGCCACCGGTGCCTTCCTTTCCCGCCGCCGCCCAGCCGCCGTCC GGCCTCCCTCGGGCCCGAGCGCAGACCAGGCTCCAGCCGCGCGGCGCCGGCAGCCTCGCGCTCCCTCTCGGGTCTCTCTCGGGC CTCGGGCACCGCGTCCTGTGGGCGGCCGCCTGCCTGCCCGCCCGCCCGCAGCCCCTTGCCTGCCGGCCCCTGGGCGGCCCGTGC CATGGGCACCGACAGCCGCGCGGCCAAGGCGCTCCTGGCGCGGGCCCGGACCCTGCACCTGCAGACGGGGAACCTGCTGAACTG GGGCCGCCTGCGGAAGAAGTGCCCGTCCACGCACAGCGAGGAGCTTCATGATTGTATCCAAAAAACCTTGAATGAATGGAGTTC- CCAAATCAACCCAGATTTGGTCAGGGAGTTTCCAGATGTCTTGGAATGCACTGTATCTCATGCAGTAGAAAAGATAAATCCTGA TGAAAGAGAAGAAATGAAAGTTTCTGCAAAACTGTTCATTGTAGAATCAAACTCTTCATCATCAACTAGAAGTGCAGTTGACAT GGCCTGTTCAGTCCTTGGAGTTGCACAGCTGGATTCTGTGATCATTGCTTCACCTCCTATTGAAGATGGAGTTAATCTTTCCTT GGAGCATTTACAGCCTTACTGGGAGGAATTAGAAAACTTAGTTCAGAGCAAAAAGATTGTTGCCATAGGTACCTCTGATCTAGA CAAAACACAGTTGGAACAGCTGTATCAGTGGGCACAGGTAAAACCAAATAGTAACCAAGTTAATCTTGCCTCCTGCTGTGTGAT GCCACCAGATTTGACTGCATTTGCTAAACAATTTGACATACAGCTGTTGACTCACAATGATCCAAAAGAACTGCTTTCTGAAGC AAGTTTCCAAGAAGCTCTTCAGGAAAGCATTCCTGACATTCAAGCGCACGAGTGGGTGCCGCTGTGGCTACTGCGGTATTCGGT CATTGTGAAAAGTAGAGGMTTATCAAATCAAMGGCTACATTTTACAAGCTAAAAGAAGGGGTTCTTAACTGACTTAGGAGCA TAACTTACCTGTAATTTCCTTCAATATGAGAGAAAATTGAGATGTGTAAAATCTAGTTACTGCCTGTAAATGGTGTCATTGAGG CAGATATTCTTTCGTCATATTTGACAGTATGTTGTCTGTCAAGTTTTAAATACTTATCTTGCCTCCATATCAATCCATTCTCAT GAACCTCTGTATTGCTTTCCTTAAACTATTGTTTTCTAATTGAAATTGTCTATAAAGAAAATACTTGCAATATATTTTTCCTTT ATTTTTATGACTAATATAAATCAAGAAAATTTGTTGTTAGATATATTTTGGCCTAGGTATCAGGGTAATGTATATACATATTTT TTATTTCCAAAAAAAATTCATTAATTGCTTCTTAACTCTTATTATAACCAAGCAATTTAATTACAATTGTTAAAACTGAAATAC TGGAAGAAGATATTTTTCCTGTCATTGATGAGATATATCAGAGTAACTGGAGTAGCTGGGATTTACTAGTAGTGTAAATAAAAT 5 TCACTCTTCAATAC
115
MTAIIKEIVSRNKRRYQEDGFD DLTYIYPNIIAMGFPAERLEGVYRIWIDDWRF DSKHKNHYKIYNLCAERHYDTAKFNCR VAQYPFEDHNPPQLELIKPFCEDLDQWLSEDDNHVAAIHCKAGKGRTGVMICAY HRGKFLKAQEALDFYGEVRTRDKKGVTI PSQRRYVYYYSY LKNH DYRPVA LFH MMFETIPMFSGGTCNPQFWCQLKVKIYSSNSGPTRRED FMYFEFPQPLPVCGD 10 IKVEFFHKQNKMLKKDMFHFWWTFFIPGPEETSEKVENGSLCDQEIDSICSIERADNDKEYLVLTLTKNDLDRA KDKM.RY FSPNFKVKLYFTKTVEEPSNPEASSSTSVTPDVSDNEPDHYRYSDTTDSDPENEPFDEDQHTQITKV
116
CCTCCCCTCGCCCGGCGCGGTCCCGTCCGCCTCTCGCTCGCCTCCCGCCTCCCCTCGGTCTTCCGAGGCGCCCGGGCTCCCGGC GCGGCGGCGGAGGGGGCGGGCAGGCCGGCGGGCGGTGATGTGGCAGGACTCTTTATGCGCTGCGGCAGGATACGCGCTCGGCGC
' 15 TGGGACGCGACTGCGCTCAGTTCTCTCCTCTCGGAAGCTGCAGCCATGATGGAAGTTTGAGAGTTGAGCCGCTGTGAGGCGAGG CCGGGCTCAGGCGAGGGAGATGAGAGACGGCGGCGGCCGCGGCCCGGAGCCCCTCTCAGCGCCTGTGAGCAGCCGCGGGGGCAG CGCCCTCGGGGAGCCGGCCGGCCTGCGGCGGCGGCAGCGGCGGCGTTTCTCGCCTCCTCTTCGTCTTTTCTAACCGTGCAGCCT CTTCCTCGGCTTCTCCTGAAAGGGAAGGTGGAAGCCGTGGGCTCGGGCGGGAGCCGGCTGAGGCGCGGCGGCGGCGGCGGCGGC ACCTCCCGCTCCTGGAGCGGGGGGGAGAAGCGGCGGCGGCGGCGGCCGCGGCGGCTGCAGCTCCAGGGAGGGGGTCTGAGTCGC
20 CTGTCACCATTTCCAGGGCTGGGAACGCCGGAGAGTTGGTCTCTCCCCTTCTACTGCCTCCAACACGGCGGCGGCGGCGGCGGC ACATCCAGGGACCCGGGCCGGTTTTAAACCTCCCGTCCGCCGCCGCCGCACCCCCCGTGGCCCGGGCTCCGGAGGCCGCCGGCG GAGGCAGCCGTTCGGAGGATTATTCGTCTTCTCCCCATTCCGCTGCCGCCGCTGCCAGGCCTCTGGCTGCTGAGGAGAAGCAGG CCCAGTCGCTGCAACCATCCAGCAGCCGCCGCAGCAGCCATTACCCGGCTGCGGTCCAGAGCCAAGCGGCGGCAGAGCGAGGGG CATCAGCTACCGCCAAGTCCAGAGCCATTTCCATCCTGCAGAAGAAGCCCCGCCACCAGCAGCTTCTGCCATCTCTCTCCTCCT
25 TTTTCTTCAGCCACAGGCTCCCAGACATGACAGCCATCATCAAAGAGATCGTTAGCAGAAACAAAAGGAGATATCAAGAGGATG GATTCGACTTAGACTTGACCTATATTTATCCAAACATTATTGCTATGGGATTTCCTGCAGAAAGACTTGAAGGCGTATACAGGA ACAATATTGATGATGTAGTAAGGTTTTTGGATTCAAAGCATAAAAACCATTACAAGATATACAATCTTTGTGCTGAAAGACATT ATGACACCGCCAAATTTAATTGCAGAGTTGCACAATATCCTTTTGAAGACCATAACCCACCACAGCTAGAACTTATCAAACCCT TTTGTGAAGATCTTGACCAATGGCTAAGTGAAGATGACAATCATGTTGCAGCAATTCACTGTAAAGCTGGAAAGGGACGAACTG
30 GTGTAATGATATGTGCATATTTATTACATCGGGGCAAATTTTTAAAGGCACAAGAGGCCCTAGATTTCTATGGGGAAGTAAGGA CCAGAGACAAAAAGGGAGTAACTATTCCCAGTCAGAGGCGCTATGTGTATTATTATAGCTACCTGTTAAAGAATCATCTGGATT ATAGACCAGTGGCACTGTTGTTTCACAAGATGATGTTTGAAACTATTCCAATGTTCAGTGGCGGAACTTGCAATCCTCAGTTTG TGGTCTGCCAGCTAAAGGTGAAGATATATTCCTCCAATTCAGGACCCACACGACGGGAAGACAAGTTCATGTACTTTGAGTTCC CTCAGCCGTTACCTGTGTGTGGTGATATCAAAGTAGAGTTCTTCCACAAACAGAACAAGATGCTAAAAAAGGACAAAATGTTTC
35 ACTTTTGGGTAAATACATTCTTCATACCAGGACCAGAGGAAACCTCAGAAAAAGTAGAAAATGGAAGTCTATGTGATCAAGAAA TCGATAGCATTTGCAGTATAGAGCGTGCAGATAATGACAAGGAATATCTAGTACTTACTTTAACAAAAAATGATCTTGACAAAG CAAATAAAGACAAAGCCAACCGATACTTTTCTCCAAATTTTAAGGTGAAGCTGTACTTCACAAAAACAGTAGAGGAGCCGTCAA ATCCAGAGGCTAGCAGTTCAACTTCTGTAACACCAGATGTTAGTGACAATGAACCTGATCATTATAGATATTCTGACACCACTG ACTCTGATCCAGAGAATGAACCTTTTGATGAAGATCAGCATACACAAATTACAAAAGTCTGAATTTTTTTTTATCAAGAGGGAT
40 AAAACACCATGAAAATAAACTTGAATAAACTGAAAATGGACCTTTTTTTTTTTAATGGCAATAGGACATTGTGTCAGATTACCA
.■ GTTATAGGAACAATTCTCTTTTCCTGACCAATCTTGTTTTACCCTATACATCCACAGGGTTTTGACACTTGTTGTCCAGTTGAA.
AAAAGGTTGTGTAGCTGTGTCATGTATATACCTTTTTGTGTCAAAAGGACATTTAAAATTCAATTAGGATTAATAAAGATGGCA
CTTTCCCGTTTTATTCCAGTTTTATAAAAAGTGGAGACAGACTGATGTGTATACGTAGGAATTTTTTCCTTTTGTGTTCTGTCA
CCAACTGAAGTGGCTAAAGAGCTTTGTGATATACTGGTTCACATCCTACCCCTTTGCACTTGTGGCAACAGATAAGTTTGCAGT
45 TGGCTAAGAGAGGTTTCCGAAAGGTTTTGCTACCATT,CTAATGCATGTATTCGGGTTAGGGCAATGGAGGGGAATGCTCAGAAA GGAAATAATTTTATGCTGGACTCTGGACCATATACCATCTCCAGCTATTTACACACACCTTTCTTTAGCATGCTACAGTTATTA ATCTGGACATTCGAGGAATTGGCCGCTGTCACTGCTTGTTGTTTGCGCATTTTTTTTTAAAGCATATTGGTGCTAGAAAAGGCA GCTAAAGGAAGTGAATCTGTATTGGGGTACAGGAATGAACCTTCTGCAACATCTTAAGATCCACAAATGAAGGGATATAAAAAT
AATGTCATAGGTAAGAAACACAGCAACAATGACTTAACCATATAAATGTGGAGGCTATCAACAAAGAATGGGCTTGAAACATTA
50 TAAAAATTGACAATGATTTATTAAATATGTTTTCTCAATTGTAAAAAAAAAA 118
TTCTATCAGAAATTGTATTTATTTACCAGCATTTATGGCAAATGGCCAGACCTGGGCAGGGTGGTAGCAATGATAGATTTTACA AATTAAGGCATTGTTCTTTATTTCAAATTTTCATTTACCNATATTTTCCTTGGTCTTAGAAATATGAATANTTTAGAGCTGGC AATACTCACCATCAGGATATAATAAACGGAGGTTTCTTTNTCCGAAATCCATAAANTGTAGTATACTCTNTTGTACTTTTAAA ATTCCNATTTTTGCAGTNGGCTTCCTCTCAGTGATTTAGTTAGGNAGTTTTGGTACATTTTGGNGGGGTCATAAACATGTTCAT AGGATAGGAGTACNGGGCATTTNTGGAAAAACCCG
119
MERVKMI VQRLEAAEFLERRERECEHGYASSFPSMPSPRLQHSKPPRR SRAQKHSSGTSNTSTANRSTHNELEKNRRAHLR LCLERLKVLIP GPDCTRHTTLG LNKAKAHIKK EEAERKSQHQLENLEREQRFLK RLEQLQGPQEMERIRMDSIGSTISSD RSDSEREEIEVDVESTEFSHGEVDNISTTSISDIDDHSSLPSIGSDEGYSSASVKLSFTS
120
AGATTATGATCGCCTGAGGCCCCTCTCCTACCCAGATACCGATGTTATACTGATGTGTTTTTCCTTTTTTTTTTTTTTTTTTTA AGTAATTAAGGGTAGTTAAATTATTTAAAGTATACAAAGTCCAAACAGCCAGGGGTAAGGTCTCCAAGAGGCCTTCCCAGGGTA AGGGAGTGCGGAGAGGCCCCGGTCGCCACCCGCGGTGCCCATGGAGCGGGTGAAGATGATCAACGTGCAGCGTCTGCTGGAGGC TGCCGAGTTTTTGGAGCGCCGGGAGCGAGAGTGTGAACATGGCTACGCCTCTTCATTCCCGTCCATGCCGAGCCCCCGACTGCA GCATTCAAAGCCCCCACGGAGGTTGAGCCGGGCACAGAAACACAGCAGCGGGACGAGCAACACCAGCACTGCCAACAGATCTAC ACACAATGAGCTGGAAAAGAATCGACGAGCTCATCTGCGCCTTTGTTTAGAACGCTTAAAAGTTCTGATTCCACTAGGACCAGA CTGCACGCGGCACACAACACTTGGTTTGCTCAACAAAGCCAAAGCACACATCAAGAAACTTGAAGAAGCTGAAAGAAAAAGCCA GCACCAGCTCGAGAATTTGGAACGAGAACAGAGATTTTTAAAGTGGCGACTGGAACAGCTGCAGGGTCCTCAGGAGATGGAACG AATACGAATGGACAGCATTGGATCAACTATTTCTTCAGATCGTTCTGATTCAGAGCGAGAGGAGATTGAAGTGGATGTTGAAAG CACAGAGTTCTCCCATGGAGAAGTGGACAATATAAGTACCACCAGCATCAGTGACATTGATGACCACAGCAGCCTGCCGAGTAT TGGGAGTGACGAGGGTTACTCCAGTGCCAGTGTCAAACTTTCATTCACTTCATAGAACCCAGCATGACATAACAGTGCAGGGCA AAATATTCACTGGGCCAATTCAATACAAACAATCTCTTAAATTGGGTTCATGATGCAGTCTCCTCTTTAAAACAAAACAAAACA AAACAAAACTATACTTGAACAAAAGGGTCAGAGGACCTGTATTTAAGCAAATACTTAGCAAAAAGTGGGGCAGAGCTCCCAAGG AGAACAAATATTCAGAATATTCATATTGGAAAAATCACAATTTTTAATGGCAGCAGAAAACTTGTGTGAAATTTTCTTGATTTG AGTTGATTGAGAAGAGGACATTGGAGATGCCATCCTCTTTCTCTTTTCTCGTTTGCTCATACTACATTGAGTAGACACATTTAA GGATGGGGTTATGAACCCTTCCTGAGCTTTATGGTCCTAAAAGCAAAATAAAAACTATTCGAATGAAAAGACAAGAAAATCAGG TATTAATCTTGGATAGCTAATAATGAGCTATTAAAACTCAGCCTGGGACAGTTTATCATGAAGCCTGTGGATGATCAATCCTTT ATTATTATTTTTTTTTTTTGAAAAAAGCTCATTTCATGCTCTGCAAAAGGAGAGACTCCCATGAAGCCTTTTGAAAGGGATCAT CATGCAGCTCAACTTTCTGTTGGATTCCATGCTAAGCAAGCTAACCTTATCCTGCATTGTTAGCACTAGGCACCCAGCTGCCAC CTCTCCATCCTGCTGCCCTTAGGCCACATGGGAGCAGTCCATGCATGACAGCCTCTATCCTACAAGGCCTATGAGTATGGATTG GGGGGGCCAAAAGGAAAAAGCTCCATGTGCCTCTTTGTCTGCGTGGGTCAGAAGAGTTGTGCACGCAGATTAGCAGGCCAAGGT CTGAGCCACAGCAGCATTTTTATTTCAGATTTTGATAACTGTTTATATGTGTTGAAAACCAAAATGACATCTTTTTAAAGCTTA TCCATAAAAAAAAATAGATGTCTTTTATAGTGGAAAAACACATGGGGAAAAAAATCATCTATTTTGATGCAGCATTTGATAATG ATAAAACACCTCACACCTCACTCTTTATAGTGCACAAAATGAATGAGGTCTGGGCTAGGTAGAAAAAGGGTCAATGCTATTTTT GTTTTTAGAATCATTACCTTTTACCAGCTTTTAACCATCTGATATCTATAGTAGACACACTATCATAGTTAACATAGTTAAGTT CAGCACTTGTCTCATTTTAATGTAAAGATTTGCTTCCATTTTCCTACAGGCAGTCTCTCTCTTCCTCACAGTCCCACTGTGCAG GTGCTATTGTTACTCTTACGAATATTTTCAGTAATGTTATTTTCTTCTAAGTGAAATTTCTAGCCTGCACTTTGATGTCATGTG TTCCCTTTGTCTTTCAAACTCCAAGGTTCCCCTGTGGCCCTCTCCCTTACCCTGGGAAGGCCTCTTGGAGACCTTACCCCTGGC TGTTTGGACTTTGTATACTTTAAATAATTTAACTACCCTTAATTACTTAAAAAAAAAAAAAAAA
121
M SNFITFDLKMS LPSNLFSAFITLCFGAIFFLPDSSKLLSGVLFHSSPALQPAADHKPGPGARAEDAAEGRARRREEGAPGD PEAA EDNLARIRENHERA REAKETLQKLPEEIQRDILLEKKKVAQDQLRDKAPFRGLPPVDFVPPIGVESREPADAAIREKR AKIKEmKHA YKGYAWGLNE KPISKGGHSSS FGNIKGATIVDALDTLFIMEMKHEFEEAKSWVEENLDF VNAEISVFE WIRFVGGL SAYY SGEEIFRKKAVELGW LPAFHTPSGIPWALLMKSGIGRMPWASGGSSILAEFGTLH EFMHLSH S GNPIFAEKVMNIRTVLNKLEKPQGLYPNYLNPSSGQWGQHH¥SVGGLGDSFYEY KA LMSDKTDLEAKKMYFDAVQAIETHL IRKSSSG TYIAEWKRGLLEHKMGHLTCFAGGMFALGADAAPEGMAQHYLELGAEIARTCHESY RTFMKLGPEAFRFDGGVEA IATRQNEKYYILRPEWETYMYM RLTHDPKYRKWAWEAVEA ENHCRV GGYSGLRDVYLLHESYDDVQQSFFLAETLKYLY IFSDDDLLPLEHWIFNSEAHLLPILPKDKKEVEIREE 122
CCAACTTATTTAAAACAAAACAATTTTGTAGGTATTATTATACCCATTTCACAGATGATGATAAATGAGACCAATAGAAGTTAA ATAACTTGCCAAAGGCCACACAGCTGGTGAGTGATGGAGAACGAATTAAAACTCAAGTGAGCATAATTCTAAAAGCCATCTTCT CGTTAGTGTTTCTCACTATCCAGGTCTGCCTTTGCCTTATTTAACTGAAGTTAAGCCATCCTTACCTGTGATCACCTAGCCTCT CAGTTTGGGGGGATCATTACAGCGGGTTTTTAACTCCCAATGTTCTGGTCCAGTTTGCTTTACATGTTCTTATTTATACATTGT CAAGGATGACCTCAGGACAGTACAGCAAGGACACAGTGGCACTTCACATTTTGTTCCCACGAAATGACTGGGGCATAATCTCAG ATCATCTTCCTTTAGAATGTGGAAACATCAGCAGAAGAATATTAGTCTTTATACAAGTCAAATCCAAAATGACACATGTGAAAA CTAATAGAGCTGACTTTCAGCCATGATAGCTTTGGCACACCTCACATCCCTTTGTTCAACCTCTCTTCCCTCAACGGAGAGCTG CATTCCTGGGAATTTCTGTTGTGCACTTTTCCCACTTGCCCTGCTGTCATTTAAAGGTGAACATTCTAGTTTTGCTAAGAAAAC CCTTTCCTTCATTTGGAATGAACAGCAATTTTATTACTTTTGACCTTAAAATGAGTTTGCTGCCTTCAAATCTTTTCAGCGCCT TCATCACGCTCTGCTTCGGGGCGATCTTCTTCCTGCCAGACTCCTCCAAGCTGCTCAGCGGGGTCCTGTTCCACTCCAGCCCCG CCTTGCAGCCGGCCGCCGACCACAAGCCCGGGCCCGGGGCGCGCGCCGAGGACGCGGCCGAGGGGCGAGCCCGGCGCCGCGAGG AGGGGGCACCCGGGGACCCGGAGGCCGCCCTGGAGGACAACTTGGCCAGGATCCGCGAAAACCACGAGCGGGCTCTCAGGGAAG CCAAGGAGACCCTGCAGAAGCTGCCCGAGGAGATCCAAAGAGACATCCTACTGGAGAAGAAGAAGGTGGCCCAGGACCAGCTGC GTGACAAGGCGCCGTTCAGAGGCCTGCCCCCGGTGGACTTCGTGCCCCCAATCGGGGTGGAGAGCCGGGAGCCCGCCGACGCCG CCATCCGCGAGAAAAGGGCAAAGATCAAAGAGATGATGAAACATGCTTGGAATAATTATAAAGGTTATGCCTGGGGATTAAATG AACTCAAACCTATATCAAAAGGAGGCCATTCAAGCAGTTTGTTTGGTAACATCAAAGGAGCAACTATAGTAGATGCCCTGGATA CACTTTTTATTATGGAAATGAAACATGAATTTGAAGAAGCAAAATCATGGGTTGAAGAAAATTTAGATTTTAATGTGAATGCTG AAATTTCTGTCTTTGAAGTAAATATACGCTTTGTTGGTGGACTACTCTCAGCCTACTATCTGTCTGGAGAAGAGATTTTTCGAA AGAAAGCAGTGGAACTTGGGGTAAAATTGCTACCTGCATTTCATACTCCCTCTGGAATACCTTGGGCATTGCTGAATATGAAAA GTGGTATTGGAAGGAACTGGCCCTGGGCCTCTGGAGGCAGCAGTATTCTGGCAGAATTTGGAACCCTGCATTTGGAGTTTATGC ACTTGAGCCACTTATCAGGAAACCCCATCTTTGCTGAAAAGGTAATGAATATTCGAACAGTACTGAACAAACTGGAAAAACCAC AAGGCCTTTATCCTAACTATCTGAATCCCAGTAGTGGACAGTGGGGTCAACATCATGTATCAGTTGGAGGACTTGGAGACAGCT TCTATGAGTATTTGCTGAAGGCCTGGTTAATGTCTGACAAGACAGATCTGGAAGCTAAGAAGATGTATTTTGATGCTGTTCAGG CTATCGAGACTCATTTGATCCGCAAGTCTAGCAGCGGACTAACTTATATCGCAGAGTGGAAAAGGGGCCTCCTGGAGCACAAGA TGGGCCACCTGACCTGCTTCGCGGGGGGCATGTTCGCACTCGGGGCTGATGCAGCTCCCGAAGGCATGGCCCAACACTACCTTG AACTCGGGGCTGAAATTGCCCGTACTTGTCATGAATCATATAATCGAACATTTATGAAACTGGGACCAGAAGCTTTCAGATTTG ATGGTGGTGTTGAAGCCATCGCTACAAGACAAAATGAAAAATACTACATCTTACGGCCAGAAGTTATGGAGACTTACATGTATA TGTGGAGACTGACTCATGATCCAAAGTACAGGAAATGGGCCTGGGAAGCCGTAGAGGCCTTGGAAAACCATTGCAGAGTGAATG GAGGCTATTCAGGCCTAAGGGATGTTTACCTTCTTCATGAGAGTTATGATGATGTGCAGCAGAGTTTCTTCCTGGCAGAGACAT TGAAATATTTGTACCTAATATTTTCTGACGACGATCTTCTTCCACTGGAGCATTGGATCTTCAATAGCGAGGCACATCTTCTCC CTATCCTCCCTAAAGATAAAAAGGAAGTTGAAATCAGAGAGGAATAAAAAAGACATTTATATTTTATTCTGCTCCATTCCCTTC ACTGTATACCTTAATAATTCCTTTTCTGGTAATCAGGCACATGATGAACTTTGATTAGTAGGTCTGTGATTAAGTTCTTAAATT GTTTTGCAGTCTTTTATGTTTATTATCATAGGTATAGGTGGACCTAAATTCCTTATCATATCTTTATTAATTCAGCCAGTGTAT CCACCAGTTTTTTGTTTATGTTTTTAAGTAACCTATTATCTCTGGATTTCATGAAGGTGTAATATCGTTTTTGTTAAACTGAAT AGAATTGTATAGCGATGACCTCTTAATTATAATTTGATTTGACTGCAAAACTTTTTCCTCCTCTAAGAGGAGATGATGTCTGCT TTAAGCTGTAATGTTTTGCCATGTTGCAAAAAGCCATAATAATAAGTATAAAAAAGCTTTTTCCTTTACAATTTCATGTTAATC TGGTTTGTCTGTCCACCAGAGACAGATCTTCTGTGACAGCCTCCTTATGCAGGTCTATCATTATTTGATAGAATGTCTTCTAAA ATACTTCACTCACATTGTAATTCAAATTAGAAAGTCATTCCAAAAGGTCATGTCATGTTGACCTCATTTCATCGGAACTGCAGT ATATTTTTGTTGGTTAATTATATTAGTGTTTTCTATTTTGAAAAAAAAAAAAAAAAAA
124
TTTTGGTCTGAGAATGATGGACATTTAGACACTGGCGCCAGGTTTGCGCTGGACCGGCGCACGCAGGGGTTGGGCGGACGAAAG ACACACAGGTGGGCTACAGGTGTCACACGGCACCAGCCAGGGCCCGGGGTGGCTGGGGTGAGGATGGGTGTTTGGCCAGTGACC AGGAGTCAGGTCAAGTCCAGGTGGTCAGTGCCAGGGGTCCCAGGAGGGGAGGGCAGTGCATTAACCCTCCTGGTGTCCAGCGTC ACCAGGCGGTCGTCACAGAAAGCAACCTCGGCCCGGGGCCG
126 TTATATATTACATGTTTATTAAGAGCACAACTTTTATGTAAAATTTACATTTAATGAAAAAAATCAAAAATATTTACAAAAT CTTGGAAGACAGATGTGCATTGTTCTAATTACAATCCAAAGTAGTAAATAACAATCCTTTAAAACTCACATTTATTAGAGTTGT GTTTACAAATTCTTGGTTAAAGAGGCAGCTACAAAGTTTACCACTATATATAAGCAAGAACCAGCTTGCTAGGTACATTTCCCA TTGAAAATCTACTGGTCTCTTTTACACCATTAGTGGATTTTTAAATGGAAAAAAAAAATCAATATAAACTCATATGGCTTCAAA ATTGTA
128
AATATAGTTATCTTCTTAAAAACCATTATAACAATTCAGAGAGAGTTCTTTACAAAGCCATGAATATGAACTATGGGGAATCAT GGTTCTTTTAAAGCAATTTTCAAAATAAGTACCAATTAAAGCTTTAGGTTCCAAGAAGATTCTGGGACTCAGGAAGAAAAAGTG CCATCAGGTGACCAGCTGTTGCATTTCTTGCTTATTCTGTTTTGTTTTTGCACATCATAATGGATTTTTCTTAGTGCCCTAATT GTGAAGGGTTTCTCTAGCTTTGGTTATGTGTAATGTTCACGTGACCTTTTTTTGTCAATCGTTTTTGGAATTTTTCTTTCTTTC TGTGCTTTATTACTAATAAGTCCAATGAGTGAGTAGTAGCTAGATGACTAGTATGTAGTTTTATATTTTGGTAAAATTATTTGC CCTTTCAGAAATGCCTCATCTAAAGATACATGATAATTTTGGAGTTGGAGGGGGCCTTAGAGGCTCTCCAGCTCTGCTTCTTGC CCATTGCCAAATACTGAAATGGAAGCCCGTCTTACCTGGGGTCACTAACTGGTTGGTTAACTGAGCTAAGAATAGGCTGTGGGT CTCCTCACTTGTGGCCCAGTGCTCTTTCTGCTATACAAAATGTCTAATCTCAGATTTTTCTTCTGCTGCTTGACTGCTTCATCT GGATGAACTACAAAAAACCCATGATTAAGGTTTATGAATTCAAGTAATAATTAGATTTTTTTTGCACAGACTTACTTAACTTCC TTATTGGATATGTTTGTAACACATAAACACAAAGCACTTTTCAAACATGATGCACTTTTATCTTTGTGAATAATTTACTGTCCT TTCCTCCTGGGATATGAGAAACATTTTAAAAAACGTATTTAACAGAAGAGAGCAAATAAAGATATATCAGGAAGGATGTATTAG TTATTTACTTAAATGTTTATAATATCTGGATTTTTTTTGTTTTGTTACTCATAGAACTGGTGTTGTTTGCTGTTTTTATTTCTC TAATTGTTGCAGAGTTCTGCCTGTTACAAAGCTACAGAACTGTATTGTTTTTATTTTCCTTCTTGAGCACATGTTAACAAACTA AGCTTCACATTAGAGTGATGTCATAATGTAAAATGTTTGCATTGTGGTTAGGTATTGAAGTTTATGTCCTGTCTGTGTAAAGAT TCATCTTTTATTGTAAATATTTAGACTTTACCACAGAAATATTGGAACAGTTTGCTTTATAAGATTAAAAAGCATCCTTCAGAA TGGAGCTTGCCTTGTGCTTAGAAATAATATGTTGAACTATTTTGCAATATACTATTTTAAATCTAAATTCTGTCACTTCGCTGC CTTCTTAAAATAGTGTGGTATTTCAAATATTGCTAGAGCTATTTTCCTGAAATACATTTGCAAAATAAGGCTGCTTTGTAATCA AGGAATATTTTTATTGATTGAAGGAAATGACTGTACTGCGATTCAAAAGTAAACTTATTTTATTATACAGATTATTTCTTAAAA ACTCTATTTATACCTTAACATGAAATCCATGACCACACCAAACTTGGTTATTCATAATTTTTCCTGTTAAATATAAAACACTGT AAGTTAAAAACAGTAATGCCAACATTGAATTTATTTTTGAGGTCAAAGAACCAGTTGTTCTTTTTATATTTAGATGAGGATGAT TGAGTCCATATACTATGTATGTTTACATATACTATACATGCACATTAGGTGTTTTCATTTGTGTTTTGCTTATGAAATGTCATT TAAAGTTCACTTCTTGAGCATCAATAAAAAGGGAAGCTGTGTGGTTTTGG
129
MSLMVSAGRGLGAVWSPTHVQVTV QARG RAKGPGGTSDAYAVIQVGKEKYATSVSERSLGAPVWREEATFELPSLLSSGPAA AAT QLTVLHRALLGLDKFLGRAEVDLRDLHSSLGKSFFKTLKKRAWAIFLRLCLKKN
130 GTGGAGGCCGCCAGTCGCGGCGATCTTCTCCTCGCTTCTGGAGTGTTATCGTCACCATGTCCCTAATGGTCTCGGCTGGCCGGG GCCTGGGGGCCGTGTGGTCCCCAACCCACGTGCAGGTGACGGTGCTGCAGGCGCGGGGCCTGCGGGCCAAGGGCCCCGGGGGCA CGAGCGACGCGTACGCGGTGATCCAGGTGGGCAAGGAGAAGTACGCCACCTCCGTGTCGGAGCGCAGCCTGGGCGCGCCCGTGT GGCGCGAGGAGGCCACCTTCGAGCTGCCATCGCTGCTGTCCTCCGGACCCGCGGCCGCCGCCACCCTGCAGCTCACCGTGCTGC ACCGCGCGCTGCTCGGCCTCGACAAGTTCCTGGGCCGCGCCGAGGTGGACCTGCGGGATCTGCACTCCAGCCTGGGCAAGAGTT TTTTTAAGACTCTTAAAAAAAGAGCCTGGGCAATTTTTTTAAGACTCTGTCTTAAAAAAAACTAAAAAGAAAAAAAGAAGCCCC TTCACTCTACAGGGGACAGGAGACCATGGATTGGACCCCAAAGGGATTGAACTGCATCTGCATGTCTGTCCTTTGAACACTTTC TCTCCCTGCCCAAAAGGAAACCCAAATTATTTGTGGGATACTGGGGAAATTGTAGTGAAGGGCTTAATGTAGTTAATAAAAGTT AAAAGTCAGTAGAAAACAGGTGCCTCAGCCTTCAAATGGTTGCTTTTTTTCCATTTTCCCTCATGAATAGACTCACCAGCATTT TACCCCCTTGTTATAAAACTGTGCAGAGCAAGAAGATGATACTTATTTTTGAATTTGTATTTTTAAAACTAGATTTATAGACTT TTTTTTTTTTTAACTAGGGCACTTGCTTCCTTCTTAGCTAAAAGCACCAGCTGAGATTTTTCAGGTAATTTTGTTGTTACTCAC TTAAGACTGGAATTAGAATGTTTCTGGTATTTCTCATTTTTTTCCCTGGCTATGATAGAATCTCATCTAATCTTGACATCTCTC CTAGGGGAAGAATATCACAGGCTAATAGCGTGGTTGGGGGTGAAGATGATAGCAGTTATTAAATCAGGAATCTCTTTTATGTAT GTCCTTGTTACATTGAGGTTAAGAGACAAAATCATTGGCAGTGCAATCTCTTTCCAGGATTTCGTTTGCTGTGGCATTGGTTAT ATCAGAGCACTTTAATCTGAAGGATGATACTGTAACTTGATTTATCTAATTAGCTTTTAATTATCTACAGCTATTTTATTTTAT TTAATTCTCTCCTACAGTACTGGGACCACTGTAAACTTCTCAGATGACTTGTATTTTTGTAGTGCTATGAAATTTATTTACATA CTTATAAAGAAAACTGTATGTTCACTTGAAAAAAAAAAAAAAAAAA
131 MCAFP L QEGSQRR R CGSEEWAVL ESISLPLEIPPDEEVENIIWSSHKSLATWPGKEGHPATIMVTNPHYQG QVSFLDPSYSLHISNLSWEDSGLYQAQVNLRTSQISTMQQYNLCVYRW SEPQITV FESSGEGACSMSLVCSVEKAGMDMTYS LSRGDSTYTFHEGPVLSTSWRPGDSALSYTCRA NPISNVSSCPIPDGPFYADPNYASEKPSTAFCLLAKGLLIFLL VILAM G WVIRVQKRHKMPP-MKKLMRNRMKLRKEAKPGSSPA 132
ACTAGGAGCCTCCTAATGCAGTCTTCTGCACAGTCCTGGGGACTGACTGACTGAATCACACCTCTGGGGCTGGGGGCTGCTGAC ATGTGTGCCTTTCCTTGGCTGCTTCTTCTCCTGCTGCTCCAGGAGGGCAGCCAAAGGAGACTCTGGAGATGGTGTGGATCCGAG GAAGTGGTTGCGGTCCTTCAGGAGTCCATCAGCCTCCCCCTGGAAATACCACCAGATGAAGAGGTTGAGAACATCATCTGGTCC TCTCACAAAAGTCTTGCCACTGTGGTGCCAGGGAAAGAGGGACATCCAGCTACCATCATGGTGACCAATCCACACTACCAGGGC CAAGTGAGCTTCCTGGACCCCAGCTATTCCCTGCATATCAGCAATCTGAGCTGGGAGGATTCAGGGCTTTACCAAGCTCAAGTC AACCTGAGAACATCCCAGATCTCTACCATGCAGCAGTACAATCTATGTGTCTACCGATGGCTGTCAGAGCCCCAGATCACTGTG AACTTTGAGAGTTCTGGGGAAGGTGCCTGCAGTATGTCCCTGGTGTGCTCTGTGGAGAAGGCAGGCATGGATATGACCTACAGC TGGCTCTCCCGGGGGGATAGCACTTATACATTCCATGAAGGCCCTGTCCTCAGCACATCCTGGAGGCCGGGGGACAGTGCCCTC TCCTACACCTGCAGAGCCAACAACCCCATCAGCAACGTCAGTTCTTGCCCCATCCCTGATGGGCCCTTCTATGCAGATCCTAAC TATGCTTCTGAGAAGCCTTCAACAGCCTTCTGCCTCCTGGCCAAGGGATTGCTCATCTTCTTGCTCTTGGTAATTCTGGCCATG GGACTCTGGGTCATCCGAGTCCAGAAAAGACACAAAATGCCAAGGATGAAGAAACTCATGAGAAACAGAATGAAATTGAGGAAG GAGGCAAAGCCTGGCTCCAGCCCTGCCTGACTGCTCCTTGGGAACCCCAGTCCTGAGCTTGGTTTCTTCCCAGCACCCAGAGAA TCCTTCCTCAGCTCTCTTCTTTCCAGGGGAAGGAGGTGCTCAGGGGTGGGTATCCAGAGAGCCATACTTCTGAGGGAAGACTGG CTGGCAATAAAGTCAAATTAAGTGACCACCAAAAAAAAAAAAAAAAA 133
MIEEKSDIETLDIPEPPPNSGYECQLRLRLSTGKDLKLWRSTDTVFHMKRRLHAAEGVEPGSQRWFFSGRPLTDKMKFEELKI PKDYWQVIVSQPVQNPTPVEN
134
ATATCAGCTTCCAGTGTATTGCTTGGCACCGCCAATCAACATGATAGAGGAAAAGAGCGACATAGAGACTCTGGATATTCCTGA GCCACCACCCAATTCTGGATATGAATGTCAGCTTCGTTTGCGC.CTTTCCACAGGCAAAGACCTCAAGCTTGTGGTTCGCAGCAC AGACACAGTATTCCACATGAAGAGACGGTTGCATGCAGCAGAGGGAGTGGAACCAGGTAGTCAGCGGTGGTTTTTTTCTGGCAG ACCTCTCACTGACAAAATGAAGTTCGAAGAGCTGAAGATCCCAAAGGACTATGTTGTACAGGTTATAGTGAGCCAACCTGTGCA GAACCCAACACCAGTGGAGAACTGAACTGAGCCCTGTTGGCCAGCTCCCACATCCCTCTGCTCCTTTTTATGGTTCTTGTTGTC ATTTCCTACTCTGCGGCGTGAAATCTATTTCACTGCTCTAAATTCCCTATGAATGGATTTAGTTCTGAGGAATTACCAGTGAAA AATTCCATCTGTGATGGAGACCAACAAAAATAATAAAACACAAAGAGCCAGGCTTTGAGACTCATGTAATTACAATTTCTAATT TGAAAGGCAGT.TAAGAAATAGATAACCATTTATTTTAGAACACTCAACAACTATGTAATGGCTATATTTCAGTGACTTGGACTG TAAATGAAACATTGCATCCATGAAGGACAGCACCAAGCACCTTTTTGAATACAGAATTTTTTTAGAAAAATATATCAAATTATA TAATTTCCAGAAACCATAAATAATGGATATAAAACTTAACCTTTTTGTTTTGTTTTGTTTTGTTTTGTTTTGTTTTGTTTTGGT TAATGGAAACTGAAAAGAGCAGTATTTGAGGTTGCTTCTATTCTGGTTTTTTATTCTTAGCTCAATTAATATTTAGCCATAAAT GAGTAGAGACTGGCAAATTGTGCTTTAGTGTTGCTTTCCTCATCCCCACATCTTGAGCTCCTTATTTACATTCACACTAAATTT TGGTGCCTTCCAGCACATTAGTGGCAGGCACCCTTCTGGAACACTAGGCAATAATTTCATCAATACAGTCAGGTCTCTTGAGTT TCAACAGATACTCAGTTGAAAAGTCGCTGTCATCTTGCTGCATAAGTATTTTGAAAGGTCTGTATAACGAAGCCATTTTTATAT CCAGGCTTAGAAGGTCACTACTATATAGTACCTTCATTGATCTATCTATTCTGCTTGGAACTTTTCATAGCTAAGTATAACCCC CAAATGCATGGTTCCTGGGTCAGGAGACACCAAAATCAATTATAGCTGTTCCCACTCAAGTTAATAAAGTAAATGATTTCCTCC ACTTTGCATGGAGGGGTGTAAGGAAAGCCTATTTTATCTGTGCCTGGGAGAACTGTGCCTATTTTCAGTCTTTTAGAGGAAATT TCAACTCAAAATTTTTAAGTGTGAAAGGTTTACTGGTGTCACATAAACATTAGCAGTGAGACCAAATAATGAAACATTGCTTTA TACCTTAGTGCTTTCCAGTTCACTGTTACCTCTAGTCATGGTAGATGACAATTTTCCTCCCTCATCTTTTGTAGCAAAGAAGCA AATTAAGAGCCTTTTGCAAGTTAGATTAGGGGACTGAAAAATCCAGGGAGATAACCTGATTCTTCTATACTATGACTGGAGTAA AGCTGCCAAGAGTTAGGTTGAATTTGGAGCCTTTTAAAAGTTGGTTCCATAAGTGAGAAGGGGGGCTAACATGTGACCACTGTG CCCCTGAGAATCCATGAGATGGAAAAGTACAGACAAGAAGGCACTTAACGCTGTTCTCAGTTGGAAAATGTCAGCCCTCCACAC CTGTTTGGATGTGAAGTGCATTATTAATTTTAATGACAAAATGAAACTGCTAATTAGTTTAAATGTAATGTTTAAATGGTATTG AATTTCCTATTGCCTGATTAAATATATCTGTAATTGTAACATCATGTTTCTGAGAGCTTTAACTACTTCCTTATTTTTATGCAA TCATTTTAAAGATTGTGGCTATATCTAATTTAAATTTGCTGATGATTGAATCTAAATTCAAGTGAAGACCACAGCATTAATCCC AAAGGAGATTTTTTTTATGTTTAGAGGTGGAGATATTAGGGTAAATCAGTATATTGCTCCTGTCATCAAAGTTTTTGTTCATTT GTGTGCCACATCGAATAGCAGCACTTCTCAAAGTTTGTCAACTGGAAAAAAGTGTTTAAAACTGTTTTTTTCTTAAGCAGATTT GGTGATGTCATCAATATCTATGATATCGATTGGTAAAAGGTCTTTCTTTGTTGAGGATTTGAGCTCTCTTTTTAAGAGTTTATT TTATTTTAAAGGAACATATGCTTTGAATAACAATTCTCTGGGCATGTTTAACTAACCTAGGTGGGAAAACCATGGTGCTGTTTA ATTGTAAATAGATTGATATAAGATTGGACCAGTACTTGATGTGTATAATTTTAGTATGTAGGGTTTATGTGCTTTTTTTAAAAA AAAAAAAAAGGTTCAATTTT
136
GGAAGGTATTAGACAAACATGCCCATGAAACCCCAGCTTCCCTTTTCTATGTGCTAGGCATGGAAACTTATGAAATTTTAGCAC TCCAAAGTCATTTGGACTTCAAGGCATTTAAAATCATTTTTCTAAGGATTTAAACAGCTCCACTATAAGTCTTCACCTGACATG AATTGGTGAGAGACCAGGCTGATCCTGGCAAAGGTCTTGTGTCTTTCTGCCAGGCAAAATCCTGGGTTCTTCTAGCAGGACCTA AGCCAGTCTGGGGACGCTGATATTGAGGATGAGCTGGGGGACTCTGCTCTGTCCTCTGTGAACACACAGGAGGCCCATCCAGAG TGAGTGAGGTTGATTCTCTCTCCCTCTTTGC . .
137 ' '
MGTS SPNDPWPLNPLSIQQTTLLLLLSVLATVHVGQRLLRQRRRQLRSAPPGPFAWP IGNAAAVGQAAHLSFARLARRYGDV ' FQIRLGSCPIWLNGEP-AIHQALVQQGSAFADRPAFASFRWSGGRS FGHYSEHWKVQRRAAHSMMRNFFTRQPRSRQVLEG HVLSEARELVAL VRGSADGAF DPRPLTWAVANVMSAVCFGCRYSHDDPEFRELLSHNEEFGRTVGAGSLVDVMP LQYFPN PVRTVFREFEQ NrøFSNFILDKFLRHCESLRPG PRDMMDAFILSAEKKAAGDSHGGGAR D EN¥PATITDIFGASQDT S TALQWLLLLFTRYPDVQTRVQAELDQWGRDRLPCMGDQPNLPYVLAFLYEAMRFSSFVPVTIPHATTA TSVLGYHIPKDTVV FWQWSWHDPVKWPNPENFDPARF DKDGLINKDLTSRVMIFSVGKRRCIGEELSKMQ FLFISI AHQCDFRANPNEPAKMN FSYG TIKPKSFKV VT RESME LDSAVQNLQAKETCQ
138
ACTCTGGAGTGGGAGTGGGAGCGAGCGCTTCTGCGACTCCAGTTGTGAGAGCCGCAAGGGCATGGGAATTGACGCCACTCACCG ACCCCCAGTCTCAATCTCAACGCTGTGAGGAAACCTCGACTTTGCCAGGTCCCCAAGGGCAGCGGGGCTCGGCGAGCGAGGCAC CCTTCTCCGTCCCCATCCCAATCCAAGCGCTCCTGGCACTGACGACGCCAAGAGACTCGAGTGGGAGTTAAAGCTTCCAGTGAG GGCAGCAGGTGTCCAGGCCGGGCCTGCGGGTTCCTGTTGACGTCTTGCCCTAGGCAAAGGTCCCAGTTCCTTCTCGGAGCCGGC TGTCCCGCGCCACTGGAAACCGCACCTCCCCGCAGCATGGGCACCAGCCTCAGCCCGAACGACCCTTGGCCGCTAAACCCGCTG TCCATCCAGCAGACCACGCTCCTGCTACTCCTGTCGGTGCTGGCCACTGTGCATGTGGGCCAGCGGCTGCTGAGGCAACGGAGG CGGCAGCTCCGGTCCGCGCCCCCGGGCCCGTTTGCGTGGCCACTGATCGGAAACGCGGCGGCGGTGGGCCAGGCGGCTCACCTC TCGTTCGCTCGCCTGGCGCGGCGCTACGGCGACGTTTTCCAGATCCGCCTGGGCAGCTGCCCCATAGTGGTGCTGAATGGCGAG CGCGCCATCCACCAGGCCCTGGTGCAGCAGGGCTCGGCCTTCGCCGACCGGCCGGCCTTCGCCTCCTTCCGTGTGGTGTCCGGC GGCGGCAGCATGGCTTTCGGCCACTACTCGGAGCACTGGAAGGTGCAGCGGCGCGCAGCCCACAGCATGATGCGCAACTTCTTC ACGCGECAGCCGCGCAGCCGCCAAGTCCTCGAGGGCCACGTGCTGAGCGAGGCGCGCGAGCTGGTGGCGCTGCTGGTGCGCGGC AGCGCGGACGGCGCCTTCCTCGACCCGAGGCCGCTGACCGTCGTGGCCGTGGCCAACGTCATGAGTGCCGTGTGTTTCGGCTGC CGCTACAGCCACGACGACCCCGAGTTCCGTGAGCTGCTCAGCCACAACGAAGAGTTCGGGCGCACGGTGGGCGCGGGCAGCCTG GTGGACGTGATGCCCTGGCTGCAGTACTTCCCCAACCCGGTGCGCACCGTTTTCCGCGAATTCGAGCAGCTCAACCGCAACTTC AGCAACTTCATCCTGGACAAGTTCTTGAGGCACTGCGAAAGCCTTCGGCCCGGGGCCGCCCCCCGCGACATGATGGACGCCTTT ATCCTCTCTGCGGAAAAGAAGGCGGCCGGGGACTCGCACGGTGGTGGCGCGCGGCTGGATTTGGAGAACGTACCGGCCACTATC' ACTGACATCTTCGGCGCCAGCCAGGACACCCTGTCCACCGCGCTGCAGTGGCTGCTCCTCCTCTTCACCAGGTATCCTGATGTG CAGACTCGAGTGCAGGCAGAATTGGATCAGGTCGTGGGGAGGGACCGTCTGCCTTGTATGGGTGACCAGCCCAACCTGCCCTAT GTCCTGGCCTTCCTTTATGAAGCCATGCGCTTCTCCAGCTTTGTGCCTGTCACTATTCCTCATGCCACCACTGCCAACACCTCT GTCTTGGGCTACCACATTCCCAAGGACACTGTGGTTTTTGTCAACCAGTGGTCTGTGAATCATGACCCAGTGAAGTGGCCTAAC CCGGAGAACTTTGATCCAGCTCGATTCTTGGACAAGGATGGCCTCATCAACAAGGACCTGACCAGCAGAGTGATGATTTTTTCA GTGGGCAAAAGGCGGTGCATTGGCGAAGAACTTTCTAAGATGCAGCTTTTTCTCTTCATCTCCATCCTGGCTCACCAGTGCGΆT TTCAGGGCCAACCCAAATGAGCCTGCGAAAATGAATTTCAGTTATGGTCTAACCATTAAACCCAAGTCATTTAAAGTCAATGTC ACTCTCAGAGAGTCCATGGAGCTCCTTGATAGTGCTGTCCAAAATTTACAAGCCAAGGAAACTTGCCAATAAGAAGCAAGAGGC AAGCTGAAATTTTAGAAATATTCACATCTTCGGAGATGAGGAGTAAAATTCAGTTTTTTTCCAGTTCCTCTTTTGTGCTGCTTC TCAATTAGCGTTTAAGGTGAGCATAAATCAACTGTCCATCAGGTGAGGTGTGCTCCATACCCAGCGGTTCTTCATGAGTAGTGG GCTATGCAGGAGCTTCTGGGAGATTTTTTTGAGTCAAAGACTTAAAGGGCCCAATGAATTATTATATACATACTGCATCTTGGT TATTTCTGAAGGTAGCATTCTTTGGAGTTAAAATGCACATATAGACACATACACCCAAACACTTACACCAAACTACTGAATGAA GAAGTATTTTGGTAACCAGGCCATTTTTGGTGGGAATCCAAGATTGGTCTCCCATATGCAGAAATAGACAAAAAGTATATTAAA CAAAGTTTCAGAGTATATTGTTGAAGAGACAGAGACAAGTAATTTCAGTGTAAAGTGTGTGATTGAAGGTGATAAGGGAAAAGA TAAAGACCAGAAATTCCCTTTTCACCTTTTCAGGAAAATAACTTAGACTCTAGTATTTATGGGTGGATTTATCCTTTTGCCTTC TGGTATACTTCCTTACTTTTAAGGATAAATCATAAAGTCAGTTGCTCAAAAAGAAATCAATAGTTGAATTAGTGAGTATAGTGG GGTTCCATGAGTTATCATGAATTTTAAAGTATGCATTATTAAATTGTAAAACTCCAAGGTGATGTTGTACCTCTTTTGCTTGCC AAAGTACAGAATTTGAATTATCAGCAAAGAAAAAAAAAAAAGCCAGCCAAGCTTTAAATTATGTGACCATAATGTACTGATTTC AGTAAGTCTCATAGGTTAAAAAAAAAAGTCACCAAATAGTGTGAAATATATTACTTMCTGTCCGTAAGCAGTATATTAGTATT ATCTTGTTCAGGAAAAGGTTGAATAATATATGCCTTGTGTAATATTGAAAATTGAAAAGTACAACTAACGCAACCAAGTGTGCT AAAAATGAGCTTGATTAAATCAACCACCTATTTTTGACATGGAAATGAAGCAGGGTTTCTTTTCTTCACTCAAATTTTGGCGAA TCTCAAAATTAGATCCTAAGATGTGTTCTTATTTTTATAACATCTTTATTGAAATTCTATTTATAATACAGAATCTTGTTTTGA AAATAACCTAATTAATATATTAAAATTCCAAATTCATGGCATGCTTAAATTTTAACTAAATTTTAAAGCCATTCTGATTATTGA GTTCCAGTTGAAGTTAGTGGAAATCTGAACATTCTCCTGTGGAAGGCAGAGAAATCTAAGCTGTGTCTGCCCAATGAATAATGG AAAATGCCATGAATTACCTGGATGTTCTTTTTACGAGGTGACAAGAGTTGGGGACAGAACTCCCATTACAACTGACCAAGTTTC TCTTCTAGATGATTTTTTGAAAGTTAACATTAATGCCTGCTTTTTGGAAAGTCAGAATCAGAAGATAGTCTTGGAAGCTGTTTG GAAAAGACAGTGGAGATGAGGTCAGTTGTGTTTTTTAAGATGGCAATTACTTTGGTAGCTGGGAAAGCATAAAGCTCAAATGAA ATGTATGCATTCACATTTAGAAAAGTGAATTGAAGTTTCAAGTTTTAAAGTTCATTGCAATTAAACTTCCAAAGAAAGTTCTAC AGTGTCCTAAGTGCTAAGTGCTTATTACATTTTATTAAGCTTTTTGGAATCTTTGTACCAAAATTTTAAAAAAGGGAGTTTTTG ATAGTTGTGTGTATGTGTGTGTGGGGTGGGGGGATGGTAAGAGAAAAGAGAGAAACACTGAAAAGAAGGAAAGATGGTTAAACA TTTTCCCACTCATTCTGAATTAATTAATTTGGAGCACAAAATTCAAAGCATGGACATTTAGAAGAAAGATGTTTGGCGTAGCAG AGTTAAATCTCAAATAGGCTATTAAAAAAGTCTACAACATAGCAGATCTGTTTTGTGGTTTGGAATATTAAAAAACTTCATGTA ATTTTATTTTAAAATTTCATAGCTGTACTTCTTGAATATAAAAAATCATGCCAGTATTTTTAAAGGCATTAGAGTCAACTACAC
AAAGCAGGCTTGCCCAGTACATTTAAATTTi?TTGGCACT'TGCCATTCCAAAATATTATGCCCCACCAAGGCTGAGACAGTGAAT
TTGGGCTGCTGTAGCCTATTTTTTTAGATTGAGAAATGTGTAGCTGCAAAAATAATCATGAACCAATCTGGATGCCTCATTATG
TCAACCAGGTCCAGATGTGCTATAATCTGTTTTTACGTATGTAGGCCCAGTCGTCATCAGATGCTTGCGGCAAMGAMGCTGT GTTTATATGGAAGAAAGTAAGGTGCTTGGAGTTTACCTGGCTTATTTAATATGCTTATAACCTAGTTAAAGAAAGGAAAAGAAA ACAAAAAACGAATGAAAATAACTGAATTTGGAGGCTGGAGTAATCAGATTACTGCTTTAATCAGAAACCCTCATTGTGTTTCTA CCGGAGAGAGAATGTATTTGCTGACAACCATTAAAGTCAGAAGTTTTACTCCAGGTTATTGCAATAAAGTATAATGTTTATTAA ATGCTTCATTTGTATGTCAAAGCTTTGACTCTATAAGCAAATTGCTTTTTTCCAAMCAAAAAGATGTCTCAGGTTTGTTTTGT GAATTTTCTAAAAGCTTTCATGTCCCAGAACTTAGCCTTTACCTGTGAAGTGTTACTACAGCCTTAATATTTTCCTAGTAGATC TATATTAGATCAAATAGTTGCATAGCAGTATATGTTAATTTGTGTGTTTTTAGCTGTGACACAACTGTGTGATTAAAAGGTATA CTTTAGTAGACATTTATAACTCAAGGATACCTTCTTATTTAATCTTTTCTTATTTTTGTACTTTATCATGAATGCTTTTAGTGT GTGCATAATAGCTACAGTGCATAGTTGTAGACAAAGTACATTCTGGGGAAACAACATTTATATGTAGCCTTTACTGTTTGATAT ACCAAATTAAAAAAAAATTGTATCTCATTACTTATACTGGGACACCATTACCAAAATAATAAAAATCACTTTCATAATCTTGAA AAAA 139
MDISTRSKDPGSAERTAQKRKFPSPPHSSNGHSPQDTSTSPIKKKKKPGLLNS KEQSELRHGPFYYMKQPLTTDPVDWPQD GMDFYCWVCHREGQV CCELCPRVYHAKCLR TSEPEGDWFCPECEKITVAECIETQSKAMTMLTIEQLSYLLKFAIQKMKQP GTDAFQKPVPLEQHPDYAEYIFHPMDLCTLEKNAKKKMYGCTEAFLADAK I HNCIIYNGGNHKLTQIAKWIKICEHEMNEI EVCPECYL CQKRDMFCEPCSNPHP AKLKGFPFWPAKALRDKDGQVDARFFGQHDRAWVPINNCY MSKEIPFSVKKTK SIFNSAMQEMEVYVENIRRKFGVFNYSPFRTPYTPNSQYQM LDPTNPSAGTAKIDKQEKVKL-.FDMTASPKI S PVLSGGT GRRISLSDMPRSPMSTNSSVHTGSDVEQDAEKKATSSHFSASEESMDFLDKSTASPASTKTGQAGSLSGSPKPFSPQLSAPITT KTDKTSTTGSILNLNLDRSKAEMDL ELSESVQQQSTPVPLISPKRQIRSRFQLNLDKTIESCKAQLGINEISEDVYTAVEHSD SEDSEKSDSSDSEYISDDEQKSK EPEDTEDKEGCQMDKEPSAVKKKPKPTNPVEIKEELKSTSPASEKADPGAVKDKASPEPE KDFSEKAKPSPHPIKDKLKGKDETDSPTVHLGLDSDSESELVIDLGEDHSGREGRKNKKEPKEPSPKQDVVGKTPPSTTVGSHS PPETPV TRSSAQTSAAGATATTSTSSTVTVTAPAPAATGSPVKKQRPLLPKETAPAVQRWraSSSKFQTSSQKWHMQ MQRQ QQQQQQQNQQQQPQSSQGTRYQTRQAVKAVQQKEITQSPSTSTITLVTSTQSSPLVTSSGSMSTLVSSVNAD PIATASADVAA D1AKYTSKVNGCNKR NDR IQRSF
140
GGAGTGTAGAGGAAATAAAATCATGTCTGTGGCTCATGACAGCATTCCATATTCAGTTGTTGGGTTGTGTTGTTGTTGTTGTGT GTGTTTTTAATAATACCATGTAACTGTTTAAAAAAATTTCCTTTTTGATCAAGTCCCAAATCTGCCAGCCTGTTCTCTCTTCCT AACTGTGGAAAAATGAGACGGTTGCTTGAACATTTGTTGGCTTGGCTGAAGAGGAAATAAAAACAGAACAGGAGGTGGTAGAGG GCATGGATATCTCTACTCGCTCCAAAGATCCTGGCTCTGCAGAGAGAACAGCCCAGAAAAGAAAGTTCCCCAGCCCTCCACATT CTTCCAATGGCCACTCGCCGCAGGACACATCAACAAGCCCCATTAAAAAGAAAAAGAAACCTGGCTTACTGAACAGTAACAATA AGGAGCAGTCAGAACTAAGACATGGTCCGTTTTACTATATGAAGCAGCCACTCACCACAGACCCTGTTGATGTTGTACCGCAGG ATGGACGGAATGATTTCTACTGCTGGGTTTGTCACCGGGAAGGCCAAGTCCTTTGCTGTGAGCTCTGTCCCCGGGTTTATCACG CTAAGTGTCTGAGACTGACATCGGAACCAGAGGGGGACTGGTTTTGTCCTGAATGTGAGAAAATTACAGTAGCAGAATGCATCG AGACCCAGAGTAAAGCCATGACAATGCTCACCATTGAACAGTTATCCTACCTGCTCAAGTTTGCCATTCAGAAAATGAAACAGC CAGGGACAGATGCATTCCAGAAGCCCGTTCCATTGGAACAGCACCCTGACTATGCGGAATACATCTTCCATCCAATGGACCTTT GTACATTGGAAAAGAATGCGAAAAAGAAAATGTATGGCTGCACAGAAGCCTTCCTGGCTGATGCAAAGTGGATTTTGCACAACT GCATCATTTATAATGGGGGAAATCACAAATTGACGCAAATAGCGAAAGTAGTCATCAAAATCTGTGAACATGAGATGAATGAAA TCGAAGTATGTCCAGAATGTTATCTAGCTGCTTGCCAAAAACGAGATAACTGGTTTTGTGAGCCTTGTAGCAATCCACATCCTT TGGTCTGGGCCAAACTGAAGGGGTTTCCATTCTGGCCTGCAAAAGCTCTAAGGGATAAAGACGGGCAGGTCGATGCCCGATTCT TTGGACAACATGACAGGGCCTGGGTTCCAATAAATAATTGCTACCTCATGTCTAAAGAAATTCCTTTTTCTGTGAAAAAGACTA AGAGCATCTTCAACAGTGCCATGCAAGAGATGGAGGTTTACGTGGAGAACATCCGCAGGAAGTTTGGGGTTTTTAATTACTCTC CATTTAGGACACCCTACACACCCAACAGCCAGTATCAAATGCTGCTCGATCCCACCAACCCCAGCGCCGGCACTGCCAAGATAG ACAAGCAGGAGAAGGTCAAGCTCAACTTTGACATGACGGCATCCCCCAAGATCCTGATGAGCAAGCCTGTGCTGAGTGGGGGCA CAGGCCGCCGGATTTCCTTGTCGGATATGCCGCGCTCCCCCATGAGCACAAACTCTTCTGTGCACACGGGCTCCGACGTGGAGC AGGATGCTGAGAAGAAGGCCACGTCGAGCCACTTCAGTGCGAGCGAGGAGTCCATGGACTTCCTGGATAAGAGCACAGCTTCAC CAGCCTCCACCAAGACGGGACAAGCAGGGAGTTTATCCGGCAGCCCAAAGCCCTTCTCTCCTCAACTGTCAGCTCCTATCACGA CGAAAACGGACAAAACCTCCACCACCGGCAGCATCCTGAATCTTAACCTGGATCGAAGCAAAGCTGAGATGGATTTGAAGGAGC TGAGCGAGTCGGTCCAGCAACAGTCCACCCCTGTTCCTCTCATCTCTCCCAAGCGCCAGATTCGTAGCAGGTTCCAGCTGAATC TTGACAAGACCATAGAGAGTTGCAAAGCACAATTAGGCATAAATGAAATCTCGGAAGATGTCTATACGGCCGTAGAGCACAGCG ATTCGGAGGATTCTGAGAAGTCAGATAGTAGCGATAGTGAGTATATCAGTGATGATGAGGAGAAGTCTAAGAACGAGCCAGAAG ACACAGAGGACAAAGAAGGTTGTCAGATGGACAAAGAGCCATCTGCTGTTAAAAAAAAGCCCAAGCCTACAAACCCAGTGGAGA TTAAAGAGGAGCTGAAAAGCACGTCACCAGCCAGCGAGAAGGCAGACCCTGGAGCAGTCAAGGACAAGGCCAGCCCTGAGCCTG AGAAGGACTTTTCCGAAAAGGCAAAACCTTCACCTCACCCCATAAAGGATAAACTGAAGGGAAAAGATGAGACGGATTCCCCAA CAGTCCATTTGGGCCTGGACTCTGATTCAGAGAGCGAACTTGTCATAGATTTAGGAGAAGACCATTCTGGGCGGGAGGGTCGAA AAAATAAGAAGGAACCCAAAGAACCATCTCCCAAACAGGATGTTGTAGGTAAAACTCCACCATCCACGACGGTGGGCAGCCATT CTCCCCCGGAAACACCGGTGCTCACCCGCTCTTCCGCCCAAACTTCCGCGGCTGGCGCCACAGCCAGCACCAGCACGTCCTCCA CGGTCACCGTCACGGCCCCGGCCCCCGCCGCCACAGGAAGCCCAGTGAAAAAGCAGAGGCCGCTTTTACCGAAGGAGACTGCCC CGGCCGTGCAGCGGGTCGTGTGGAACTCATCAAGTAAGTTTCAAACGTCCTCCCAAAAGTGGCACATGCAGAAGATGCAGCGTC AGCAGCAGCAGCAGCAGCAGCAAAACCAGCAGCAGCAGCCTCAGTCTTCCCAGGGGACGAGATATCAGACCAGACAGGCTGTGA AAGCTGTCCAGCAGAAGGAGATCACACAGAGCCCATCCACGTCCACCATCACCCTGGTGACCAGCACACAGTCATCGCCCCTGG TCACCAGCTCGGGGTCCATGAGCACCCTTGTGTCCTCAGTCAACGCTGACCTGCCCATCGCCACTGCCTCAGCTGATGTCGCCG CTGATATTGCCAAGTACACTAGCAAAATGATGGATGCAATAAAAGGAACAATGACAGAAATATACAACGATCTTTCTAAAAACA CTACTGGAAGCACAATAGCTGAGATTCGCAGGCTGAGGATCGAGATAGAGAAGCTCCAGTGGCTGCACCAGCAAGAGCTCTCCG AAATGAAACACAACTTAGAGCTGACCATGGCGGAGATGCGGCAGAGCCTGGAGCAGGAGCGGGACCGGCTCATCGCCGAGGTGA AGAAGCAGCTGGAGTTGGAGAAGCAGCAGGCGGTGGATGAGACCAAGAAGAAGCAGTGGTGCGCCAACTGCAAGAAGGAGGCCA TCTTTTACTGCTGTTGGAACACCAGCTACTGTGACTACCCCTGCCAGCAAGCCCACTGGCCTGAGCACATGAAGTCCTGCACCC AGTCAGCTACTGCTCCTCAGCAGGAAGCGGATGCTGAGGTGAACACAGAAACACTAAATAAGTCCTCCCAGGGGAGCTCCTCGA GCACACAATCAGCACCTTCAGAAACGGCCAGCGCCTCCAAAGAGAAGGAGACGTCAGCTGAGAAAAGCAAGGAGAGTGGCTCGA CCCTTGACCTTTCTGGCTCCAGAGAGACGCCCTCCTCCATTCTCTTAGGCTCCAACCAAGGCTCTGACCATTCCCGGAGTAATA AATCCAGTTGGAGCAGCAGTGATGAGAAGAGGGGATCGACACGTTCCGATCACAACACCAGTACCAGCACGAAGAGCCTCCTCC CGAAAGAGTCTCGGCTGGACACCTTCTGGGACTAGCAGTGAATCGGGACACAAACCACCCACCCCATTGGGAGAAAAACCCAGA CGCCAGGAAAAGAAGAAACAAGAAAGGCAGGAGAACAGCCACTTTCAGACTTGAAAATGAGAAAACCCTCAGTTGAGCCTGAGC CCCCGGCGCGGGGGCTGCTACACTACAGGACACCCAGCATCGGCTTTGACTGCAGACTGTTCACCCACACGAGCCCTGTGCTTT TGGTGTAAATAATGTACAATTTGTGGATGTCATTGAATCTAGAGGACTTTCCCCTTTTTATATTTGTATTAACTTTAACTTATT AAAAAAAAAAAAAGAAAAAGAAAAACGATTT
141 ALSSQIWAACLL LLLLASLTSGSVFPQQTGQLAELQPQDRAGARAS MPMFQRRRRRDTHFPICIFCCGCCHRSKCGMCCKT 142
TCAAGACCCAGCAGTGGGACAGCCAGACAGACGGCACGATGGCACTGAGCTCCCAGATCTGGGCCGCTTGCCTCCTGCTCCTCC TCCTCCTCGCCAGCCTGACCAGTGGCTCTGTTTTCCCACAACAGACGGGACAACTTGCAGAGCTGCAACCCCAGGACAGAGCTG GAGCCAGGGCCAGCTGGATGCCCATGTTCCAGAGGCGAAGGAGGCGAGACACCCACTTCCCCATCTGCATTTTCTGCTGCGGCT GCTGTCATCGATCAAAGTGTGGGATGTGCTGCAAGACGTAGAACCTACCTGCCCTGCCCCCGTCCCCTCCCTTCCTTATTTATT CCTGCTGCCCCAGAACATAGGTCTTGGAATAAAATGGCTGGTTCTTTTGTTTTCC
144
AAAGTCCTTGTAACATTGAGTTACAGGGCTTTAACTCCTGTGTCTGAAAAATCACAAACACTGATGACAATCAAAGCCTCATCT TAAGGCCCCGTAGAAGATGCCAATCAAAATAAACTGCATTCCTGAGGCACTAGGCAAGAAATTAAAGCTATTCAACTCCTCAAG GCCCAGGGACTATTGCGGAAGAGGTGGGCGCGTAAGATTGTAAGGGCCGATTTTGAAAGATCCAGTAAGTTCAGTTTCTCTATG AACTAATCATTCAAGTCAAAGGCACACTGATGCAAAATCAGTATATGGGACCCCTGTGTCTGGATTAGGCAAGGTTTTTCTTGG AAGCCTTTAACCAACTCCTTCCNTAAAGGGTTATTAAAAGGGCTTATGGGGAGTTATTATTTT
145
MGLPRGSFF LLL TAACSGLLFA YFSAVQRYPGPAAGARDTTSFEAFFQSKASNS TGKGQACRHLLHLAIQRHPHFRGLF NLSIPVLLWGDLFTPA DRLSQHKAPYG RGLSHQVIASTLSLLNGSESAKLFAPPRDTPPKCIRCAWGNGGILNGSRQGPN IDAHDYVFRLNGAVIKGFERDVGTKTSFYGFTWTMKNS VSYrøLGFTSVPQGQDLQYIFIPSDIRDYVMLRSAILGVPVPEG LDKGDRPHAYFGPEASASKFK LHPDFISYLTERFLKSKLINTHFGDLYMPSTGAL LLTALHTCDQVSAYGFITSNYWKFSDH. YFERKMKP IFYA HDLSLEAALWRD HKAGI QLYQR
146 GGGACGTCAGCGGACGGGGCGCTCGCGGGCCGGGGCTGTATGGGGCTCCCGCGCGGGTCGTTCTTCTGGGTGCTGCTCCTGCTC ACGGCTGCCTGCTCGGGGCTCCTCTTTGCCCTGTACTTCTCGGCGGTGCAGCGGTACCCGGGGCCAGCGGCCGGAGCCAGGGAC ACCACATCATTTGAAGCATTCTTTCAATCCAAGGCATCGAATTCTTGGACAGGAAAGGGCCAGGCCTGCCGACACCTGCTTCAC CTGGCCATTCAGCGGCACCCCCACTTCCGTGGCCTGTTCAATCTCTCCATTCCAGTGCTGCTGTGGGGGGACCTCTTCACCCCA GCGCTCTGGGACCGCCTGAGCCAACACAAAGCCCCGTATGGCTGGCGGGGGCTCTCTCACCAAGTCATCGCCTCCACCCTGAGC CTTCTGAACGGCTCAGAGAGTGCCAAGCTGTTTGCCCCGCCCAGGGACACCCCTCCAAAGTGTATCCGGTGTGCCGTGGTGGGC
AACGGAGGCATTCTGAATGGGTCCCGCCAGGGTCCCAACATCGATGCCCATGACTATGTATTCAGACTCAATGGAGCTGTGATC
• AAAGGCTTCGAGCGCGATGTGGGCACCAAGACTTCCTTCTATGGTTTCACTGTGAACACGATGAAGAACTCCCTCGTCTCCTAC
TGGAATCTGGGCTTCACCTCCGTGCCACAAGGACAGGACCTGCAGTATATCTTCATCCCCTCAGACATCCGCGACTATGTGATG
CTGAGATCGGCCATTCTGGGCGTGCCTGTCCCTGAGGGCCTAGATAAAGGGGACAGGCCGCACGCCTATTTTGGACCAGAAGCC TCTGCGAGTAAATTCAAGCTGCTACATCCGGACTTCATCAGCTACCTGACAGAAAGGTTCTTGAAATCAAAGTTGATTAACACA CATTTTGGAGACCTATATATGCCTAGTACCGGGGCTGTCATGCTGCTGACAGCTTTGCATACCTGTGACCAGGTCAGTGCCTAT GGATTCATCACAAGCAACTACTGGAAATTTTCCGACCACTATTTCGAACGAAAAATGAAGCCATTGATATTTTATGCAAACCAC GATCTGTCCCTGGAAGCTGCCCTGTGGAGGGACCTGCACAAGGCCGGCATCCTTCAGCTGTACCAGCGCTGACCCCAATGCACT GAGCGCTTTGCTTCTTCAAGAGTTGCGGCCCTGATCCTCTCAAGTGGCCAAAAGCTTTTTTAACTTTTCAATCTTCACCTTCCC TTGCCAACAGAGGGCACTGGGGTGAATTCAAGATTTTCATCGAGGTCTGTTCAATATAGGACACCCCAGCTTGTCCTTGGCTCA TCCAAGAACTCTTCTGTATCTAAAACAATACATCTCAATCTTGGCCAAGGGAAAATGGACTGCTTTGCTGGATTGGCACTGAGC AACTTTAGGAAATGTCGGTGGAGTGTTCAGCAAGATCAGACAGCAGTCCAGGTCAAAGGCAAACACACACGCTCCAGCCCAAAT CCTCCTGGTGGCACATCCTACCCCAGATGCTAAAGTGATTCAAGGACTCCAGGACACCTCTTAAGAGCCTTTCTAAGAACATGA TAGGCTTACTTCTGCTCCATAATAAAGTGGGAGAAAAAAGCCAGAATATAACTTAAGACTAGATAACTGCGTACATGATGGACC ATTTTTTTTTTTTTTGGCTGGGTAGAGAAATCATATAAAACGCAGGCTGTTTAGCATGGAGATGACTCTCAGAACACTGGGAGG GTCTGGCACTTGATGGGGGTTAGTTGCTTGGCAGCCTGCCTGCCACTGAGGGAAG.TCCCATTAGAGATGTATCACCACCTTGTC ACCAACAGGATGATGTCACCAACAGGATGATGTCACCAGGTAATAAACCTTCATCCTCAC
• 148
GGGGATAAGTTTTTTTTTTTTCTTTTTTTTCTTTTCTCTAGTTTTTCTTTCTGGCTGAGATTTCCGTGCAAGACAGCACCCAAT AGACTATTTAGAGTTGACATTTGACATTTTAATGGGCGCCATGGCTCATTTTGTAGATTGAGAAGGTGCGTCTCCCCTGCTCCA AGTCTCATCATGACAGCGTGCTGACAGCTGGGAGTCTGTGGCCTTCCTCACGCAGAGGCCTTAAAGCTGGACACAGATGCACGC CTAGGCTGGGCAGGGATGGGACCCATGCCCCCTCCTTAGAGGACGGGCTTCCTGGTTAGGAAAGGACACGTGGGGGTGCCTTGC ATAATAGTTCACTGGTCACCGTGCTTTTATGAGTAGTGTTTTTGTGCACTTGCCAGGGGTTTTCTCTCTGTGTGCGAGGGGAGT GATTTAAGCAATGGTGTCTGGAGTAAGCCTTACAATTTTAATAGACTTTTTCTTATCATATCCCTCATTTCTTTCCCTGAAATA • AAAATACACACAAGCAAAAAAAAAATGATAGTTTCACATCTCTTAGTTCCCTTGCCCAAACAAGAATATTCTTAGTTCCACTGG CCAGGATTTTCCTACATAGTCAGAACTTACACATTACTAGAGGCACACCCACCAAGGAGTATTGTGTCTACTTTTATCTGTGCA CCAGCCACAAATACCCACATTGGAAAGACCCATTTGTGATGGGTAAACATCCCTTCCTGTCTCCCACAACCCCTGTGACTGCCC TGCATGTGTTCATGACCTCCGAAGGCCCTAATTCATGAAGCAGCAAACCCAGCAGATCTCCACCCCCCTGCCTCAGGACCTCTG CTGAAGAGGGGGATGAAGTGGGTCTCCAGGGAGGCAGTGGGGGCCTTGTTGGCAGCTGGCTCGGGAGCCGGCTTACAGGAGGGC AGCTCTGCAGTTGGGAGGGGCACCGTCCGGAGGAGACCAGGCCTCTACACACCCCCCACTCTACTTATCATCCCTGCTCACACA CCCTTGTCCAAGGCTTTATGCATCGGATTTATTTTTCCAAATCGAGAGGACAGTGATAGATGCATTTTCCCCAGGCTGTCTCAG AAAGGTCGCTAAATGTATACTGTTGTCAGAATTGCTGAGATCTCCCCCCACTTTTGGTTTTTGCAGCAGTAAAAACTCTTTCCA CTGTGACTTATTTTCTCTCTCAGGCAGCCAGCCACCTGGTCCCTTGTGCTGACTCTAGCACAGTGGCCAGGATCCAATACGAGT CCAGGGGTGACCGCAGGATGGTGGGGGCAGCGGGCTTCTCCACCTACCCCAGCCACCAAGGCCCTGACGCACTGCCTCCTGCAC CTTCAGCACATCCCTGTGCACAGCTGGAAGGGTGCATGGCCCGCTCACCTTTGTTCAGATGGGTGGAAACGCTGATGATACCAG CTCCTCCCTGCCGTGCCCCTGCCACGGAGCAGGCATTGTGAACTGGCTGGTGTTTGCAGTCCCACGTGGCATGGCCTCCAGCCC AACCCACAGTGGAGACTGGAGACAGGGCAATGAGTCTGGTCGGGGGCACGTGGACATGCCCCATAGGGGCCCCACCCAGACTTA ACAGGCAAGGTCCTGGGCATTGCGCGACGCAGGACTCAATGCTAAAGCAAGCCTGCCTGGCTCTGTGCCAGGGCCCCTCTTCTG ATTTACACATCCCATTTTTACACAGACCCTTCCTTCTTAATAAAGGCTGACAGTTCTGTTGGCAGCCAAGAACCCACACCATGA AGACAGGGAGTGAGGGGCCTTTGTGCCCAACTCCAGCACAGCTGCGTTCTGGGGTGTGTGAGAGGCATGTTCGTGTCTGTGCGC TGGTGGTCTCGTGAGACAGTTCCGAGGACGGGGAAATTGCAGGGTGGTGGGGGCGTGAGGCTTATATGTGGAACTGATGCAGAG TTCGCCTGCAGACGGATCTGGATATACACTATGTATAATTGTTACGTGTAATTTAAAATATATCTGTTTGCCATCGTCATGAGA AGATTATATGTAAGGCTCTGAAGGGAGAGGGAGATGTACATTCTGCCAGGCTCCTGGGGACCTTATCCGAGTCATGAAATTGAT
GACTGTTGATCCAGTGGTGCAAGAAGCTACACTCCATGTGTCATCACGCTTATGACTCCTAATGTATTTTTAAGGCAAAAAATG
TCAGCCGACTCCATCTTCACCCCTCGATTCCTCGAGTCCAGCCTTTCTGTGCCAGTGCTTCACTGAGCCACAACGCTCTCGCCA
* TCGGGACCCGGCTGGGCCTGGAGTCTCGGGGCACAGTTGCCATGGAGCCCTCCTGGGTCATTCTACAAATGTGCTGAGTGCCAG
CTGAAAACCCCACAGGAGATGGAGTACCTTGGCCAAGCTTAAAGAGAAGATTTTCTCAGGGTATTTATTAGTGTGTCCAGCAGG GTCAGGAAGCAGGATGGAAAGATGCATTCAGACTGTTAATTTATTAACAAGGCAAATGATTTTGTGTTTCTTGATGACAGACTA TTAAGTTTGGGACTTATTTTCCCATTTGAGAAGTTATAATATATATTTAAGATGATAAGTTTCCTGCTTAAGTTGTGCCTTTCA GCTTCAATGAGTTTAAGGAGCACTAAGGCTAATGATACCAATGAGGGTTGGTTTATTATCAAACCTGAATAGCTGTGGTTTCTC CAGTAAATATTTTCTTCTACTGAACATGGAGCCATTATTAAGAGTTGTGTGTTTTTTATTATGTACATTTGTATATTTTTTTGC TTGTTTGATGTTCTATTTTTCTAATAGTTTTCTTTTAGTTTCTTAAAGTTGTGATACTAGATTTAGATTCTGATGCTAACTGCA AATCAGGTTGGTCTCTGCTGGGTCTCTCCTGCTTTTATTTTACTTTAAGGACAAGTGTAGTTGTCGTCCACCACCTTTCAAAAA ATGTGAAACTGCCCTGCCTCCCCTTTTTGCTGACAACACTGTGTACATTGACCACTTCCTACCATACTTTATGTTGTAAAATCA AACTCTTTTGTGGTACATTATCTCATGCTTCTGCAAATTCGAATAAATTCTATGGCTTCCAAAAAAAAAAAAAAAAAAAA
150
AAGATCTATGTCCTGGGGGGCCGCCAGGGCAAGCTCCCGGTGACTGCTTTTGAAGCCTTTGATCTGGAGGCCCGTACATGGACC CGGCATCCAAGCCTACCCAGCCGTCGGGCCTTTGCTGGCTGCGCCATGGCTGAAGGCAGCGTCTTTAGCCTGGGTGGCCTGCAG CAGCCTGGGCCCCACAACTTCTACTCTCGCCCACACTTTGTCAACACTGTGGAGATGTTTGACCTGGAGCATGGTGAGCAGTGG CTGTTCTGGGCTGTCCTCCCGCTCTCTGTGGGATGGAGGGGCATAGTGTGTACATGACTAGATCTGACCTCCCCTCTCCTGCAG GGTCCTGGACCAAATTGCCCCGCAGCCTGCGCATGAGGGATAAGAGGGCAGACTTTGTGGTTGGGTCCCTTGGGGGCCACATTG TGGCCATTGGGGGCCTTGGTAAGTCTCTATGGGGCTGGGGAGAGGAGGGAGTCCCAAGACAGGAAAGACTAGCCCCCAGCATGT GTGTCACCTTCTGCCCATCTCCAGGCACTCCAGGGGTCAGGGCTTTGTGAGCTCTTTTCCCTATCTATGAAGTAGGCAGGATGT GGTCTGCCTGGCCCAGCACTCAGGGTGTTCCTCAGTGACTGGGGGCTCTGTCAAGCACCAGCAAGGGTCTACGAGACAGCAGCA GGACAAATGACCACTGTATGCACAGTCAAGAGAACATATAGAAACATAAATGAATGAACAAATGATGAACATAGGCAATGAGGA GCAAGGCCCTGATAGCTCATCCTGGGGTGATAACTACTGGGCTATTCTCTGGGCTTAGGGAGCAGAAGGGCCTGGAGTCCCTAC GGCCTGTGCCTCTCACAGCCTTCTCTCTCCTTCTTGCAGGAAACCAGCCATGTCCTTTGGGCTCTGTGGAGAGCTTTAGCCTTG CACGGCGGCGCTGGGAGGCATTGCCTGCCATGCCCACTGCCCGCTGCTCCTGCTCTAGTCTGCAGGCTGGGCCCCGGCTGTTTG TTATTGGGGGTGTGGCCCAGGGCCCCAGTCAAGCCGTGGAGGCACTGTGTCTGCGTGATGGGGTCTGAAGGCTTGGTGGGAGCT GTCCACTGGAGCAGCTCATTGCCAGAGGCAGCTATTTCTATGGCTCCTTTTGCTGCTGAGGACACTCACTGTGGCTCTGTGGGA TGAGAGAGGCATGGGGGTGAGCACTTGAAACACTGCCTTGGGGCCTTGGGTTAGGGGAGCCTTTGTCTTTAGTGCAGGACACAC ATATGCTTACACCTACCTTTATCACCATTCGTTCATGAATCATGCCTAGCTCCATCCTTGCCCTGGGACCTACTAGGCCTTCCA TCCAACTGGGAAATGGGGAGAAGCAAAGCTGGCCCCATGCTCTTCAGGGTCAGTTCCTATCTGGAGTTGACCAGGCCTACCCCA GTTGCCATTCCTGAAAAATCTCAGCTGCCAGGCTGCCTTTAGGGTCCCTGTAGACCCAGGAGAGTTGAGAGGGTGGGGGACACA GAGAGAATAGAGAGGATGTGGGAACTGCCAGAGGGCCGGAGCGCAGGAGTTCAAGTGGAGGAATGCTGGCTT'TGAGCCCTCTAC ACTGCTGGTTGTATGACCTTGGACAAGTCACTTCACCTCTCTGTGCCTCAGCATCCTCATCTATAAATGGGGATCTCTGAAACC TTCCTACCCTACCTACCTCACAGGGCTGTTGTGAGGACCCAGGGAGTTTGGATGTGGAAGTAAAAGTGCTGCTAAAACCT
151 RSRLTAVSAS VQAHPPADMGRRKSKRKPPPKKKMTGT ETQFTCPFCNHEKSCDVKMDRARNTGVISCTVCLEEFQTPITY LSEPVDVYSD IDACEAAQ
152
GGCACGAGGGGCTCATCCAGCTGCAGACATGGGGCGCAGAAAGTCAAAACGAAAGCCGCCTCCCAAGAAGAAGATGACAGGCAC CCTCGAGACCCAGTTCACCTGCCCCTTCTGCAACCACGAGAAATCCTGTGATGTGAAAATGGACCGTGCCCGCAACACCGGAGT .CATCTCTTGTACCGTGTGCCTAGAGGAATTCCAGACGCCCATAACGTATCTGTCAGAACCCGTGGATGTGTACAGTGATTGGAT AGACGCCTGCGAGGCGGCCAATCAGTAGCGACACAGAGGACCCGCCCCCTGAGCAGCCCCGCGTACTGTGGATCCAGCTGTTCG GTTCTGGTCCAGAGACATTCCAGGGGTCCAGGGTGTGGGTCCTGGGCTGTCACAGCCGTGTGTGTGTGTGTGTGTGTGTGTGTG TGTGTGTGTGTGTGTGTAGTGGGTGTGCGTGTGGGTGTGGGTGTGAGTGAGTGTGGGTGTGTGTGGCTGCACGTGTCACTGGGG TGGCCGTGAGTGTGTGCTCACAGGTACGCGGTGGTGTCGGGTTCCTGGGCCTGAGGGGCCTGAACTGATCTCACTTGGCTCCGA AAGCCTTTGCTGTGTTCCCTGCAGCCCCTGGCCCCCCAGCCTTGGGGCTCTGGCTCCCCCCGGCGGAATTGGGGGACTGTTTCC TGACATCCTGGACAAGGGAAGCCCACTAGAGGCTGGAACAGGACCTCTCCAGCCTCCTCACCAGCACCGTGCCCATCTCAACTG GACTTCCCGCCCTCCTTCTCCACCTTCTAGTGCCCGTGGCCGGGGATTCAAAGCCGCCGTTCCCCAGGTCCCTGGGCTGGGCCC TGACAGGGAG.CCGCCCCCCTCCCCATGGTAACCAGGAAGCCCGTTTCATGTTCAGTTGCTTTTGTAGAGGAAGCAAGGGCTGGG ATGGGGACAGCTGTCAATCACAAGCCCTTAAATAAAGCAGCCAGCGCACAAAAAAAAAAAAAAAAAA 153
MPPPSDIVKVAIE PGANAQ LEIDQKRPLASIIKEVCDGWSLPNPEYYTLRYADGPQLYITEQTRSDIKNGTILQLAISPSRA ARQLMERTQSSMETRLD KELAKLSADVTFATEFIrøDGIIVLTRLVESGTKLLSHYSEMLAFT TAF ELMDHGIVS DMV SITFIKQIAGYVSQPMVDVSILQRSLAILESMVLNSQSLYQKIAEEITVGQLISHLQVSNQEIQTYAIA INALFLKAPEDKRQ DMANAFAQKHLRSIILNHVIRGNRPIKTEMAHQLYVLQVTFN LEERMMTKMDPNDQAQRDIIFELRRIAFDAESDPSNAPGS GTEKRK YTKDYKMLGFTNHINPAMDFTQTPPGMLA D MLY AKVHQDTYIRIVLENSSREDKHECPFGRSAIELTKM CEI LQVGELPNEGRNDYHPMFFTHDRAFEELFGICIQLLNKT KEMRATAEDFNKVMQVVREQITRA PSKPNSLDQFKSK RSLSY SEILR RQSERMSQDDFQSPPIVELREKIQPEILE IKQQRNR CEGSSFRKIGNRRRQERF YCRALNHKVLHYGD DDNP QGEVTFESLQEKIPVADIKAIVTGKDCPHMKE SALKQNKEVLELAFSILYDPDETLNFIAPNKYEYCIWIDGLSALLGKDMSS ELTKSD DTLLSMEMKLRLLDLENIQIPEAPPPIPKEPSSYDFVYHYG 154
GGAGGGAGGTGTAGAAAGAGGTACATGGAGAACAAGTTTGTCAATCCGTCTGAACTTCAGTTGCCTTACCTGTAAGGCAGCCGT GTCTGTGTTTTTGTCTCGCAGAATTAGAGCCCATTGGGAACGATGCCACCACCGTCAGACATTGTCAAAGTGGCCATTGAGTGG CCAGGTGCTAACGCCCAGCTCCTTGAAATCGACCAGAAACGGCCCCTGGCATCCATTATCAAGGAAGTTTGTGATGGGTGGTCG TTGCCAAACCCAGAGTATTATACCCTCCGTTATGCAGATGGTCCTCAGCTGTACATCACCGAACAGACTCGCAGTGACATTAAG AATGGGACAATC.TTACAACTGGCTATCTCCCCGTCCCGGGCTGCACGCCAGCTGATGGAGAGGACCCAGTCATCCAACATGGAG ACCCGGCTGGATGCCATGAAGGAGCTGGCCAAGCTCTCTGCCGACGTGACTTTGGCTACTGAGTTCATCAACATGGATGGCATC ATTGTGCTGACAAGGCTCGTGGAAAGTGGAACCAAGCTCTTGTCCCAGCTACAGTGAGATGCTGGCATTCACCCTGACTGCCTT CCTAGAGCTCATGGACCATGGCATTGTCTCCTGGGACATGGTTTCAATCACCTTTATTAAGCAGATTGCAGGGTATGTGAGCCA GCCCATGGTGGACGTGTCAATCCTTCAGAGGTCCCTGGCCATCCTGGAGAGCATGGTCTTGAACAGCCAGAGTCTGTACCAGAA. GATAGCCGAGGAAATCACCGTGGGACAGCTCATCTCACACCTCCAGGTCTCCAACCAGGAGATTCAGACCTACGCCATTGCACT GATTAATGCACTTTTTCTGAAGGCTCCTGAGGACAAACGACAGGATATGGCAAATGCATTTGCACAGAAGCATCTCCGGTCTAT AATCCTGAATCATGTGATCCGAGGGAACCGCCCCATCAAAACTGAGATGGCCCATCAGCTATATGTCCTTCAAGTCCTAACCTT TAACCTTCTGGAAGAAAGGATGATGACCAAGATGGACCCCAATGACCAGGCTCAAAGGGACATCATATTTGAACTGAGGAGGAT TGCATTTGACGCAGAGTCTGATCCTAGCAATGCCCCTGGGAGTGGGACCGAAAAACGCAAAGCCATGTACACAAAGGACTACAA - AATGCTGGGATTTACCAACCACATCAATCCAGCCATGGACTTTACCCAGACTCCTCCTGGAATGCTGGCGTTGGACAACATGCT GTACTTGGCTAAAGTCCACCAGGACACCTACATCCGGATTGTCTTGGAGAACAGTAGCCGGGAAGACAAACATGAATGCCCCTT TGGCCGCAGTGCCATTGAGCTCACCAAAATGCTCTGTGAAATCCTGCAGGTTGGGGAACTACCAAATGAAGGACGCAATGACTA CCACCCGATGTTCTTTACCCATGACCGAGCCTTTGAAGAGCTCTTTGGAATCTGCATCCAGCTGTTGAACAAGACCTGGAAGGA GATGAGGGCAACAGCAGAGGACTTCAACAAGGTTATGCAAGTCGTCCGAGAGCAAATCACTCGAGCTTTGCCCTCCAAACCCAA CTCTTTGGATCAGTTCAAGAGCAAATTGCGTAGCCTGAGTTACTCTGAGATTCTACGACTGCGCCAGTCTGAGAGGATGAGTCA GGATGACTTCCAGTCCCCGCCAATTGTGGAGCTGAGGGAGAAGATCCAGCCCGAGATCCTTGAGCTGATCAAGCAGCAGCGCCT GAACCGGCTCTGTGAGGGCAGCAGCTTCCGAAAGATTGGGAACCGCCGAAGGCAAGAACGGTTCTGGTACTGCCGGTTGGCACT GAACCACAAGGTCCTTCACTATGGTGACTTGGATGACAACCCACAAGGGGAGGTGACATTTGAATCCCTGCAGGAGAAAATTCC TGTTGCAGACATTAAGGCCATTGTCACTGGGAAAGATTGTCCCCACATGAAAGAGAAAAGTGCTCTGAAACAGAACAAGGAGGT GTTGGAATTGGCCTTCTCCATCCTGTATGACCCTGATGAGACCTTAAACTTCATCGCACCTAATAAATATGAGTACTGCATCTG GATTGATGGCCTCAGTGCCCTTCTGGGGAAGGACATGTCCAGTGAGCTGACCAAGAGTGACCTGGACACCCTGCTGAGCATGGA GATGAAGCTGCGGCTCCTGGACCTGGAGAACATCCAGATTCCCGAAGCCCCACCCCCCATCCCCAAGGAGCCCAGCAGCTATGA CTTTGTCTATCACTATGGCTGAGCCTGGAGCCAGAAACGACGGTACCCAGGAGAAGGGATTTTGGGCCCAGGAGAAACACTTAC ATTCTGGTGCCTTGTCTTTTGCTTGTACAGAATCTGTAGTGATTTTGGTGGCCAGTAAATGCCAGCCATTTCTCAAACCCACCT CGGACCACCCAGAGTTTCCTCTTGGTCCCTGTCTACTAAGAGTCATGAAGGCAGGGTGCTCTGCCCACTCCATCACCATGAAGC CTGGGATTGGGCCACGAGGAACAAACAGCAGATGCCCTTGCCTTCCAGTCCAAGAAACTGCTTCTTGAAATGGATTTAACAACA GCCACTCACCTTTTCCTCCTGAGCCTGCTCTCTGATCAGCTGGATCCCCACGTGAGCAACAGCTGGCCCAGGAAAGGCTGCCTG CAGAGGACAGGTGTGTTGGGCGTGTTGAGAGCCTTGAAGTGACTACCTGTATCTTAGATCTGAGTACAAGCCTGAGGCTTTTGC
TTTTGTCTTTTTTGATGAGGGCTCACTCCAGCTTCATATGGTGCCAAGACGTTGCTGCTTCTGAGGTTGGCTCTAACATCTCTG
GTCTTTAGAGCCACCAGATCTCTCTGGCCCATACAGATATCAGAGCAGACGGAAATTTCTCCCTGCAAGCGCTCAGTCTCATCC CAGCAAGTCAAAGACCTCCTGGCCAAGTCCTGCCCTCTTAAGTCTCCAGGAACGCTGCAGGGAAMCCCAGCTGAGGCCTGGGC
CTAGACTGTGGTGAGGTCACTAGATTCTACTGCTCTTCCCCCACATTAATACCTTTTCCTTCCTCAGAGAGAAATCTCCCCTAA CCTGAATTGCAGCCCCCTCCAGTTTGCTTTCCTTTGGCCTTCCAGACCCCAGGAAGTTGGCCTTCCCTTCCTAGTGCTATGGTT TCTGCCATTGGCCATGATTTCAGGGAGCTGGCTGAGGCCGGCTGAGGCCACACCTGTGCCAGTGGGGCTTCCCTGGTGCTGCAG CACTTGTAAACCACACACACAGCCTCTCTCCCTGGACATACGTTAGCACATTGGCATTCAGTATTGGTGGCCTGGCATGGTAGG TACTACCCAATGAAGAGTGTACTATATATTTTCATTACTATAGGCCATACTTATACAGACGTGTATATATATTTATATAAGATC TACCTATCTTAGGATGGAACCTTGGGGAAAAATAAAATTGAGGGGAAGTAAAAAGTATGTAACACTTCCAGTTGTGAGCCAAGA TTGTAACCAGAGAGCAGCCAGGAGCTTCCTGTCAGTAACCATGTTTTCAATAAATACTCTTTCATGT
156
AGAGCAATACTCAAGGGAAAAGGTGTTTATTTAGAACAATGAAAACAATGAGACATTAACTTCCAGCTTAAATAAAGTTGATTG TGTGCATAAAAATGGTGAAAATATTGGACTTTCTTGGCAAAAGAAGAAAGGAGAAGACTTTATATTTTCTGACATAATATTCAT CATTTGTCTTTGGTTTGTGTATTATGTGTATGATTTTGAAAAAATGCATCAAAGATATAACTTTCTGGTGTTTGCTTTGATATT ATC
157 HQQQQQQQKAGEQQLSEPED EMEAGDTDDPPRITQNPVINGVALSDGHNTAEEDMEDDTS RSEATFQFTVERFSRLSES V SPPCFVR LP KIMVMPRFYPDRPHQ SVGFF QCNAESDSTSWSCHAQAVLKIINYRDDEKSFSRRISHLFFHKENDWGFS NF SEVTDPEKGFIDDDKVTFEVFVQADAPHGVAWDSKKHTGWGLK QGATCYM SLLQTLFFTNQ RKAVYMMPTEGDDS SKSVPLALQRVFYELQHSDKPVGTKK TKSFG ETLDSFMQHDVQELCRV DNVE MKGTCVEGTIPK FRGKMVSYIQCKE VDYRSDRREDYYDIQLSIKGKK IFESF¥DYVAVEQ DGDNKYDAGEHGLQEAEKGVKFLTLPPVLHLQLMRFMYDPQTDQNIK INDRFEFPEQLPLDEFLQKTDPKDPANYILHAVLVHSGDNHGGHYVVYLNPKGDGK CKFDDDWSRCTKEEAIEHNYGGHDDD LSVRHCTNAYMVYIRESK SEVLQAVTDHDIPQQLVERLQEEKRIEAQKRKERQEAHLYMQVQIVAEDQFCGHQGNDMYDEEK VKYTVFKV K SS AEFVQSLSQTMGFPQDQIRLWPMQARSNGTKRPAMLDNEADGNKTMIELSDNENP TIFLETVDPELAAS GATLPKFDKDHDV LFLKMYDPKTRSLNYCGHIYTPISCKIRDLLPVMCDRAGFIQDTSLILYEEVKPNTERIQDYDVSLDKTV LDELMDGDIIVFQKDDPENDNSELPTAKEYFRDLYHRVDVIFCDKTIPNDPGFVVTLSNRMNYFQVAKTVAQRNTDPM LQFF KSQGYRDGPGNPLRHNYEGT RDLLQFFKPRQPKKLYYQQLKMKITDFENRRSFKCIWLNSQFREEEITLYPDKHGCVRDLLEE CKKAVELGEKASGK R LEIVSYKIIGVHQEDE LECLSPATSRTFRIEEIP DQVDIDKENEMVTVAHFHKEVFGTFGIPF LRIHQGEHFREVMKR1QSL DIQEKEFEKFKFAIVMTGRHQYINEDEYEVNLKDFEPQPGNMSHPRP GLDHFNKAPKRSRYT YLEKAIKIHN
158
GTACGTGCGCGTCTCCCTGCCGCCGCCGCCGCCCGCCGCGGGCCGCCCCGGGGCCGCCGTCGCCGACGACGCGCGGGAGGAGGA GGAGGAGGCCGCCCCGCCGCCGCCGCCGCCGCCGCCGCCCCGGCTCGCCGCCGCCCGCCCGCCGGGCTCGCAGCCCCGGCCCCC GGCCGCAGGCGAGGCCCAGGCCGCGGCCGACATGAACCACCAGCAGCAGCAGCAGCAGCAGAAAGCGGGCGAGCAGCAGTTGAG CGAGCCCGAGGACATGGAGATGGAAGCGGGAGATACAGATGACCCACCAAGAATTACTCAGAACCCTGTGATCAATGGGAATGT GGCCCTGAGTGATGGACACAACACCGCGGAGGAGGACATGGAGGATGACACCAGTTGGCGCTCCGAGGCAACCTTTCAGTTCAC TGTGGAGCGCTTCAGCAGACTGAGTGAGTCGGTCCTTAGCCCTCCGTGTTTTGTGCGAAATCTGCCATGGAAGATTATGGTGAT , GCCACGCTTTTATCCAGACAGACCACACCAAAAAAGCGTAGGATTCTTTCTCCAGTGCAATGCTGAATCTGATTCCACGTCATG GTCTTGCCATGCACAAGCAGTGCTGAAGATAATAAATTACAGAGATGATGAAMGTCGTTCAGTCGTCGTATTAGTCATTTGTT CTTCCATAAAGAAAATGATTGGGGATTTTCCAATTTTATGGCCTGGAGTGAAGTGACCGATCCTGAGAAAGGATTTATAGATGA TGACAAAGTTACCTTTGAAGTCTTTGTACAGGCGGATGCTCCCCATGGAGTTGCGTGGGATTCAAAGAAGCACACAGGCTACGT CGGCTTAAAGAATCAGGGAGCGACTTGTTACATGAACAGCCTGCTACAGACGTTATTTTTCACGAATCAGCTACGAAAGGCTGT GTACATGATGCCAACCGAGGGGGATGATTCGTCTAAAAGCGTCCCTTTAGCATTACA GAGTGTTCTATGAATTACAGCATAG TGATAAACCTGTAGGAACAAAAAAGTTAACAAAGTCATTTGGGTGGGAAACTTTAGATAGCTTCATGCAACATGATGTTCAGGA GCTTTGTCGAGTGTTGCTCGATAATGTGGAAAATAAGATGAAAGGCACCTGTGTAGAGGGCACCATACCCAMTTATTCCGCGG CAAAATGGTGTCCTATATCCAGTGTAAAGAAGTAGACTATCGGTCTGATAGAAGAGAAGATTATTATGATATCCAGCTAAGTAT CAAAGGAAAGAAAAATATATTTGAATCATTTGTGGATTATGTGGCAGTAGAACAGCTCGATGGGGACAATAAATACGACGCTGG GGAACATGGCTTACAGGAAGCAGAGAAAGGTGTGAAATTCCTAACATTGCCACCAGTGTTACATCTACAACTGATGAGATTTAT GTATGACCCTCAGACGGACCAAAATATCAAGATCAATGATAGGTTTGAATTCCCAGAGCAGTTACCACTTGATGAATTTTTGCA AAAAACAGATCCTAAGGACCCTGCAAATTATATTCTTCATGCAGTCCTGGTTCATAGTGGAGATAATCATGGTGGACATTATGT GGTTTATCTAAACCCCAAAGGGGATGGCAAATGGTGTAAATTTGATGACGACGTGGTGTCAAGGTGTACTAAAGAGGAAGCAAT TGAGCACAATTATGGGGGTCACGATGACGACCTGTCTGTTCGACACTGCACTAATGCTTACATGTTAGTCTACATCAGGGAATC AAAACTGAGTGAAGTTTTACAGGCGGTCACCGACCATGATATTCCTCAGCAGTTGGTGGAGCGATTACAAGAAGAGAAAAGGAT CGAGGCTCAGAAGCGGAAGGAGCGGCAGGAAGCCCATCTCTATATGCMGTGCAGATAGTCGCAGAGGACCAGTTTTGTGGCCA CCAAGGGAATGACATGTACGATGAAGAAAMGTGAAATACACTGTGTTCAAAGTATTGAAGAACTCCTCGCTTGCTGAGTTTGT TCAGAGCCTCTCTCAGACCATGGGATTTCCACAAGATCAAATTCGATTGTGGCCCATGCAAGCAAGGAGTAATGGAACAAAACG ACCAGCAATGTTAGATAATGAAGCCGACGGCAATAAAACAATGATTGAGCTCAGTGATAATGAAAACCCTTGGACAATATTCCT GGAAACAGTTGATCCCGAGCTGGCTGCTAGTGGAGCGACCTTACCCAAGTTTGATAAAGATCATGATGTAATGTTATTTTTGAA GATGTATGATCCCAAAACGCGGAGCTTGAATTACTGTGGGCATATCTACACACCAATATCCTGTAAAATACGTGACTTGCTCCC AGTTATGTGTGACAGAGCAGGATTTATTCAAGATACTAGCCTTATCCTCTATGAGGAAGTTAAACCGAATTTAACAGAGAGAAT TCAGGACTATGACGTGTCTCTTGATAAAGCCCTTGATGAACTAATGGATGGTGACATCATAGTATTTCAGAAGGATGACCCTGA AAATGATAACAGTGAATTACCCACCGCAAAGGAGTATTTCCGAGATCTCTACCACCGCGTTGATGTCATTTTCTGTGATAAAAC AATCCCTAATGATCCTGGATTTGTGGTTACGTTATCAAATAGAATGAATTATTTTCAGGTTGCAAAGACAGTTGCACAGAGGCT CAACACAGATCCAATGTTGCTGCAGTTTTTCAAGTCTCAAGGTTATAGGGATGGCCCAGGTAATCCTCTTAGACATAATTATGA AGGTACTTTAAGAGATCTTCTACAGTTCTTCAAGCCTAGACAACCTAAGAAACTTTACTATCAGCAGCTTAAGATGAAAATCAC AGACTTTGAGAACAGGCGAAGTTTTAAATGTATATGGTTAAACAGCCAATTTAGGGAAGAGGAAATAACACTATATCCAGACAA GCATGGGTGTGTCCGGGACCTGTTAGAAGAATGTAAAAAGGCCGTGGAGCTTGGGGAGAAAGCATCAGGGAAACTTAGGCTGCT AGAAATTGTAAGCTACAAAATCATTGGTGTTCATCAAGAAGATGAACTATTAGAATGTTTATCTCCTGCAACGAGCCGGACGTT TCGAATAGAGGAAATCCCTTTGGACCAGGTGGACATAGACA GAGAATGAGATGCTTGTCACAGTGGCGCATTTCCACAMGA GGTCTTCGGAACGTTCGGAATCCCGTTTTTGCTGAGGATACACCAGGGCGAGCATTTTCGAGAAGTGATGAAGCGAATCCAGAG CCTGCTGGACATCCAGGAGAAGGAGTTTGAGAAGTTTAAATTTGCAATTGTAATGACGGGCCGACACCAGTACATAAATGAAGA CGAGTATGAAGTAAATTTGAAAGACTTTGAGCCACAGCCCGGTAATATGTCTCATCCTCGGCCTTGGCTAGGGCTCGACCACTT CAACAMGCCCCAMGAGGAGTCGCTACACTTACCTTGAAAAGGCCATTAAAATCCATAACTGATTTCCAAGCTGGTGTGTTCA AGGCGAGGACGGTGTGTGGGTGGCCCCTTAACAGCCTAGAAGTTTGGTGCACGTGCCCTCTAGCCGAAGTCTTCAGCAAGAGGA TTCGCTGCTGGTGTTAATTTTATTTTATTGAGGCTGTTCAGTTTGGCTTCTCTGTATCTATTGACTGCCCTTTTTGAGCAAAAT GAAGATGTTTTTATAAAGCTTGGATGCCAATGAGAGTTATTTTATGGTAACCACAGTGCAAGGCAACTGTCAGCGCAATGGGGG AGAAGAGGTTAGTGGATCGGGGGTCCCTGGCTCAAGGTCTCTGGGCTGTCCCTAGTGGGCACGAGTGGCTCGGCTGCCTTCCTG GGGTCCCGTGCACCAGCCCTGCAGCTAGCAAGTCTTGTGTTTAGGCTCGTCTGACCTATTTCCTTCAGTTATACTTTCAATGAC CTTTTGTGCATCTGTTAAGGCAAAACAGAGAAACTCACAACCTAATAAATAGCGCTCTTCCCTTCAAAAAAAAA
159 ATFSGPAGPILS NPQEDVEFQKEVAQVRKRITQRKKQEQLTPGWYVRH PNL DETQIFSYFSQFGTVTRFRLSRSKRTGN SKGYAPVEFESEDVAKIVAET-M^ FGER LECHFMPPEKWKELFKDWNIPF QPSYPSVKRY RNRTLTQ RMEERFKKK ERLLRKKLAKKGIDYDFPSLILQKTESISKTNRQTSTKGQVLRKKKKKVSGT DTPEKTVDSQGPTPVCTPTFLERRKSQVAEL NDDDKDDE1VFKQPISCVKEEIQETQTPTHSRKKRRRSSNQ 160
TGGGAGCCCGACGTTTCCGGGAGCGCCGCGTGGTTAGCGTCGGCGGCTTTTGGCATGGCGACTTTTTCTGGCCCGGCTGGGCCA ATCCTGTCGCTTAATCCGCAGGAAGATGTCGAGTTTCAAAAGGAGGTGGCGCAGGTTCGCAAGCGCATAACCCAGCGAAAAAAA CAAGAACAACTTACTCCTGGAGTAGTCTATGTGCGCCACCTACCTAACCTACTTGACGAAACCCAGATCTTTTCATATTTCTCC CAGTTTGGCACTGTGACACGGTTCAGGCTGTCCAGAAGTAAAAGGACTGGAAATAGCAAAGGCTATGCATTTGTGGAGTTTGAG TCTGAGGATGTTGCCAAAATAGTTGCTGAAACAATGAACAACTACCTGTTTGGTGAAAGACTCTTGGAGTGTCATTTTATGCCA CCTGAAAAAGTACATAAAGAACTCTTTAAAGACTGGAATATTCCATTTAAGCAGCCATCATATCCATCAGTGAAACGGTATAAT CGGAATCGGACACTAACACAAAAGCTACGGATGGAGGAGCGATTTAAAAAGAAAGAAAGATTACTCAGGAAGAAATTAGCTAAA AAAGGAATTGACTATGATTTTCCTTCTTTGATTTTACAGAAAACGGAAAGTATTTCAAAAACTAATCGTCAGACGTCTACAAAA GGCCAGGTTTTACGTAAGAAGAAGAAAAAAGTTTCAGGTACTCTTGACACTCCTGAGAAGACTGTGGATAGCCAGGGCCCCACA CCAGTTTGTACACCAACATTTTTGGAGAGGCGAAAATCTCAAGTGGCTGAACTGAATGATGATGATAAAGATGATGAAATAGTT' TTCAAACAGCCCATATCCTGTGTAAAAGAAGAAATACAAGAGACTCAAACACCTACACATTCACGGAAAAAAAGACGAAGAAGC AGCAATCAGTGATTTTCAATGTATTATATTTCTTTTGAAAAATATAATATTTTTATGAGAAAAAAAAAAAAAAAAAAAAAA
162 GTAAAAATGACTTGGATTGAAAATATGTGGTAGCCTTTTTATTTCTACATTAAGTTCTACCTAGGATATTTCCAAGGACTGCCA CAAAACCCATATGTGCAGTACTTTACTACTTTGGGAAAGCTGCATCTTTCTACCACATTTTAACATCTAATATATTTAATTTCT TTGAAGAGGGTTCTGrnGTACGTTATTGTAGTTCCCAGTTTAATATAGTTCTTTGTATCTCTTAACAGGTTGAAGTTATTGCAAA ACACTCTGGAAAGTAATAATTACATCATAATCATTTATTTTTTAAACTTAAAAGCCTAGAAATTTCCTAGAAAGAAAATAGGAG ACATCTCAGAGCAATTTGGTTTTGGTGTATATGTTCTCAACAGAAAACCAGTGTTAATGAATATCATGCCTCAGCACTGTCACT TTTAAAACCTGTCAGGATCCCACCGTAAAATTGGAAATGGGCAGTTCTGAATTTTCACGTTTGAAATGTAAAATATAAACTTCA GTCAATATCCAGGTTTATTGTGTCCTACTATTTAATAATGAGAGAAGTAATGGCAAGGCCTTTACTTTCAGGAAAGGATAGAAG TATAGATTAATGACTGGAAAGTTTTAATATATTTAGCCCAAAGGTTACTTTGAATTGAAGTCTTTGCATTGACTGTTTGTGTTT GGTTTATTTGTTTAGCTTTACAAGGTACACATAAGTTAGGTTGAGGGGTTGTTAACCCTTCCGTGGTCTGCTTTCATTCCGTGT GCTTCCTGTCACAGGTAATGGAAAACATAAGTAGAATAGGTGACCTCTTAGTTTTGAACTTATTTAAGTGTGGGGATGAATTTT TCATCAGAAGTGCTTACAGGGTTACTACCTGAGTTTACAATCTACCTGGTCATTATTTTATTTCTATCCAGTTCTAAGAACTGC CTCCACTGTTTATATATTCATAATTAAACACATTGAGAATGCAACACTATAAAAGCTGGTCAAATTTTTGCAGAGCCCTTATTC TGTGTGTTTTTTGTTTTTTTCTTTTTTTTTTGAGACAGAGTCTCGTTCGGTCCCCCAGCTTGGAGTGCAGTGGCGCGATCTCGG CTCACTGCAACCTCCGCCTCCTGGGTTCACGCGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACACACCACC ACGCCCGGCTAATTTTTTGTGTCTTTTTAGTAGAGACGGGGTTTCGCTATGTTGGCCAGACTGGTCTTGAACTGCTGACCTCGT GATCCGCCCGCCTCGGCCTCTCAAAGTGCTGGGATTCTGTGTGTTTTGTGCACCTCCACTTTAGGTAATCATAGGGAGCACATT TACAGGATGGTCTAATAACATGAAAACAGGCTAGTTTCAAGCAACAGCAATGTCGGTTGGAAAGCAGGCGTCATTTGCCTTGAA AAAAGCCTTTTGACAACATACAGGCATTCTTTTAAAACCAGGCTGAAACATTTTATTTCCGAGACTTAACGTTGTGTTTCCTGT TTCTTAAACCTAGCACCTCTGTGTATTTGAAAATAATGAGACATCTTTCATTGGATTTTGGAAAATTGTTCCCCATGGGATTCT AACCTCACTACCAAATGAGTGAAAGCTTGATTAAGAGTT.CTTCCATATACTAGCCTCCTTGGAAGAAGTGATCAGAAGGTGATA AGAAGGACAGAAAGGACTATTTTAAAGTTGGACTGAAGGAGAAAAAAGCAAAATTCTTGTTTCATCCCAATTCTAGTTAGAACA AAGTTAAACCCCCGTAATCTTAAAGAGAAAATCTTTGGAGGTTTTAATTAAACATTTTATACATTTAAAGTCTTGTTAATGGTG CTTTAAGTGTCAATGTAGCATGTAAAAGGCTTTGTACAGACAGGTAAAAGTTCCATTTCTGAGTGATGAAATGTAACACTTCTT CATCTTTAACTTGAAATCAAAACTATCAGATTTTATTTTTGTATAATTTAAGGAAGGTAAAGTTAGGGGACTAGAAGACTCTAA ATTGGCTTCTACAGATCAATAATTTAAATGTAACTAGTTGGGATTTTATAGTTAAAATTATATTTGTGTATATAACATAATTAA TCTGTAAATTGTAATAAATATATTTGCAATTATTAAATGTTAAGTGAT
163 MARDPPNRVPPTTEGTRGLLSCLPDVERATLT LLDHLR VSSFHAYNRMTPQNLAVCFGPVLLPARQAPTRPRARSSGPGLAS AVDFKHHIEVLHYLLQSWPDPRLPRQSPDVAPYLRPKRQPPLHLPLADPE TRPRGRGGPESPPSNRYAGDWSVCGRDFLPCG RDFLSGPDYDHVTGSDSEDEDEEVGEPRVTGDFEDDFDAPFNPH NLKDFDALILD ERELSKQINVCL 164
ATGGCCCGGGACCCCCCAAACAGAGTTCCCCCCACCACTGAGGGCACCCGAGGGCTCCTCAGCTGCCTGCCAGATGTGGAAAGG GCCACGCTGACGCTTCTCCTGGACCACCTGCGCCTCGTCTCCTCCTTCCATGCCTACAACCGeATGACCCCACAGAACTTGGCC GTGTGCTTCGGGCCTGTGCTGCTGCCGGCACGCCAGGCGCCCACAAGGCCTCGTGCCCGCAGCTCCGGCCCAGGCCTTGCCAGT GCAGTGGACTTCAAGCACCACATCGAGGTGCTGCACTACCTGCTGCAGTCTTGGCCAGATCCCCGCCTGCCCCGACAATCTCCA GATGTCGCGCCTTACTTGCGACCCAAACGACAGCCACCTCTGCACCTGCCGCTGGCAGACCCCGAAGTGGTGACTCGGCCCCGC GGTCGAGGAGGCCCCGAAAGCCCCCCGAGCAACCGCTACGeCGGCGACTGGAGCGTTTGCGGGCGGGACTTCCTGCCCTGTGGG CGGGATTTCCTGTCCGGGCCAGACTACGACCACGTGACGGGCAGTGACAGCGAGGACGAGGACGAGGAGGTCGGCGAGCCGAGG GTCACCGGTGACTTCGAAGACGACTTCGATGCGCCCTTCAACCCGCACCTGAATCTCAAAGACTTCGACGCCCTCATCCTGGAT CTGGAGAGAGAGCTCTCCAAGCAAATCAACGTGTGCCTCTGAGCCAGATGACGGGGTGGGACCCCGGTTAGTAAGGACCGGGCG CCCAGTGGCTAAGGCGGTGCCCTGGTGACCAAGGAGAGCCAGACCTGTTGCTCAGGCCGAGCTCCTGGTTGCCAGCGAGTTACC ACGGGACCAGTCGCGTGTATGGCTGAGACTCATTCCCAGTTTCCAGGGCCCGGTATTTGGACACTAGTTGCCAAGTCTGGGGCC TGGGGATTTTAGGGACCAGCGGTTGTGACCATCTTTCCTGAGCACCAAGGGCTTCCCCTTTTGTTGCCAAAAAGGTAGTTCTCG- CGCTTGCTAGGCTGGCCTCTCTTGCCTCCCCTTGGCCGGGGCAACACCAGTTACTGTGAGCATCACCCTGGTGTGGTGAGTCAC CTCTAGTCGGCCCTCTTGCTGCTGCCAACCAAATCAGTATTAGCTTTGAGCACTGCACTGTTTCTCCCTCCCTTGGACGACACA AAGACTAGCATGAGGCACTCTTTGTGGGGGGCAGCCCCTATCCTGGGTTCCAGCATGGACACAGGGGTAGCCTGGGGCTTATAG AGAAACAGCTGGTTTCCCCTACCCTTTCCCGGGGAAGACCCCACGATTGGCCTCTAGTCAGCAAATGGAGATAACAGAGTCTGG CCTTTCCAATCCCCATCTCCTTGCCCCCCCCTTGCCCCCCCCCCGAAAAAAATTGAGCACTTAAACCCCTCCCTTTTGGAGGGG GCCCCCTGAAGCGTCAGGCTGGGGGCAGTCTGGTACGGAACATATTTATTGCCTCCATGCATGTGTGTGTGTGTCTGTGAGGAC TGGTGTGCGTGGACACGTCTGAAGCAGGCGTGTGGGGCTCTTTCAGGGACCACAGAGGAGGGAGCAGTTTGCAGTGCCCAGCCA CCCTGAAATCCCCAATAATGGTGCCTCAGTGGGCCCCAGAGTTCCAGTGGGAGAGTACGGTTCCCTCCTGTCTCCCTCTTCTTT TCCGCACCTCCATCTTTGTGGATAATAAATAAATATGCACAGGT
166
TTTTAGGATGGGGTGTGGGAATGAGGGTGTGTGTAGGGAGGGGGTGCGGGGTGGGGACGGAGGGGAGCGTCCTAAGGGTCGATT TAGTGTCATGCCTCTTTCACCACCACCACCACCACCGAAGATGACAGCAAGGATCGGCTAAATACCGCGTGTTCTCATCTAGAA GTGGGAACTTACAGATGACAGTTCTTGCATGGGCAGAACGAGGGGGACCGGGGACGCGGAAGTCTGCTTGAGGGAGGAGGGGTG GAAGGAGAGACAGCTTCAGGAAGAAAACAAAACACGAATACTGTCGGACACAGCACTGACTACCCGGGTGATGAAATCATCTGC ACACTGAACACCCCCGTCACAAGTTTACCTATGTCACAATCTTGCACATGTATGCTTGAACGACAAATAAAAGTTAGGGGGGAG AAGA 168
TTTTTTTTTGTATTGTATACACAGTGGAAAGCTGGTTTTATTTGGGAGACAATGGGAGCTTTTACATTGTTGAGCAAAGGAGTG ACGAGATCAGTCTTGCTTTTTAGAAAGATTAGTTTGGCAGTTACTTATTTGTAACCAGANTTAGACAGCAAATCGGGATGCAGG GGGAGAAGTCAGGTGACTATTAGTCTGCGAGTAATTCTGGGACAAGAGCAGTGGTAATGGAATTNAAAGGGATTAAAGTNTTTA CCAGGTTTTGGCATAAAT 169
MDFPC WLGL DPLV LDFNYHRQEGMEAFLKTVAQNYSSVTH HSIGKSVKG-^L VLWGRFPKEHRIGIPEFKYVANMHG DETVGRELLLHLIDYLVTSDGKDPEITNLINSTRIHIMPSM PDGFEAVKKPDCYYS1GRENYNQYDLNR FPDAFEYNNVSRQ PETVAVMKW KTETFVLSMLHGGALVASYPFDNGVQATGALYSRSLTPDDDVFQYLAHTYASRNP MKKGDECK KMFPNGV TNGYSWYPLQGGMQDYIWIWAQCFEIT E SCCKYPREEK PSFMMKASLIEYIKQVHLGVKGQVFDQNGNP PNVIVEVQD RKHICPYRTNKYGEYY LLPGSYIINVTVPGHDPHITKVIIPEKSQNFSA KKDILLPFQGQLDSIPVSNPSCPMIPLYRNLP DHSAATKPSLFLFLVSLLHIFFK
170
GCATTTCTTCCTTCTGCGTATGGGACAGGACCCTTTCTGGAATGGGGGTCTTATGACCTACAATCAAACAAGAACATGGACTTC CCGTGCCTCTGGCTAGGGCTGTTGCTGCCTTTGGTAGCTGCGCTGGATTTCAACTACCACCGCCAGGAAGGGATGGAAGCGTTT TTGAAGACTGTTGCCCAAAACTACAGTTCTGTCACTCACTTACACAGTATTGGGAAATCTGTGAAAGGTAGAAACCTGTGGGTT CTTGTTGTGGGGCGGTTTCCAAAGGAACACAGAATTGGGATTCCAGAGTTCAAATACGTGGCAAATATGCATGGAGATGAGACT GTTGGGCGGGAGCTGCTGCTCCATCTGATTGACTATCTCGTAACCAGTGATGGCAAAGACCCTGAAATCACAAATCTGATCAAT AGTACCCGGATACACATCATGCCTTCCATGAACCCAGATGGATTTGAAGCCGTCAAAAAGCCTGACTGTTACTACAGCATCGGA AGGGAAAATTATAACCAGTATGACTTGAATCGAAATTTCCCCGATGCTTTTGAATATAATAATGTCTCAAGGCAGCCTGAAACT GTGGCAGTCATGAAGTGGCTGAAAACAGAGACGTTTGTCCTCTCTGCAAACCTCCATGGTGGTGCCCTCGTGGCCAGTTACCCA TTTGATAATGGTGTTCAAGCAACTGGGGCATTATACTCCCGAAGCTTAACGCCTGATGATGATGTTTTTCAATATCTTGCACAT ACCTATGCTTCAAGAAATCCCAACATGAAGAAAGGAGACGAGTGTAAAAACAAAATGAACTTTCCTAATGGTGTTACAAATGGA TACTCTTGGTATCCACTCCAAGGTGGAATGCAAGATTACAACTACATCTGGGCCCAGTGTTTTGAAATTACGTTGGAGCTGTCA TGCTGTAAATATCCTCGTGAGGAGAAGCTTCCATCCTTTTGGAATAATAACAAAGCCTCATTAATTGAATATATAAAGCAGGTG CACCTAGGTGTAAAGGGTCAAGTTTTTGATCAGAATGGAAATCCATTACCCAATGTAATTGTGGAAGTCCAAGACAGAAAACAT ATCTGCCCCTATAGAACCAACAAATATGGAGAGTATTATCTCCTTCTCTTGCCTGGGTCTTATATTATAAATGTTACAGTCCCT GGACATGATCCACACATCACAAAGGTGATTATTCCGGAGAAATCCCAGAACTTCAGTGCTCTTAAAAAGGATATTCTACTTCCA TTCCAAGGGCAATTGGATTCTATCCCAGTATCAAATCCTTCATGCCCAATGATTCCTCTATACAGAAATTTGCCAGACCACTCA GCTGCAACAAAGCCTAGTTTGTTCTTATTTTTAGTGAGTCTTTTGCACATATTCTTCAAATAAAGTAAAATGTGAAACTCAACC CACATCACCACCTGGAATCAGGGATTGCTCACTCCAGGTTACTGCAACCCTAACTCACTCTAGTGGGACCTTGACTGGAGAAAC TCCACGATCTTCCTGAAGAAGAGAAATGGATGTTTCCAAATTCCACAATAAGCAATATGTGGTGATAATGAAAAGAATGATTCA GTCTTGACGGTGAATGGAAGACACTTACCTAACAAGTACTGCTCATTTACACTCAAATTAATCTTGAAGTAGTCTTAAAATGTG TAAGAAGTTAAAACTTGAGAAGCAAAAAATGCCTGCAAAAAGAAGATCATTTTGTATACAGAGAACCGGATGAATATAAGCAAT
GAAGATGAACATTTATTGATCTTCTACATACAAGACTTCACCATAAGGCCAGGAGCAGTGCTCACGCCTTGTAATCCCAGCACT
TTGGGAGGCCAAGGTGGGCGGATCACCTTGAGGTCAGGAGTTCAAGACCAGCCTGACCAACATGGTGAAACCCTGTCTCTACTA AATATTAGCGGGGTGTGGTGGCGGGCACCTGTAGTCGCAGCCTTTCGGGAGGCTGAGACAGGAGAATCGCTTGAACCCTAGAGG
CGGAGTTTGCAGTGAGCCGAGATAGTGCCATTGTACTCCAGCTTGGGCAACAGAGTAAGACTCTGTCTC 172
AGGTTTGAGGGGGGATGCTGTCATGAAAAGGAACTTTCGCTTTTCAGGTTATGTATGTATAGTTTTCTGAACTGGTATCACAAC CACATGCTGCTTCTGTGTAACACTGATTTGGTCAAAAAGCCCTGTTCCTCCTGAGAATCACCAAATTGCTTCCCAAAGATGCTA TATCCTTCACACCAAACTTAAATCACTGGCTACTGAGAATATGCAGTCTTTGCGCACAATTGCGTCTTCTGTCTGCCCCTCCCG CAGGTCCCAGACACAATTTCTTCATGGCTTCTTCAGCCTTTCCACCCTCAGCCTCTGTCTCCAAATTGTAACCCATTTTACATG ACCACACAGGGACACATCATCATTCTTTATGGAAGAAGGTGAGATAGAAACAAATAATGAGGTGTTGATTGATTGAATTTCCTG AATCCTAGACCTTAGGATCTTGAAATGGCCCCTTTTCCTGCTACGATAGCCCATCCAATGCCTTCCGGCTCCACCGGCTCCTGT GGAGAGCTCAAACTCATGAATAACN
174
TAATAAAGTGCTGAATATCTGTCATTTATTGAATTGAATACTGTACATTACATCAAAATTGCAACTGTTTCACATCATCATAAA GTCAATATGTCATGACGTTGCACCATCAGAAGTTGGGGACCATCTGTATAAGTTATCACCTTAGTTCATAGACTACGTAGGTGT AGCATGAAAGAGTTAAACCTCCCTCCCCACACATACACAGGGCACAGGGCTGCTGCGCTGGGTGGGAGGGTGCACTT
176 AMTA AGTTTGAGGGAAAGGAGGTAAGAATTGACACAAATAAGTAATGTCATGTGCCTAAAATGACTGAAGATTCAGTAAAGA
CCAAATGGAAAAAAATCTCATTTTTTTAATTCCNCTCATATTTGATGTTTGTGAAAGTCTGTATTGGTGCAGGCACTTTGGGTG TTTCTGTGGCCGCAAGAGGCTCCTGATCTTGCCCTCAGATGAGTTTTTTTTTTTGAAAAAAGGAGCACAATGGAGAGCAAGAAA
AATAAAGGGAAATACAGCCTTTGTGAATGGGAAGGAACTGTGGTTTCAGTTGCAGAGGTGGGCCAAATAGTTTTGGCCTTTTTT
TTGTCAGGCAGACACATGCACACGTATGTTTATTGCGGTACTATTCACAATAGCAAAGACTT * *
178
AGGATGGGGTGTGACCTTAATCTACTGACAAAGACAAAAGAAAATTTCAATTATATGTTGATAGTCCACCAGAAGGGGCCTTGG AGGGAAACAGTATACCCCCCAGTAATGCAAAAGAGGTATAATGGTCCTAGAAGTGATAGGGTTGTGGACAACTGCAATTATTCA CATTAACTGTTCAAATGTAAAGATCATAAGGAGTGGGCACCCACTATTGAAAAGAGGTGGGGCATCCTTGTCTAGGGCACAAGA ACCAACATAAATGCAATTATGCATGTCAACAAGCCAAGAAAAGGGGACTTAGGGGGTCAGCAACCCTGGTATACTGCAAATTGG AGGGTGAGAAGGTAAGAACTTTGTTTAATTAAGGATGAACCCTGTGGGTGATTACNTACCTTTAATGTCCCAGGGGACNTTTGT TGTGG . . 180
TTTTTTTTTGGTTTGAGGGGGAATGCTGGAGAAAACATCAACATTGAGTTGACATTTGTTTTGCTGAAGTATAGCTACCATCCA CTATCATGAATTTTTGTTTCATTACAAATGATAGAAAAGCCAGATTCTCAAAATAAAGTATAATTCTTTGTATTAAATAAATGT TTATAAATGTTTATGAAGCTCATTACATTATCTTTTTTAAAAAAGTAAAATTTTAGAACATATGACGCTTTTCATAATTAATG CTTTTGATATAGATTTGAGGAAAGAGTCTCCAGTTTGCAGTTCTGAAAATGTAATTTTCAAATTAAATTTCATTGGCATTTGAG GGTGACACCTTCCNCTATAATTTCATTACCCGGATTGTAAGGTTTCCCCC
181 MGQQPGKVLGDQRRPSLPALHFIKGAGKKESSRHGGPHCNVFVEQALQRPVASDFEPQGLSEAARrøSKENLLAGPSENDPNLF VALYDFVASGDNT SITKGEKLRVLGYNHNGEWCEAQTrøGQGWPSNYITPVWSLEKHS YHGPVSrøAAEYPLSSGINGSFL VRESESSPSQRSISLRYEGRVYHYRINTASDGK YVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSP YDK WEMERTDITMKHKLGGGQYGEVYEGV KKYSLTVAVKTLKEDT EVEEF KEAAVMKEIKHPNLVQ LGVCTREPPFYIITEFM TYGN LDYLRECNRQEV-.AWL YMATQISSAMEYLEKKNFIHRD AAR CLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFP IKWTAPESLAY KFSIKSDWAFGVLL EIATYGMSPYPGIDRSQWELLEKDYRMKRPEGCPEKWEL RACWQ PSDRPSF AEIHQAFETMFQESS1SDEVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSP LLPRKERGPPEGGLNEDERLLPKDKKTN FSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGAAFTPLDTA DPAKSPKPSNGAGVPNGARESGGSGFRSPHLWKSSTLTSSRATGEEEGGGSSSKRF RSCSVSCVPHGAKDTEWRSVT PR DLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMESSPGSSPPN TPKPLRRQV TVAPASGLPHKEEAWKGSALGTPAAAEPVTPTSKAGSGAPRGTSKGPAEESRVRRHKHSSESPGRDKGK SK KPAPPPPPAAS AGKAGGKPSQRPGQEAAGEAVLGAKTKATS VDAVNSDAAKPSQPAEG KKPV PATPKPHPAKPSGTPISPAPVPLST PSAS SALAGDQPSSTAFIP ISTRVS RKTRQPPERASGAITKGVV DSTEALCLAISGNSEQMASHSAV EAGKNLYTFCVSY¥DSI QQMRNKFAFREAINKLENNLRELQICPASAGSGPAATQDFSK LSSVKEISDIVQR 182
ATGGGGCAGCAGCCTGGAAAAGTACTTGGGGACCAAAGAAGGCCAAGCTTGCCTGCCCTGCATTTTATCAAAGGAGCAGGGAAG AAGGAATCATCGAGGCATGGGGGTCCACACTGCAATGTTTTTGTGGAACAAGCCCTTCAGCGGCCAGTAGCATCTGACTTTGAG CCTCAGGGTCTGAGTGAAGCCGCTCGTTGGAACTCCAAGGAAAACCTTCTCGCTGGACCCAGTGAAAATGACCCCAACCTTTTC GTTGCACTGTATGATTTTGTGGCCAGTGGAGATAACACTCTAAGCATAACTAAAGGTGAAAAGCTCCGGGTCTTAGGCTATAAT CACAATGGGGAATGGTGTGAAGCCCAAACCAAAAATGGCCAAGGCTGGGTCCCAAGCAACTACATCACGCCAGTCAACAGTCTG GAGAAACACTCCTGGTACCATGGGCCTGTGTCCCGCAATGCCGCTGAGTATCCGCTGAGCAGCGGGATCAATGGCAGCTTCTTG GTGCGTGAGAGTGAGAGCAGTCCTAGCCAGAGGTCCATCTCGCTGAGATACGAAGGGAGGGTGTACCATTACAGGATCAACACT GCTTCTGATGGCAAGCTCTACGTCTCCTCCGAGAGCCGCTTCAACACCCTGGCCGAGTTGGTTCATCATCATTCAACGGTGGCC GACGGGCTCATCACCACGCTCCATTATCCAGCCCCAAAGCGCAACAAGCCCACTGTCTATGGTGTGTCCCCCAACTACGACAAG TGGGAGATGGAACGCACGGACATCACCATGAAGCACAAGCTGGGCGGGGGCCAGTACGGGGAGGTGTACGAGGGCGTGTGGAAG AAATACAGCCTGACGGTGGCCGTGAAGACCTTGAAGGAGGACACCATGGAGGTGGAAGAGTTCTTGAAAGAAGCTGCAGTCATG AAAGAGATCAAACACCCTAACCTAGTGCAGCTCCTTGGGGTCTGCACCCGGGAGCCCCCGTTCTATATCATCACTGAGTTCATG ACCTACGGGAACCTCCTGGACTACCTGAGGGAGTGCAACCGGCAGGAGGTGAACGCCGTGGTGCTGCTGTACATGGCCACTCAG ATCTCGTCAGCCATGGAGTACCTAGAGAAGAAAAACTTCATCCACAGAGATCTTGCTGCCCGAAACTGCCTGGTAGGGGAGAAC CACTTGGTGAAGGTAGCTGATTTTGGCCTGAGCAGGTTGATGACAGGGGACACCTACACAGCCCATGCTGGAGCCAAGTTCCCC ATCAAATGGACTGCACCCGAGAGCCTGGCCTACAACAAGTTCTCCATCAAGTCCGACGTCTGGGCATTTGGAGTATTGCTTTGG GAAATTGCTACCTATGGCATGTCCCCTTACCCGGGAATTGACCGTTCCCAGGTGTATGAGCTGCTAGAGAAGGACTACCGCATG AAGCGCCCAGAAGGCTGCCCAGAGAAGGTCTATGAACTCATGCGAGCATGTTGGCAGTGGAATCCCTCTGACCGGCCCTCCTTT GCTGAAATCCACCAAGCCTTTGAAACAATGTTCCAGGAATCCAGTATCTCAGACGAAGTGGAAAAGGAGCTGGGGAAACAAGGC GTCCGTGGGGCTGTGACTACCTTGCTGCAGGCCCCAGAGCTGCCCACCAAGACGAGGACCTCCAGGAGAGCTGCAGAGCACAGA GACACCACTGACGTGCCTGAGATGCCTCACTCCAAGGGCCAGGGAGAGAGCGATCCTCTGGACCATGAGCCTGCCGTGTCTCCA TTGCTCCCTCGAAAAGAGCGAGGTCCCCCGGAGGGCGGCCTGAATGAAGATGAGCGCCTTCTCCCCAAAGACAAAAAGACCAAC TTGTTCAGCGCCTTGATCAAGAAGAAGAAGAAGACAGCCCCAACCCCTCCCAAACGCAGCAGCTCCTTCCGGGAGATGGACGGC CAGCCGGAGCGCAGAGGGGCCGGCGAGGAAGAGGGCCGAGACATCAGCAACGGGGCACTGGCTTTCACCCCCTTGGACACAGCT GACCCAGCCAAGTCCCCAAAGCCCAGCAATGGGGCTGGGGTCCCCAATGGAGCCCTCCGGGAGTCCGGGGGCTCAGGCTTCCGG TCTCCCCACCTGTGGAAGAAGTCCAGCACGCTGACCAGCAGCCGCCTAGCCACCGGCGAGGAGGAGGGCGGTGGCAGCTCCAGC AAGCGCTTCCTGCGCTCTTGCTCCGTCTCCTGCGTTCCCCATGGGGCCAAGGACACGGAGTGGAGGTCAGTCACGCTGCCTCGG GACTTGCAGTCCACGGGAAGACAGTTTGACTCGTCCACATTTGGAGGGCACAAAAGTGAGAAGCCGGCTCTGCCTCGGAAGAGG GCAGGGGAGAACAGGTCTGACCAGGTGACCCGAGGCACAGTAACGCCTCCCCCCAGGCTGGTGAAAAAGAATGAGGAAGCTGCT GATGAGGTCTTCAAAGACATCATGGAGTCCAGCCCGGGCTCCAGCCCGCCCAACCTGACTCCAAAACCCCTCCGGGGGCAGGTC ACCGTGGCCCCTGCCTCGGGCCTCCCCCACAAGGAAGAAGCCTGGAAAGGCAGTGCCTTAGGGACCCCTGCTGCAGCTGAGCCA GTGACCCCCACCAGCAAAGCAGGCTCAGGTGCACCAAGGGGCACCAGCAAGGGCCCCGCCGAGGAGTCCAGAGTGAGGAGGCAC AAGCACTCCTCTGAGTCGCCAGGGAGGGACAAGGGGAAATTGTCCAAGCTCAAACCTGCCCCGCCGCCCCCACCAGCAGCCTCT GCAGGGAAGGCTGGAGGAAAGCCCTCGCAGAGGCCCGGCCAGGAGGCTGCCGGGGAGGCAGTCTTGGGCGCAAAGACAAAAGCC ACGAGTCTGGTTGATGCTGTGAACAGTGACGCTGCCAAGCCCAGCCAGCCGGCAGAGGGCCTCAAAAAGCCCGTGCTCCCGGCC ACTCCAAAGCCACACCCCGCCAAGCCGTCGGGGACCCCCATCAGCCCAGCCCCCGTTCCCCTTTCCACGTTGCCATCAGCATCC TCGGCCTTGGCAGGGGACCAGCCGTCTTCCACTGCCTTCATCCCTCTCATATCAACCCGAGTGTCTCTTCGGAAAACCCGCCAG' CCTCCAGAGCGGGCCAGCGGCGCCATCACCAAGGGCGTGGTCTTGGACAGCACCGAGGCGCTGTGCCTCGCCATCTCTGGGAAC TCCGAGCAGATGGCCAGCCACAGCGCAGTGCTGGAGGCCGGCAAAAACCTCTACACGTTCTGCGTGAGCTATGTGGATTCCATC CAGCAAATGAGGAACAAGTTTGCCTTCCGAGAGGCCATCAACAAACTGGAGAATAATCTCCGGGAGCTTCAGATCTGCCCGGCG TCAGCAGGCAGTGGTCCGGCGGCCACTCAGGACTTCAGCAAGCTCCTCAGTTCGGTGAAGGAAATCAGTGACATAGTGCAGAGG TAGCAGCAGTCAGGGGTCAGGTGTCAGGCCCGTCGGAGCTGCCTGCAGCACATGCGGGCTCGCCCATACCCATGACAGTGGCTG AGAAGGGACTAGTGAGTCAGCACCTTGGCCCAGGAGCTCTGCGCCAGGCAGAGCTGAGGGCCCTGTGGAGTCCAGCTCTACTAC CTACGTTTGCACCGCCTGCCCTCCCGCACCTTCCTCCTCCCCGCTCCGTCTCTGTCCTCGAATTTTATCTGTGGAGTTCCTGCT CCGTGGACTGCAGTCGGCATGCCAGGACCCGCCAGCCCCGCTCCCACCTAGTGCCCCAGACTGAGCTCTCCAGGCCAGGTGGGA ACGGCTGATGTGGACTGTCTTTTTCATTTTTTTCTCTCTGGAGCCCCTCCTCCCCCGGCTGGGCCTCCTTCTTCCACTTCTCCA AGAATGGAAGCCTGAACTGAGGCCTTGTGTGTCAGGCCCTCTGCCTGCACTCCCTGGCCTTGCCCGTCGTGTGCTGAAGACATG TTTCAAGAACCGCCATTTCGGGAAGGGCATGCACGGGCCATGCACACGGCTGGTCACTCTGCCCTCTGCTGCTGCCCGGGGTGG GGTGCACTCGCCATTTCCTCACGTGCAGGACAGCTCTTGATTTGGGTGGAAAACAGGGTGCTAAAGCCAACCAGCCTTTGGGTC CTGGGCAGGTGGGAGCTGAAAAGGATCGAGGCATGGGGCATGTCCTTTCCATCTGTCCACATCCCCAGAGCCCAGCTCTTGCTC TCTTGTGACGTGCACTGTGAATCCTGGCAAGAAAGCTTGAGTCTCAAGGGTGGCAGGTCACTGTCACTGCCGACATCCCTCCCC CAGCAGAATGGAGGCAGGGGACAAGGGAGGCAGTGGCTAGTGGGGTGAACAGCTGGTGCCAAATAGCCCCAGACTGGGCCCAGG CAGGTCTGCAAGGGCCCAGAGTGAACCGTCCTTTCACACATCTGGGTGCCCTGAAGGGCCCTTCCCCTCCCCCACTCCTCTAAG ACAAAGTAGATTCTTACAAGGCCCTTTCCTTTGGAACAAGACAGCCTTCACTTTTCTGAGTTCTTGAAGCATTTCAAAGCCCTG CCTCTGTGTAGCCGCCCTGAGAGAGAATAGAGCTGCCACTGGGCACCTCGCGACAGGTGGGAGGAAAGGGCCTGCGCAGTCCTG GTCCTGGCTGCACTCTTGAACTGGGCGAATGTCTTATTTAATTACCGTGAGTGACATAGCCTCATGTTCTGTGGGGGTCATCAG GGAGGGTTAGGAAAACCACAAACGGAGCCCCTGAAAGCCTCACGTATTTCACAGAGCACGCCTGCCATCTTCTCCCCGAGGCTG CCCCAGGCCGGAGCCCAGATACCGGCGGGCTGTGACTCTGGGCAGGGACCCGGGGTCTCCTGGACCTTGACAGAGCAGCTAACT CCGAGAGCAGTGGGCAGGTGGCCGCCCCTGAGGCTTCACGCCGGAGAAGCCACCTTCCCGCCCCTTCATACCGCCTCGTGCCAG CAGCCTCGCACAGGCCCTAGCTTTACGCTCATCACCTAAACTTGTACTTTATTTTTCTGATAGAAATGGTTTCCTCTGGATCGT TTTATGCGGTTCTTACAGCACATCACCTCTTTCCCCCCGACGGCTGTGACGCAGCGGAGAGGCACTAGTCACCGACAGCGGCCT TGAAGACAGAGCAAAGCCCCCACCCAGGTCCCCCGACTGCCTGTCTCCATGAGGTACTGGTCCCTTCCTTTTGTTAACGTGATG TGCCACTATATTTTACACGTATCTCTTGGTATGCATCTTTTATAGACGCTCTTTTCTAAGTGGCGTGTGCATAGCGTCCTGCCC TGCCCTCGGGGGCCTGTGGTGGCTCCCCCTCTGCTTCTCGGGGTCCAGTGCATTTTGTTTCTGTATATGATTCTCTGTGGTTTT TTTTGAATCCAAATCTGTCCTCTGTAGTATTTTTTAAATAAATCAGTGTTTACATTAG
184
GTAGAAAAAAAGGTCTCACTGTGCTCAGGCTGGTCTTGAGCTCCTGTCTGGGCAACTTGGCTAAACCTCATCTGTACAAAAAAT ACGAAAACTAGCTGGGTGTGGTGGTGTGCATCCGTGGTCCCAGCTACTAGAGAGGCTGAGGTGGGAGGATTCCTTCACCCCAGG AGGTCAAGGCTGCAGTGAGCCATGATCTCATCACTGTACTCCAGCTTGGGCAACAGAGTGAGACCCTGTCTCCAACAACAACAA ACAAAAACAAAAACCAAAGAATCTAATCTATCTAGGCAACTTCCAGACCTTAGGTTTGATCCCCACTTTGTCACTTCCCTACAT GTATGATGTTGGATCTCAATTTCCAAACAGTGACATGAGTACCATAACCTTTCAAAAAGTATCTATGGTGTAGCCTACTGGGGT GCTGGCTATTGTTCTNAGTGCTTTGGGACAGATTAAGTAAAACCAAGCAAACCAAAGATCTCTGGCCCTGTGGGAATTCATATT CTTGGTGAGGGCCCATTTACTTTTTCCTTCTTTTTGGATTCATATATCCCTTTTGGTTATAATTCAG
186 AACTTATAACATTTTGGGTTTATATTTAATATAGTACTTCTCATCAGGAGGATGTTACTCAGTTAATATAAAGTTTTTTTTCAA AACATTAAATCTCTTTTCCATGTCAATGTCTATAGTTTTTTTTTTAACATTAAATTTTTTTCCGCATTTCAGTATTAGATACAC TGAATACATTTNTCTAAATGTTTTTNCCCTAGNGGATAAAAGTTTTCCTTTTTACCTGGACTCTCTGGATATCTAAATATAATA TTAACTNGGGGGGGACAACAAAACAAAAATCTAATTTAAAAGGNCTCCCTCAACGGGTTCGGGGGGGCCGGGTGGATTATAACC
187 MEPQEERETQVAAWLKKIFGDHPIPQYEVNPRTTEILHHLSERNRVRDRDVYLVIEDLKQKASEYESEAKYLQDLLMESV FSP ANLSSTGSRYLNALVDSAVA ET DTSLASFIPAWDLTSDLFRTKSKSEEIKIELEKLEKNLTATLVLEKCLQEDVKKAELH STERAKVDNRRQMDFLKAKSEEFRFGIKAAEEQLSARGMDAS SHQSLVALSEKLARLKQQTIPLKKKLESYLD PNPSLAQ VKIEEAKRELDSIEAELTRR¥DMMEL
188 TAGAATAATGTCTACAAGAGGATGTCAAGAAAGCAGAGTTGCATCTGTCTACAGAAAGGGCCAAAGTTGATAATCGTCGTCAGA ACATGGACTTTCTAAAAGCAAAGTCAGAGGAATTCAGATTTGGAATCAAGGCTGCAGAGGAGCAACTTTCAGCCAGAGGCATGG ATGCTTCTCTGTCTCATCAGTCCTTAGTAGCACTATCAGAGAAACTGGCAAGATTAAAGCAACAGAGTATACCTTTGAAGAAAA AATTGGAGTCCTATTTAGACTTAATGCCGAATCCGTCTCTTGCTCAAGTGAAAATTGAAGAAGCAAAGCGAGAACTAGATAGCA TTGAAGCTGAACTTACAAGAAGAGTAGACATGATGGAACTGTGACAAAAGCCAAATAAACATCCTTTTCCCTAACAAAGTAAAT TGAATAGGACTTTACAGAGTTCTTTTTCCTCTTGGCATTTCCTAATAACAAAACTTTCTGTGTTCTTAGATTACAGAATATCAT AATTGATAGAATATGGTTTCTTACTGTGTGTTGAATTTTTGTGCCCAAATACATAGTTTTCATATTAAAAAGCCTTTTCTCTTA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
190 TTTTTTTAACAAAAGAAAAGATAAAGTTTATTCACATACTAGGAACCCACAAAGAAAATGACTTTATCCATAACTAAAGACAGG GATTTACAAGCCTACCTTAATAAGGGTAAAGGAGCAGGGAGGAAAAGGCTTCTACTGGAAGAACAAATGGGTTTATTTAGGAAA GACAAATGTATTTTTAGGAGAACAAAGCAGGAGACAAGATGGTTCTTCATCATGTTTGTTTGTGGTCTTCTTCATCTTCTTCAC AGCCGTGAAACTCCTCCAGAAAGGGGGCTAGTGGAAGTCTCACTCCCAGAAGTTTCTGCTTTTAGTCAGATAAGGGAGTATTCA GACAAAGCCTCTTTCTGCATCTGTTGATTCTCAAATGTCTTCAGGTCATAATAATTTTTACGACACAGTGGTATAATTT 192
GAGAAAATGTATTTAATAATTATTAAAAATAAAAACAGCAACCTGAAGATGTATATATAGTTGCACTGGTGATTCTTGAAATAA- AGTCTAGAACTGGCAGAGGATGGGACCCGTCAATTTAAAAAGCACTGCTTCTCCAGAACACCCTCAGAGGGGAAGCGAGGCAAA CCTGGGAACTAGAGCACCCAAGGOCCACAGGGCCTraTACCCAAGGGAGACAGGGACAACCCCTGGGGCAGGGCNTTAAACAC AGGTGAAGGAAGCACACCTTTCAAAGCAGCTGATGACTCTTGAAATCCTGAGGAAACACCCCTGCTCTCTNGAACTTCACCAGG GGCTCTGCACTTTCTTTGGGNTGCCNTACCG
194
GGCATTACANACCTTTTTGCACATAACAATGCTTTCAGAACAACTTTCTTTATGACTATTCTCAACAGTTACCNAGTATTCCAT TGTGTGGATATACATAATTTGTTTAACCAATCCCCTATATTTTAATATTACATTTCCAACTTTTCACTATGATAAAGAGCTCTG GGATGAATAATGACCTTGATTATTTCTTAAAATAAGCCCCTAAAAGTAGAATTGCTGGGNCAAAGAGTGTGTGAGCATCTACGG NCTCACTCTTCAAAGCTACCCTCTAGACCCTTATCTTGAAGGGCAGTAGGTCANGGAACTTTTACTATTTAGGGGAAGGCTACT ATGGGGCTTTCTCAAG
196
GGGTCAACAGAAGAGACTGCTTACTGTTTATTAAGTACACATTAAAACCTAAGTGGTCATTTAAATAAAAATAACAACGTATTA TTAATTTTATTACATATATGAACATAAAATGTATGAAAAGAACTGCATAAAATTGGGACTGGCAAAAAAGGTATATAATTGTAC AGTTCTTACGCATGAAGTAGTATATTACATCTCTTGAAAATAACTGTGTCACAGCTTGCCAGGAGTAAAGAATAAAATAAAAAA GAAAGAAAGAAACTGTGGTAAGTCAAGATGTACCTCTGCTACCCCTGACACAGCAAGACCAACCCTTCCTCCTCCAATACATTT ATGATGATCCCCTTTTTACTTAACGAGTTGTAAAACCCTAAAGTAAATCCCTCCAAATAACAAGAACCAAGAGTTATNATTA
198
TTTTTTTTTGTTTCTGTTTTGTTTTTTCTTTTGCACTGATATATACCATACCAACATTGCAAGATGCAAAGTGTGGAAACTGGA GTTTAAATAAAATTACAAGGCAAAACTACCCCATCCCAAGTGCGGTTGCTGTACATATCTACAGTACAATTTTTGGAATGTATT GCCATTTAAGAACATAGAAACTTTCTACAGACAATTTCACATACAGAATACGTACACCTTTTAGAAAAAAAGGCAAATATTTAT CTTACAGAGAGCATTGTATTTTACATTTGCCTGCACGTTTCTTTTTTCTGTTTCTTTTCTTTCTTTCTTTTTTTACATACTAGG ATTTATTAAAGTGACCATAAGGTGCCCGAGCGGGTTTTCTAATGGGNAAGCAGACTGGGNTTCACCAACACAGGNGCAGGATT- GGGTGGGACAGGCTTTCGGGGACCTTTCTTCCCCTGGGNCACACGGGCAGATCCGGTCCCCAAGGGCAGGNTGTTCAGCCNGGG GCTTTTNCTTTT
200
TTTTACATACTAGATTTATTAAAGTGACCATAAGTGCCGAAGCGGTTTTCTAATGGAAAGCAGACTGGATTCACAACACAGAAG CAGAATTGGTGGAACAGGCTTTCGGGAACTTTCTTCCCCTGGTCACACGGCAGATCGGTCCCCAAGGACAGGTGCTCAGCCAGG ACTTTTGCTTTAAGAAGGATTTGTCTNGAGAAAGGACTAGAGAGAAATCCAGCTCAGATGTATTGCTCATTCCTCTTCAGAAGG ACTGGGTNGGAATGGAGCAGGGGCTAGAGGAATCTGGAAGCTAATTCTTTTAGGCTTTTTCCAACAGAGGGAAGCAGAGGGACT TCTGGGTCTTGAAGTTTGGAGCTTACGGAGGCGA
201
M GKRPAEPGPARVGKKGKKEVMAEFSDAVTEETLKKQVAEAWSRRTPFSHEVIVMDMDPFLHCVIPNFIQSQDFLEG QKE M NLDFHEKYNDLYKFQQSDD KKRREPHVSTLRKILFEDFRSWLSDISKIDLEST1DMSCAKYEFTDALLCHDDELEGRRIAFIL
YLVPS DRSMGGTLDLYSIDEHFQPKQIVKSLIPSWNKLVFFEVSPVSFHQVSEVLSEEKSRLSISG FHGPSLTRPPNYFEPP
IPRSPHIPQDHEI YDWINPTYLDMDYQVQIQEEFEESSEILLKEF KPEKFTKVCEA EHGHVEWSSRGPPNKRFYEKAEESK LPEILKECMKLFRSEALFL LSNFTGLKLHF APSEEDE DKKEAETTDITEEGTSHSPPEPE QMAISN SQQSNEQTDPE
PEENETKKESSVPMCQGELRH KTGHYT IHDHSKAEFADLILYCGCEGWEPEYGGFTSYIAKGEDEELLTWPESNSLALVY RDRETLKFVKHINHRS EQKKTFPNRTGFWDFSFIYYE
202
CACGATAAAGGGGACATGCCGGGAGTTGCAGTACCCTCAGGAAGAAGTCATTGTCATGGACATGGACCCTTTTCTTCACTGTGT GATCCCAAACTTCATCCAAAGCCAAGACTTCTTAGAAGGGCTTCAGAAGGAACTGATGAACTTGGACTTCCATGAGAATCTGAT GATTTGAAGAAGAGAAGAGAGCCTCACATCTCCACTTTAAGGAAAATTCTGTTTGAAGATTTCCGGTCCTGGCTTTCTGATATT TCTAAAATTGACCTGGAATCAACCATTGACATGTCCTGTGCTAAATATGAATTCACTGATGCCCTGCTGTGCCATGATGATGAG CTGGAAGGGCGCCGGATTGCCTTCATCCTGTACCTGGTTCCTTCCTGGGACAGGAGCATGGGTGGTACCCTGGACCTGTACAGC ATAGATGAACACTTTCAGCCGAAGCAGATTGTCAAGTCTCTTATCCCTTCGTGGAACAAACTGGTTTTCTTTGAAGTATCTCCT GTGTCCTTTCACCAGGTGTCTGAAGTGCTGTCTGAAGAAAAGTCACGTTTGTCTATAAGTGGCTGGTTTCATGGTCCATCATTG ACTCGGCCTCCCAACTACTTTGAACCCCCCATACCTCGGAGCCCTCACATCCCACAAGATCATGAGATTTTGTATGATTGGATC AACCCTACTTATCTGGACATGGATTACCAAGTTCAAATTCAAGAAGAGTTTGAAGAAAGTTCTGAAATTCTCCTGAAGGAGTTT CTTAAGCCTGAGAAATTCACGAAAGTCTGTGAGGCCTTGGAGCATGGACATGTGGAATGGAGCAGCCGAGGTCCCCCTAACAAA AGGTTTTATGAGAAAGCTGAGGAGAGTAAGCTTCCTGAGATATTGAAGGAGTGCATGAAGTTATTTCGCTCTGAGGCACTATTC TTGCTGCTCTCCAACTTCACAGGCCTGAAGCTTCATTTCTTGGCCCCTTCGGAAGAAGATGAGATGAATGATAAAAAAGAGGCA GAAACCACTGATATCACTGAAGAAGGGACTAGCCATAGTCCTCCTGAGCCAGAGAATAATCAGATGGCCATCAGCAACAACAGC CAACAGAGCAATGAGCAGACAGACCCAGAGCCAGAGGAAAATGAAACAAAGAAAGAATCAAGTGTTCCCATGTGCCAAGGGGAA CTGAGGCATTGGAAGACCGGTCACTACACTTTAATTCATGACCATAGCAAGGCTGAATTTGCCCTAGACTTAATTCTGTACTGT GGCTGTGAAGGCTGGGAGCCAGAATATGGCGGTTTTACTTCTTACATTGCCAAAGGTGAAGATGAAGAGCTGCTAACAGTGAAT CCAGAAAGCAATTCTTTGGCATTGGTCTACAGAGACAGAGAGACTCTGAAATTTGTCAAGCATATTAACCACCGAAGCCTGGAA CAAAAGAAAACCTTCCCAAACAGAACAGGTTTCTGGGACTTTTCATTCATCTATTATGAATGACAGCACTGGGCAAAGCTGAAC AAAAATGTGACCCTTCGTAATTACTGGGAAGTCTGAAAGAGCTAAGCATGGAGTCAAGGAGAACTACATGGTAGCTTGCCTGAC AGTGTTCTTAAAACTGGTTGTCTTTTACTAGGACTCATAATGATTGTC'CTCAACCGAGACCTTGAGCTTGCAGCTACGTACTTA TCTCTTGATTAAAAAAAAAAAAAAGTTGGCTTTTTTTTTTTTTAACATTTAGTCCTTTTTCCATATTGGCTTCTTCAGTGAATT TTTAAGTTCAATTTGTTTTTATTGAGGTAAAATATTTATAACATAAAACTGACCAGCTTACCCATTTTTAAATATGCAATTCAG TGGATTAAGTACATTCTCATTGTTGTCCAGCCATCACCATCATCCATCTCCAGAAGTTTTCCATCTTCCCAAATTCTGTGCCCA TTGAACAATAACTCCCCACCTCCCCTTCCCCTAGCAACAGCCATACTTTTTGTCTCTATCATCAACTTCACTACTCATATTTCT CATGTAAGTGGAATCATACAGTATTTGTCCTTTTGTGACTGGTTTCACTTAGCATAAAGTCTTTAAGATGCATCCATGTTTCCA GTGTTTCGGTTTTTTTAGAAAAACTCATACGTGATTGCAGCCGGGCATGGTGGCTCACGCCTGTAATCCCAGCACTTGGGAGGC CAAGGCAGGCGGATCACCTGAGGTCAGGAGTTAAACACCAGCCTGACAAACATGGAGAAACCCCATCTCTACTAAAAATACAAA ATTAGCTGGGCGTGGTGGCACATGCCTGTAATCCCAGCTACTCAGGAGGCTGGGGCAGGAGAATTGGTTGAACCCAGGAGGCGG AGGTTGCAGTGAGCCGAGATTGTGCCACTGCACTCCAGCCTGGGCAACAAGAGTGAAACTCTGTCTC
204
•GAGTAGGAGTGCCTCCTTGTCTGCACTGCTGGTATGGGGTTAGGCCAGGTAGGACATTCCAGAGGGGCTTCTGAAAACCAAGAG TCCCTGGGGAAAGGGAACAGAGTAAGGCAGGCCTTGTTCTCACTGCCCTCTAAGGGAACTTGGTCACTCGGCACTTTTAAGCCT CAGTTTCTCCAGTTCAATAATAAGGACAAGAGCTTTTCCCATGCATTCTCTTTCCCCGGGAAAGTTGACTGAGGTGACCAGTAA TAGAATTGAAAAGGGAGAGTGTCTTCAGTGCAATGTGGCATCCTGGATTGGGTCTTGGAACAAAAACAGGACATTAGTGGGAAA ATTGGAAATCTGAAAAAAGTCTGAATTTTAGTTAATATACCAATTTCAGTCTCTTGGTTTTGACAGATGTACCATGGTGATGTA AGATGTTGACGTTGGGGTAGGCTGGGTGAAGGGTATACAGGAACTCTTTGTACTATCTCTGCAACTTCTCTGTAAATCTAGTAT CATTCCAAAATAAAAGTTTATTTAATTTAAAAAAAAAA
205 MNKFPRRIPQKSCPRI C SCQEVSPEVADAICQAI¥ SAPGPHAVLLVTQLGRFTDEDQQWRRLQEVFGVGVLGHTI VFTR KEDLAGSSLEDYWET QALAW DVT ARRHCGFNNRAQGEEQEAQLRE MEKVEAIMWENEGDYYSNKAYQYTQQNFRLKEL QERQVSQGQGSEDVPGEESWLEGLSQIQKESEEAHRCLLGKADI-
206 GAAAACATTTTGCTGAAAATATAAGCAAACATCGGCCTTGTCCTCCTTGTGTTCATACACTGTGGAAGCTTTTCTC GCCTCCT CCGTGAGAGTGCGTGGCCGGGAGACCAGAAACGTGGTCCTTTCTCTTGCCTGTGAGCTGGTGCAGAGATGGAGGAAGAAGAATA TGAACAAATTGCCCAGGAGAATCCCCCAGAAGAGCTGTCCCAGGATCCTGTGCTGGAGCTGTCAGGAGGTCTCGCCAGAGGTGG CAGACGCTATCTGCCAAGCCATCGTCTTATCCGCCCCAGGGCCCCACGCCGTGCTCCTGGTGACACAACTGGGCCGGTTCACGG ATGAGGATCAGCAGGTGGTCAGGCGCCTGCAGGAGGTCTTTGGAGTGGGGGTTCTGGGTCACACCATCCTGGTGTTCACCCGGA AGGAAGACCTGGCTGGCAGCTCCCTGGAAGACTATGTGCGAGAGACCAACAACCAGGCCCTTGCCTGGCTGGATGTGACCCTTG
CACGGCGCCATTGCGGCTTCAACAACAGGGCACAGGGGGAGGAGCAGGAGGCCCAACTGCGAGAGCTCATGGAGAAAGTTGAAG
CCATTATGTGGGAAAACGAAGGAGATTATTACAGCAACAAGGCTTACCAATATACCCAGCAAAACTTTCGGCTGAAAGAACTAC
• AGGAAAGGCAAGTAAGCCAGGGCCAAGGCTCTGAGGACGTGCCTGGTGAGGAGTCTTGGCTGGAAGGACTGTCCCAGATCCAGA
AGGAATCTGAGGAAGCCCACAGATGCCTGCTGGGGAAGGCTGACCTTTGAGCCTGTGCTGGACTTGAGCeAAGGACACCATCAG CCTTTGCACCCCCCTGTGTCCAGCCCTCTGTTTCTCTTTCCATCCCATGGAGTGCTTCCCAGTCTCCAGGTCATGACGTCTGGT GTAGGAAGAGGGGCATGGGGCTTGAGGACAGGGTCCAGCATGCCCAGATCACATTCCAGTTCCTTCATTCCTTCTTCCAGAACA TCTGGGTCCTCCCTCCTCTGTGCCCCAACAGCACGCTGTCTTCCTATTGGACCTTCTATCTCATTGGCATTGCCTTTCATGAGT TACTTGTCTATACTCTGATAGAACCAAAGTTTCTTGAGGGCAGGCCTGTATCTTTTACTTCTGTGTAACTTCCACAGCTTTTGA CTGCATTGGAGTCATGCAGTCACGTTTGGTGCGGCAACTCCATGCAAGCTGTTGACCAGATGACTTCTCATCTCTCCCCACACC ATGATGGTTTAAGGTGCCTGTTGTGTCTGGTGGAGACAGTGCTGGGAGATGATCAGAAATCTCAGGGCACAGCCTCAGGTCTAC CTGGACACTCATCCACTGTTGGAGATGCTCAACAGCTAGACACAGATGCTCACAGCCGACCTGTGGCCTCTTGCTCTGAAGCCA TCCCCCATCTTCCCTAGACACAGCAGACATCTGAGAAAGCTTCAGCATTTCTCTTGCTAACAGATTCAGAAAAGTGTCTCAAAG CAGAGCACAGAGTTATTTGGTGTTTGCTGAAGACAGCCTTTGTGCCACAATCACTTATTAAATAAGCGATCAATTTCCCATTGA ACTGAACATGCAACATTTATCATACATTCAGCTCTCATTCACACTCCTTAAGATTTGGTCAGAATTTTTATTTCTGTTCATGTC TTCTACTTTTCTACTCCTGTATGAATAAAATATTGATTTGATTACAGTGGCTTTGACTATAATGTGGGAGCCAATTTTTGCCTC AGTCTTCATTTTTATATTTACCTTGTTATTCTCAGGCATTTTTTTCTTCTATGTGAGAGTTAAAATCATTCTGTAATTTCCCCC CAAAATCATATTGGTATTCTAGTTGGCAATGTCTTACATTTATGTTAAGTTTGAGGGAATTGGTAGTTCAAGTATAAGTTAATT AAGGCCATTTTATTTCTAAGTGAACAGACTTGAAACTCCAGAGCTACTGAAGTAAAAGTTAGAATCATTTGCATTTTCATTCAG ATAGGAGATAATTTTGTAAATTTTGATGCTATTATTTTAACTCTATTAGCTTAAGTAATGTCATAATAGAAAACACAAGCATTT GACCAAATGAGATCCATTCAGCGACTAACTGGCAAGGCACTCAAAACATGTCATTCATTAAATGTTGTTTTTATTTACCTCAAA AAAAAAAAAAAAAAAAAAAA
207
MWIDVKMLSGFTPTMSSIEELENKGQVMKTEVKNDHVLFYLE VFGRADSFTFSVEQSNVFNIQPAPGMVYDYYEKDGEAFL LT 208
GGCACGAGGCCGCCTTGGGGTGTGTGCCTGCCCCGCTGCGATGGAGGTCCTAAGAGCAAGGGGGGGAAGAGGGGCTGGCTCTGG TAGATTGCAAATGACCTGCTTTTTTTCTGATCCCGAGCTGCGTTCGGACCCCTGTCGGATAGTAAATCCCAGTAAGGTACCTGC CGTGGGCAGATCTGAGCTTTCTTCTTGGACACCCCATACCCACAGTCCTCCAGGCCACCCTTAAGTACAATGTTCTCCTACCTA AGAAGGCATCTGGATTTTCTCTTTCCTTGGAAATAGTAAAGAACTACTCTTTGACTGTTTTTGACCTCACAGTGAACCTCAAAT ACACTGGAATTCGCAATAAATCCAGTATGGTGGTTATAGATGTAAAAATGCTATCAGGATTTACTCCAACCATGTCATCCATTG AAGAGCTTGAAAACAAGGGCCAAGTGATGAAGACTGAAGTCAAGAATGACCATGTTCTTTTCTACTTGGAAAATGTTTTTGGTC GAGCAGACAGTTTCACTTTTTCTGTTGAGCAGAGCAACCTTGTGTTCAACATTCAGCCAGCCCCAGGCATGGTCTACGATTACT ACGAAAAAGATGGAGAAGCATTTCTTTTAACAAACTGATTCTTCTGTATCAAACCTGGAAAAAAATCATGAACCATCTGACATC GTGAACAGTCTGCAGTGGGCTATGGTTTCTTGACAAGTCTTATTTCCTTATCATCCCATTAAATGTTGTCATTTTGCAAAAAAA AAAAAAAAAAAAAAAAAAAACTCGAGACTAGTTCTCTCTCTCATAAAATTAATTAACCGCTCATTCATCGACCTCCCCACCCCA TCCAACATCTCCGCATGATGAAACTTCGGCTCACTCCTTGGCGCCTGCCTGATCCTCCAAATCACCACAGGACTATTCCTAGCC ATGCACTACTCACCAGACGCCTCAACCGCCTTTTCATCAATCGCCCACATCACTCGAGACGTAAATTATGGCTGAATCATCCGC TACCTTCACGCCAATGGCGCCTCAATATTCTTTATCTGCCTCTTCCTACACATCGGGCGAGGCCTATATTACGGATCATTTCTC TACTCAGAAACCTGAAACATCGGCATTATCCTCCTGCTTGCAACTATAGCAACAGCCTTCATAGGCTATGTCCTCCCGTGAGGC CAAATATCATTCTGAGGGGCCACAGTAATTACAAACTTACTATCCGCCATCCCATACATTGGGGCAGACCTAGTTCAATGAATC TGAGGAGGCTACTCAGTAGACAGTCCCACCCTCACACGATTCTTTACCTTTCACTTCATCTTGCCCTTCATTATTGCAGCCCTA GCAGCACTCCACCTCCTATTCTTGCACGAAACGGGATCAAACAACCCCCTAGGAATCACCTCCCATTCCGATAAAATCACCTTC CACCCTTACTACACAATCAAAGACGCCCTCGGCTTACTTCTCTTCCTTCTCTCCTTAATGACATTAACACTATTCTCACCAGAC CTCCTAGGCGACCCAGACAATTATACCCTAGCCAACCCCTTAAACACCCCTCCCCACATCAAGCCCGAATGATATTTCCTATTC GCCTACACAATTCTCCGATCCGTCCCTAACAAACTAGGAGGCGTCCTTGCCCTATTACTATCCATCCTCATCCTAGCAATAATC CCCATCCTCCATATATCCAAACAACAAAGCATAATATTTCGCCCACTAAGCCAATCACTTTATTGACTCCTAGCCGCAGACCTC CTCATTCTAACCTGAATCGGAGGACAACCAGTAAGCTACCCTTTTACCATCATTGGACAAGTAGCATCCGTACTATACTTCACA AC TCCT TCCTMTACC CTATCTCCCT TTGAAAACAAAATACTCAAATGGGCCTAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAA
209
MATVQQLEGRWRVDSKGFDEYMKE GVGIALRKMGAMAKPDCIITCDGKN TIKTEST KTTQFSCTLGEKFEETTADGRKTQ T¥CNFTDGAVQHQE DGKESTITRKLKDGKLVVECVM VTCTRIYEKVE 210
ACCGCCGACGCAGACCCCTCTCTGCACGCCAGCCCGCCCGCACCCACCATGGCCACAGTTCAGCAGCTGGAAGGAAGATGGCGC CTGGTGGACAGCAAAGGCTTTGATGAATACATGAAGGAGCTAGGAGTGGGAATAGCTTTGCGAAAAATGGGCGCAATGGCCAAG CCAGATTGTATCATCACTTGTGATGGTAAAAACCTCACCATAAAAACTGAGAGCACTTTGAAAACAACACAGTTTTCTTGTACC CTGGGAGAGAAGTTTGAAGAAACCACAGCTGATGGCAGAAAAACTCAGACTGTCTGCAACTTΪACAGATGGTGCATTGGTTCAG CATCAGGAGTGGGATGGGAAGGAAAGCACAATAACAAGAAAATTGAAAGATGGGAAATTAGTGGTGGAGTGTGTCATGAACAAT GTCACCTGTACTCGGATCTATGAAAAAGTAGAATAAAAATTCCATCATCACTTTGGACAGGAGTTAATTAAGAGAATGACCAAG CTCAGTTCAATGAGCAAATCTCCATACTGTTTCTTTCTTTTTTTTTTCATTACTGTGTTCAATTATCTTTATCATAAACATTTT ACATGCAGCTATTTCAAAGTGTGTTGGATTAATTAGGATCATCCCTTTGGTTAATAAATAAATGTGTTTGTGCT
212 GAGAGAACTAGTCTCGAGTTTTTTTTTTTTTTTTTTGTGTAAGGGCGCAGACTGCTGCGAACAGAGTGGTGATAGCGCCTAAGC ATAGTGTTAGAGTTTGGATTAGTGGGCTATTTTCTGCTAGGGGGTGGAAGCGGATGAGTAAGAAGATTCCTGCTACAACTATAG TGCTTGAGTGGAGTAGGGCTGAGACTGGGGTGGGGCCTTCTATGGCTGAGGGGAGTCAGGGGTGGAGACCTAATTGGGCTGATT TGCCTGCTGCTGCTAGGAGGAGGCCTAGTAGTGGGGTGAGGCTTGGATTAGCGTTTAGAAGGGCTATTTGTTGTGGGTCTCATG AGTTGGAGTGTAGGATAAATCATGCTAAGGCGAGGATGAAACCGATATCGCCGATACGGTTGTATAGGATTGCTTGAATGGCTG CTGTGTTGGCATCTGCTCGGGCGTATCATCAACTGATGAGCAAGAAGGATATAATTCCTACGCCCTCTCAGCCGATGAACAGTT GGAATAGGTTGTTAGCGGTAACTAAGATTAGTATGGTAATTAGGAAGATGAGTAGATATTTGAAGAACTGATTAATGTTTGGGT CTGAGTTTATATATCACAGTGAGAATTCTATGATGGACCATGTAACGAACAATGCCACAGGGATGAATATTATGGAGAAGTAGT CTAGTTTGAAGCTTAGGGAGAGCTGGGTTGTTTGGGTTGTGGCTCAGTGTCAGTTCGAGATAATAACTTCTTGGTCTAGGCACA TGAATATTGTTGTGGGGAAGAGACTGATAATAAAGGTGGATGCGACAATGGATTTTACATAATGGGGGTATGAGTTTTTTTTGT TAGGGTTAACGAGGGTGGTAAGGATGGGGGGAATTAGGGAAGTCAGGGTTAGGGTGGTTACCCACTCCACCTTACTACCAGACA ACCTTAGCCAAACCATTTACCCAAATAAAGTATAGGCGATAGAAATTGAAACCTGGCGCAATAGATATAGTACCGCAAGGGAAA GATGAAAAATTATAACCAAGCATAATATAGCAAGGACTAACCCCTATACCTTCTGCATAATGAATTAACTAGAAATAACTTTGC AAGGAGAGCCAAAGCTAAGACCCCCGAAACCAGACGAGCTACCTAAGAACAGCTAAAAGAGCACACCCGTCTATGTAGCAAAAT AGTGGGAAGATTTATAGGTAGAGGCGACAAACCTACCGAGCCTGGTGATAGCTGGTTGTCCAAGATAGAATCTTAGTTCAACTT TAAATTTGCCCACAGAACCCTCTAAATCCCCTTGTAAATTTAACTGTTAGTCCAAAGAGGAACAGCTCTTTGGACACTAGGAAA AAACCTTGTAGAGAGAGTAAAAAATTTAACACCCATAGTAGGCCTAAAAGCAGCCACCAATTAAGAAAGCGTTCAAGCTCAACA CCCACTACCTAAAAAATCCCAAACATATAACTGAACTCCTCACACCCAATTGGACCAATCTATCACCCTATAGAAGAACTAATG TTAGTATAAGTAACATGAAAACATTCTCCTCCGCATAAGCCTGCGTCAGATTAAAACACTGAACTGACAATTAACAGCCCAATA TCTACAATCAACCAACAAGTCATTATTACCCTCACTGTCAACCCAACACAGGCATGCTCATAAGGAAAGGTTAAAAAAAGTAAA AGGAACTCGGCAAATCTTACCCCGCCTGTTTACCAAAAACATCACCTCTAGCATCACCAGTATTAGAGGCACCGCCTGCCCAGT GACACATGTTTAACGGCCGCGGTACCCTAACCGTGCAAAGGTAGCATAATCACTTGTTCCTTAAATAGGGACCTGTATGAATGG CTCCACGAGGGTTCAGCTGTCTCTTACTTTTAACCAGTGAAATTGACCTGCCCGTGAAGAGGCGGGCATGACACAGCAAGACGA GAAGACCCTATGGAGCTTTAATTTATTAATGCAAACAGTACCTAACAAACCCACAGGTCCTAAACTACCAAACCTGCATTAAAA ATTTCGGTTGGGGCGACCTCGGAGCAGAACCCAACCTCCGAGCAGTACATGCTAAGACTTCACCAGTCAAAGCGAACTACTATA CTCAATTGATCCAATAACTTGACCAACGGAACAAGTTACCCTAGGGATAACAGCGCAATCCTATTCTAGAGTCCATATCAACAA TAGGGTTTACGACCTCGATGTTGGATCAGGACATCCCAATGGTGCAGCGGCTATTAAAGGTTCGTTTGTTCAACGATTAAAGTC CTACGTGATCTGAGTTCAGACCGGAGTAATCCAGGTCGGTTTCTATCTACTTCAAATTCCTCCCTGTACGAAAGGACAAGAGAA ATAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 214
GTGTTTTTGGTGTGGTGTGATTATGTGATTGTTAATGATTTATTCACTATATCTTACATTAAGACCTATGGTGTCCTTTTAACC TAATGTGTCCTTTGAAGTCAAGCAAAACCGTAAGAATGGTTAAAAAATTAACAGCTTTGGTTCAATTGCCTTATAAACACATAA TATAGGTATTACTGATCGAAGGAAAGTTCAGTGAAGATGCTGGTAGTTTACAGCACTCCGGAGAATTAAAACAATGAGATGTAA AGGTAACAGCTCTAAAAATTCAGACATTTGCCTTATTAAGCTCTTTTCTACAAGAGACTTCATTACATTGAAAAATGAAACCTG GCACCCATCCTAGGAGAATTATCTGTGCAGAAGTTCTGATTTACAGATTTGTGATCTTAGGGAACAGTGTGCACACCCAGGGTG AAATTTC
216
GAACACCCCGCTCATCTGAGAAAGGGCAGCATTGCTCCCTCAGCAAATCAGGGGGAGAGGGAGCTTTCCCAGGCTTTTAATCAC TCTCTGATTCAGCGCCCAAAAACCCAGGGACAGGAAGCCCAGCAGATTTTGCTCAGAACTGAGATAATATATTTTCTAACCAGA AAACACATCTCAGCTAGTTACCACCTCATTCATCTTTCCAGAGTGGTTATAATTACAGTATTCATTTCATAATTGCTGCCTATT TGCAAATACAAAATCCCTGAATCTTAAAATAAATTACAGTTCTCTTTTCTATTTAACAGCCATTGTGC
217
MSSHLVEPPPPLHimNN CEENEQSLPPPAGLNSSWVELPMNSSNGNDNGNGKNGG EHVPSSSSIHNGDMEKIL DAQHESGQ SSSRGSSHCDSPSPQEDGQ1MFD¥EMHTSRDHSSQSEEEWEGEKEVEA KKSAD VSDWSSRPENIPPKEFHFRHPKRSVSLS MRKSGAMKKGGIFSAEF KVFIPSLF SHV ALGLGIYIGKRLSTPSASTY
218
GCGGCGGACTCGGCTTGTTGTGTTGCTGCCTGAGTGCCGGAGACGGTCCTGCTGCTGCCGCAGTCCTGCCAGCTGTCCGACGAT GTCGTCCCACCTAGTCGAGCCGCCGCCGCCCCTGCACAACAACAACAACAACTGCGAGGAAAATGAGCAGTCTCTGCCCCCGCC GGCCGGCCTCAACAGTTCCTGGGTGGAGCTACCCATGAACAGCAGCAATGGCAATGATAATGGCAATGGGAAAAATGGGGGGCT GGAACACGTACCATCCTCATCCTCCATCCACAATGGAGACATGGAGAAGATTCTTTTGGATGCACAACATGAATCAGGACAGAG TAGTTCCAGAGGCAGTTCTCACTGTGACAGCCCTTCGCCACAAGAAGATGGGCAGATCATGTTTGATGTGGAAATGCACACCAG CAGGGACCATAGCTCTCAGTCAGAAGAAGAAGTTGTAGAAGGAGAGAAGGAAGTCGAGGCTTTGAAGAAAAGTGCGGACTGGGT ATCAGACTGGTCCAGTAGACCCGAAAACATTCCACCCAAGGAGTTCCACTTCAGACACCCTAAACGTTCTGTGTCTTTAAGCAT GAGGAAAAGTGGAGCCATGAAGAAAGGGGGTATTTTCTCCGCAGAATTTCTGAAGGTGTTCATTCCATCTCTCTTCCTTTCTCA TGTTTTGGCTTTGGGGCTAGGCATCTATATTGGAAAGCGACTGAGCACACCCTCTGCCAGCACCTACTGAGGGAAAGGAAAAGC CCCTGGAAATGCGTGTGACCTGTGAAGTGGTGTATTGTCACAGTAGCTTATTTGAACTTGAGACCATTGTAAGCATGACCCAAC CTACCACCCTGTTTTTACATATCCAATTCCAGTAACCCTCAAATTCAATATTTTATTCAAACTCTGTTGAGGCATTTTACTAAC CTTATACCCTTTTTGGCCTGAAGACATTTTAGAATTTCCTAACAGAGTTTACTGTTGTTTAGAAATTTGCAAGGGCTTCTTTTC CGCAAATGCCACCAGCAGATTATAATTTTGTCGGCAATGCTATTATCTCTAATTAGTGCCACCAGACTAGACCTGTATCATTCA TGGTATAAATTTTACTCTTCCAACATAACTACCATCTCTCTCTTAAAACGAGATCAGGTTAGCAAATGATGTAAAAGAAGCTTT ATTGTCTAGTTGTTTTTTTTCCCCCAAGACAAAGGCAAGTTTCCCTAAGTTTGAGTTGATAGTTATTAAAAAGAAAACAAAACA AAAAAAA GGC GGCAC CAAAAAAATATCCTGGGCAATAAAAAAAATATTTTAAACCAAAAAAAAAAAAAAAA
219
MEPSS KLTGRLM AVGGAVLGS QFGYNTGVINAPQKVIEEFYNQT VHRYGESILPTTLTT WSLSVAIFSVGGMIGSFSVG LFWRFGRRNSMLMM LLAF¥SAV MGFSKLGKSFEMLILGRFIIGVYCGLTTGFVPMYVGEVSPTAFRGALGTLHQLGIVVGI LIAQVFGLDSIMGNKDLWPLLLSIIFIPALLQCIVLPFCPESPRFL INRNEENRAKSVLKKLRGTADVTHDLQEMKEESRQMM REKKVTILELFRSPAYRQPILIAWLQLSQQLSGINAVFYYSTSIFEKAGVQQPVYATIGSGIV TAFTVVSLFWERAGRRTL HLIGLAG GCAILMTIALALLEQLP MSYLSIVAIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFS WTSNFIVGM CFQYVEQLCGPYVFIIFTV L¥LFFIFTYFKVPET GRTFDEIASGFRQGGASQSDKTPEELFHPLGADSQV 220 . TAGTCGCGGGTCCCCGAGTGAGCACGCCAGGGAGCAGGAGACCAAACGACGGGGGTCGGAGTCAGAGTCGCAGTGGGAGTCCCC GGACCGGAGCACGAGCCTGAGCGGGAGAGCGCCGCTCGCACGCCCGTCGCCACCCGCGTACCCGGCGCAGCCAGAGCCACCAGC GCAGCGCTGCCATGGAGCCCAGCAGCAAGAAGCTGACGGGTCGCCTCATGCTGGCTGTGGGAGGAGCAGTGCTTGGCTCCCTGC AGTTTGGCTACAACACTGGAGTCATCAATGCCCCCCAGAAGGTGATCGAGGAGTTCTACAACCAGACATGGGTCCACCGCTATG 5 GGGAGAGCATCCTGCCCACCACGCTCACCACGCTCTGGTCCCTCTCAGTGGCCATCTTTTCTGTTGGGGGCATGATTGGCTCCT TCTCTGTGGGCCTTTTCGTTAACCGCTTTGGCCGGCGGAATTCAATGCTGATGATGAACCTGCTGGCCTTCGTGTCCGCCGTGC TCATGGGCTTCTCGAAACTGGGCAAGTCCTTTGAGATGCTGATCCTGGGCCGCTTCATCATCGGTGTGTACTGCGGCCTGACCA CAGGCTTCGTGCCCATGTATGTGGGTGAAGTGTCACCCACAGCCTTTCGTGGGGCCCTGGGCACCCTGCACCAGCTGGGCATCG TCGTCGGCATCCTCATCGCCCAGGTGTTCGGCCTGGACTCCATCATGGGCAACAAGGACCTGTGGCCCCTGCTGCTGAGCATCA 0 TCTTCATCCCGGCCCTGCTGCAGTGCATCGTGCTGCCCTTCTGCCCCGAGAGTCCCCGCTTCCTGCTCATCAACCGCAACGAGG AGAACCGGGCCAAGAGTGTGCTAAAGAAGCTGCGCGGGACAGCTGACGTGACCCATGACCTGCAGGAGATGAAGGAAGAGAGTC GGCAGATGATGCGGGAGAAGAAGGTCACCATCCTGGAGCTGTTCCGCTCCCCCGCCTACCGCCAGCCCATCCTCATCGCTGTGG TGCTGCAGCTGTCCCAGCAGCTGTCTGGCATCAACGCTGTCTTCTATTACTCCACGAGCATCTTCGAGAAGGCGGGGGTGCAGC AGCCTGTGTATGCCACCATTGGCTCCGGTATCGTCAACACGGCCTTCACTGTCGTGTCGCTGTTTGTGGTGGAGCGAGCAGGCC 5 GGCGGACCCTGCACCTCATAGGCCTCGCTGGCATGGCGGGTTGTGCCATACTCATGACCATCGCGCTAGCACTGCTGGAGCAGC' TACCCTGGATGTCCTATCTGAGCATCGTGGCCATCTTTGGCTTTGTGGCCTTCTTTGAAGTGGGTCCTGGCCCCATCCCATGGT TCATCGTGGCTGAACTCTTCAGCCAGGGTCCACGTCCAGCTGCCATTGCCGTTGCAGGCTTCTCCAACTGGACCTCAAATTTCA TTGTGGGCATGTGCTTCCAGTATGTGGAGCAACTGTGTGGTCCCTACGTCTTCATCATCTTCACTGTGCTCCTGGTTCTGTTCT TCATCTTCACCTACTTCAAAGTTCCTGAGACTAAAGGCCGGACCTTCGATGAGATCGCTTCCGGCTTCCGGCAGGGGGGAGCCA 0 GCCAAAGTGATAAGACACCCGAGGAGCTGTTCCATCCCCTGGGGGCTGATTCCCAAGTGTGAGTCGCCCCAGATCACCAGCCCG' GCCTGCTCCCAGCAGCCCTAAGGATCTCTCAGGAGCACAGGCAGCTGGATGAGACTTCCAAACCTGACAGATGTCAGCCGAGCC GGGCCTGGGGCTCCTTTCTCCAGCCAGCAATGATGTCCAGAAGAATATTCAGGACTTAACGGCTCCAGGATTTTAACAAAAGCA AGACTGTTGCTCAAATCTATTCAGACAAGCAACAGGTTTTATAATTTTTTTATTACTGATTTTGTTATTTTTATATCAGCCTGA GTCTCCTGTGCCCACATCCCAGGCTTCACCCTGAATGGTTCCATGCCTGAGGGTGGAGACTAAGCCCTGTCGAGACACTTGCCT 5 TCTTCACCCAGCTAATCTGTAGGGCTGGACCTATGTCCTAAGGACACACTAATCGAACTATGAACTACAAAGCTTCTATCCGAG GAGGTGGCTATGGCCACCCGTTCTGCTGGCCTGGATCTCCCCACTCTAGGGGTCAGGCTCCATTAGGATTTGCCCCTTCCCATC TCTTCCTACCCAACCACTCAAATTAATCTTTCTTTACCTGAGACCAGTTGGGAGCACTGGAGTGCAGGGAGGAGAGGGGAAGGG' CCAGTCTGGGCTGCCGGGTTCTAGTCTCCTTTGCACTGAGGGCCACACTATTACCATGAGAAGAGGGCCTGTGGGAGCCTGCAA ACTCACTGCTCAAGAAGACATGGAGACTCCTGCCCTGTTGTGTATAGATGCAAGATATTTATATATATTTTTGGTTGTCAATAT 0 TAAATACAGACACTAAGTTATAGTATATCTGGACAAGCCAACTTGTAAATACACCACCTCACTCCTGTTACTTACCTAAACAGA
■ TATAAATGGCΪGGTTTTTAGAAACATGGTTTTGAAATGCTTGTGGATTGAGGGTAGGAGGTTTGGATGGGAGTGAGACAGAAGT
AAGTGGGGTTGCAACCACTGCAACGGCTTAGACTTCGACTCAGGATCCAGTCCCTTACACGTACCTCTCATCAGTGTCCTCTTG
CTCAAAAATCTGTTTGATCCCTGTTACCCAGAGAATATATACATTCTTTATCTTGACATTCAAGGCATTTCTATCACATATTTG
ATAGTTGGTGTTCAAAAAAACACTAGTTTTGTGCCAGCCGTGATGCTCAGGCTTGAAATCGCATTATTTTGAATGTGAAGGGAA 5 221
MFIMGLGDPIPEELYEMLSDHSIRSFDDLQR LHGDPGEEDGAELD MTRSHSGGELES ARGRRS GSLTIAEPAMIAECKT RTEVFEISRRLIDRTNA FLVWPPCVE¥QRCSGCCMRN¥QCRPTQ¥QLRPVQVRKIEIVRKKPIFKKATVTLEDHLACKCETV AAARPVTRSPGGSQEQRAKTPQTRVTIRTVRVRRPPKGKHR FKHTHDKTA KETLGA
222 0 GTGTGTGTGTGTGTGCGCGCGCATCTGAGAGAGAGAGAGAGAGAGAGAGACTGACTGAGCAGGAATGGTGAGATGTTTATCATG
GGCCTCGGGGACCCCATTCCCGAGGAGCTTTATGAGATGCTGAGTGACCACTCGATCCGCTCCTTTGATGATCTCCAACGCCTG
* ■ CTGCACGGAGACeCCGGAGAGGAAGATGGGGCCGAGTTGGACCTGAACATGACCCGCTCCCAGTCTGGAGGCGAGCTGGAGAGC
TTGGCTCGTGGAAGAAGGAGCCTGGGTTCCCTGACCATTGCTGAGCCGGCCATGATCGCCGAGTGCAAGACGCGCACCGAGGTG
TTCGAGATCTCCCGGCGCCTCATAGACCGCACCAACGCCAACTTCCTGGTGTGGCCGCCCTGTGTGGAGGTGCAGCGCTGCTCC 5 GGCTGCTGCAACAACCGCAACGTGCAGTGCCGCCCCACCCAGGTGCAGCTGCGACCTGTCCAGGTGAGAAAGATCGAGATTGTG .CGGAAGAAGCCAATCTTTAAGAAGGCCACGGTGACGCTGGAAGACCACCTGGCATGCAAGTGTGAGACAGTGGCAGCTGCACGG CCTGTGACCCGAAGCCCGGGGGGTTCCCAGGAGCAGCGAGCCAAAACGCCCCAAACTCGGGTGACCATTCGGACGGTGCGAGTC CGCCGGCCCCCCAAGGGCAAGCACCGGAAATTCAAGCACACGCATGACAAGACGGCACTGAAGGAGACCCTTGGAGCCTAGGGG CATCGGCAGGAGAGTGTGTGGGCAGGGTTATTTAATATGGTATTTGCTGTATTGCCCCCATGGGGTCCTTGGAGTGATAATATT GTTTCCCTCGTCCGTCTGTCTCGATGCCTGATTCGGACGGCCAATGGTGCTTCCCCCACCCCTCCACGTGTCCGTCCACCCTTC CATCAGCGGGTCTCCTCCCAGCGGCCTCCGGTCTTGCCCAGCAGCTCAAAGAAGAAAAAGAAGGACTGAACTCCATCGCCATCT TCTTCCCTTAACTCCAAGAACTTGGGATAAGAGTGTGAGAGAGACTGATGGGGTCGCTCTTTGGGGGAAACGGGTTCCTTCCCC TGCACCTGGCCTGGGCCACACCTGAGCGCTGTGGACTGTCCTGAGGAGCCCTGAGGACCTCTCAGCATAGCCTGCCTGATCCCT GAACCCCTGGCCAGCTCTGAGGGGAGGCACCTCCAGGCAGGCCAGGCTGCCTCGGACTCCATGGCTAAGACCACAGACGGGCAC ACAGACTGGAGAAAACCCCTCCCACGGTGCCCAAACACCAGTCACCTCGTCTCCCTGGTGCCTCTGTGCACAGTGGCTTCTTTT CGTTTTCGTTTTGAAGACGTGGACTCCTCTTGGTGGGTGTGGCCAGCACACCAAGTGGCTGGGTGCCCTCTCAGGTGGGTTAGA GATGGAGTTTGCTGTTGAGGTGGTGTAGATGGTGACCTGGGTATCCCCTGCCTCCTGCCACCCCTTCCTCCCCATACTCCACTC TGATTCACCTCTTCCTCTGGTTCCTTTCATCTCTCTACCTCCACCCTGCATTTTCCTCTTGTCCTGGCCCTTCAGTCTGCTCCA CCAAGGGGCTCTTGAACCCCTTATTAAGGCCCCAGATGACCCCAGTCACTCCTCTCTAGGGCAGAAGACTAGAGGCCAGGGCAG
CAAGGGACCTGCTCATCATATTCCAACCCAGCCACGACTGCCATGTAAGGTTGTGCAGGGTGTGTACTGCACAAGGACATTGTA
TGCAGGGAGCACTGTTCACATCATAGATAAAGCTGATTTGTATATTTATTATGACAATTTCTGGCAGATGTAGGTAAAGAGGAA
AAGGATCCTTTTCCTAATTCACACAAAGACTCCTTGTGGACTGGCTGTGCCCCTGATGCAGCCTGTGGCTGGAGTGGCCAAATA
• GGAGGGAGACTGTGGTAGGGGCAGGGAGGCAACACTGCTGTCCACATGACCTCCATTTCCCAAAGTCCTCTGCTCCAGCAACTG CCCTTCCAGGTGGGTGTGGGACACCTGGGAGAAGGTCTCCAAGGGAGGGTGCAGCCCTCTTGCCCGCACCCCTCCCTGCTTGCA CACTTCCCCATCTTTGATCCTTCTGAGCTCCACCTCTGGTGGCTCCTCCTAGGAAACCAGCTCGTGGGCTGGGAATGGGGGAGA GAAGGGAAAAGATCCCCAAGACCCCCTGGGGTGGGATCTGAGCTCCCACCTCCCTTCCCACCTACTGCACTTTCCCCCTTCCCG CCTTCCAAAACCTGCTTCCTTCAGTTTGTAAAGTCGGTGATTATATTTTTGGGGGCTTTCCTTTTATTTTTTAAATGTAAAATT TATTTATATTCCGTATTTAAAGTTGT '223 TLKDQLIYN LKEEQTPQNKITWGVGAVGMACAISILMKDLADELALVDVIED KGEMMD QHGSLF RTPKIVSGKDYN VT SKLVIITAGARQQEGESRLNLVQRNWIFKFIIPNVVKYSPNCKLLIVSNPVD1LTYVAWKISGFPKNRVIGSGCNLDSA RFRY GERLGVHPLSCHGW GEHGDSSVPV SGMNVAGVS KTLHPDLGTDKDKEQWKEVHKQWESAYEVIKLKGYTS AI GLSVADLAESIMK RRVHPVSTMIKGLYGIKDDVFLSVPCILGQNGISD VKVTLTSEEEARLKKSADTL GIQKELQF 224
TGCTGCAGCCGCTGCCGCCGATTCCGGATCTCATTGCCACGCGCCCCCGACGACCGCCCGACGTGCATTCCCGATTCCTTTTGG TTCCAAGTCCAATATGGCAACTCTAAAGGATCAGCTGATTTATAATCTTCTAAAGGAAGAACAGACCCCCCAGAATAAGATTAC AGTTGTTGGGGTTGGTGCTGTTGGCATGGCCTGTGCCATCAGTATCTTAATGAAGGACTTGGCAGATGAACTTGCTCTTGTTGA TGTCATCGAAGACAAATTGAAGGGAGAGATGATGGATCTCCAACATGGCAGCCTTTTCCTTAGAACACCAAAGATTGTCTCTGG CAAAGACTATAATGTAACTGCAAACTCCAAGCTGGTCATTATCACGGCTGGGGCACGTCAGCAAGAGGGAGAAAGCCGTCTTAA TTTGGTCCAGCGTAACGTGAACATATTTAAATTCATCATTCCTAATGTTGTAAAATACAGCCCGAACTGCAAGTTGCTTATTGT TTCAAATCCAGTGGATATCTTGACCTACGTGGCTTGGAAGATAAGTGGTTTTCCCAAAAACCGTGTTATTGGAAGTGGTTGCAA TCTGGATTCAGCCCGATTCCGTTACCTGATGGGGGAAAGGCTGGGAGTTCACCCATTAAGCTGTCATGGGTGGGTCCTTGGGGA ACATGGAGATTCCAGTGTGCCTGTATGGAGTGGAATGAATGTTGCTGGTGTCTCTCTGAAGACTCTGCACCCAGATTTAGGGAC TGATAAAGATAAGGAACAGTGGAAAGAGGTTCACAAGCAGGTGGTTGAGAGTGCTTATGAGGTGATCAAACTCAAAGGCTACAC ATCCTGGGCTATTGGACTCTCTGTAGCAGATTTGGCAGAGAGTATAATGAAGAATCTTAGGCGGGTGCACCCAGTTTCCACCAT GATTAAGGGTCTTTACGGAATAAAGGATGATGTCTTCCTTAGTGTTCCTTGCATTTTGGGACAGAATGGAATCTCAGACCTTGT GAAGGTGACTCTGACTTCTGAGGAAGAGGCCCGTTTGAAGAAGAGTGCAGATACACTTTGGGGGATCCAAAAGGAGCTGCAATT TTAAAGTCTTCTGATGTCATATCATTTCACTGTCTAGGCTACAACAGGATTCTAGGTGGAGGTTGTGCATGTTGTCCTTTTTAT CTGATCTGTGATTAAAGCAGTAATATTTTAAGATGGACTGGGAAAAACATCAACTCCTGAAGTTAGAAATAAGAATGGTTTGTA AAATCCACAGCTATATCCTGATGCTGGATGGTATTAATCTTGTGTAGTCTTCAACTGGTTAGTGTGAAATAGTTCTGCCACCTC TGACGCACCACTGCCAATGCTGTACGTACTGCATTTGCCCCTTGAGCCAGGTGGATGTTTACCGTGTGTTATATAACTTCCTGG CTCCTTCACTGAACATGCCTAGTCCAACATTTTTTCCCAGTGAGTCACATCCTGGGATCCAGTGTATAAATCCAATATCATGTC TTGTGCATAATTCTTCCAAAGGATCTTATTTTGTGAACTATATCAGTAGTGTACATTACCATATAATGTAAAAAGATCTACATA CAAACAATGCAACQAACTATCCAAGTGTTATACCAACTAAAACCCCCAATAAACCTTGAACAGTG
225
METPAWPR¥PRPETAVART LLGWVFAQVAGASGTTNT¥AAY TWKSTNFKTILEWEPKPV QVYTVQISTKSGDWKSKCFYT TDTECDLTDEIVKDVKQTYLARVFSYPAGNVESTGSAGEPLYENSPEFTPYLETNLGQPTIQSFEQVGTKVNVTVEDERTLVRR MTFLSLRDVFGKDLIYTLYY KSSSSGK TAKTNTNEFLIDVDKGENYCFSVQAVIPSRTVNRKSTDSPVECMGQEKGEFREI FYIIGAWFWIILVI1LAISLHKCRKAGVGQSWKENSPLNVS
226
AAGACTGCGAGCTCCCCGCACCCCCTCGCACTCCCTCTGGCCGGCCCAGGGCGCCTTCAGCCCAACCTCCCCAGCCCCACGGGC 5 GCCACGGAACCCGCTCGATCTCGCCGCCAACTGGTAGACATGGAGACCCCTGCCTGGCCCCGGGTCCCGCGCCCCGAGACCGCC GTCGCTCGGACGCTCCTGCTCGGCTGGGTCTTCGCCCAGGTGGCCGGCGCTTCAGGCACTACAAATACTGTGGCAGCATATAAT TTAACTTGGAAATCAACTAATTTCAAGACAATTTTGGAGTGGGAACCCAAACCCGTCAATCAAGTCTACACTGTTCAAATAAGC ACTAAGTCAGGAGATTGGAAAAGCAAATGCTTTTACACAACAGACACAGAGTGTGACCTCACCGACGAGATTGTGAAGGATGTG AAGCAGACGTACTTGGCACGGGTCTTCTCCTACCCGGCAGGGAATGTGGAGAGCACCGGTTCTGCTGGGGAGCCTCTGTATGAG 0 AACTCCCCAGAGTTCACACCTTACCTGGAGACAAACCTCGGACAGCCAACAATTCAGAGTTTTGAACAGGTGGGAACAAAAGTG AATGTGACCGTAGAAGATGAACGGACTTTAGTCAGAAGGAACAACACTTTCCTAAGCCTCCGGGATGTTTTTGGCAAGGACTTA ATTTATACACTTTATTATTGGAAATCTTCAAGTTCAGGAAAGAAAACAGCCAAAACAAACACTAATGAGTTTTTGATTGATGTG GATAAAGGAGAAAACTACTGTTTCAGTGTTCAAGCAGTGATTCCCTCCCGAACAGTTAACCGGAAGAGTACAGACAGGCCGGTA GAGTGTATGGGCCAGGAGAAAGGGGAATTCAGAGAAATATTCTACATCATTGGAGCTGTGGTATTTGTGGTCATCATCCTTGTC 5 ATCATCCTGGCTATATCTCTACACAAGTGTAGAAAGGCAGGAGTGGGGCAGAGCTGGAAGGAGAACTCCCCACTGAATGTTTCA TAAAGGAAGCACTGTTGGAGCTACTGCAAATGCTATATTGCACTGTGACCGAGAACTTTTAAGAGGATAGAATACATGGAAACG CAAATGAGTATTTCGGAGCATGAAGACCCTGGAGTTCAAAAAACTCTTGATATGACCTGTTATTACCATTAGCATTCTGGTTTT GACATCAGCATTAGTCACTTTGAAATGTAACGAATGGTACTACAACCAATTCCAAGTTTTAATTTTTAACACCATGGCACCTTT TGCACATAACATGCTTTAGATTATATATTCCGCACTTAAGGATTAACCAGGTCGTCCAAGCAAAAACAAATGGGAAAATGTCTT 0 AAAAAATCCTGGGTGGACTTTTGAAAAGCTTTTTTTTTTTTTTTTTTTTGAGACGGAGTCTTGCTCTGTTGCCCAGGCTGGAGT GCAGTAGCACGATCTCGGCTCACTTGCACCCTCCGTCTCTCGGGTTCAAGCAATTGTCTGCCTCAGCCTCCCGAGTAGCTGGGA TTACAGGTGCGCACTACCACGCCAAGCTAATTTTTGTATTTTTTAGTAGAGATGGGGTTTCACCATCTTGGCCAGGCTGGTCTT GAATTCCTGACCTCAGTGATCCACCCACCTTGGCCTCCCAAAGATGCTAGTATTATGGGCGTGAACCACCATGCCCAGCCGAAA AGCTTTTGAGGGGCTGACTTCAATCCATGTAGGAAAGTAAAATGGAAGGAAATTGGGTGCATTTCTAGGACTTTTCTAACATAT 5 GTCTATAATATAGTGTTTAGGTTCTTTTTTTTTTCAGGAATACATTTGGAAATTCAAAACAATTGGGCAAACTTTGTATTAATG TGTTAAGTGCAGGAGACATTGGTATTCTGGGCAGCTTCCTAATATGCTTTACAATCTGCACTTTAACTGACTTAAGTGGCATTA AACATTTGAGAGCTAACTATATTTTTATAAGACTACTATACAAACTACAGAGTTTATGATTTAAGGTACTTAAAGCTTCTATGG TTGACATTGTATATATAATTTTTTAAAAAGGTTTTTCTATATGGGGATTTTCTATTTATGTAGGTAATATTGTTCTATTTGTAT ATATTGAGATAATTTATTTAATATACTTTAAATAAAGGTGACTGGGAATTGTT 0 227 ■
■ • MFLLS VHWSLALLLYLHHAK SQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIET VDIFQEYPDEIEYIFKPSCVPLMRCG GCC-.DEGLECVPTEESNITMQIMRIKPHQGQHIGEMSF QH-.KCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNT DSRCKARQLE NERTCRCDKPRR
228 5 TCGGGCCTCCGAAACCATGAACTTTCTGCTGTCTTGGGTGCATTGGAGCCTTGCCTTGCTGCTCTACCTCCACCATGCCAAGTG GTCCCAGGCTGCACCCATGGCAGAAGGAGGAGGGCAGAATCATCACGAAGTGGTGAAGTTCATGGATGTCTATCAGCGCAGCTA CTGCCATCCAATCGAGACCCTGGTGGACATCTTCCAGGAGTACCCTGATGAGATCGAGTACATCTTCAAGCCATCCTGTGTGCC CCTGATGCGATGCGGGGGCTGCTGCAATGACGAGGGCCTGGAGTGTGTGCCCACTGAGGAGTCCAACATCACCATGCAGATTAT GCGGATCAAACCTCACCAAGGCCAGCACATAGGAGAGATGAGCTTCCTACAGCACAACAAATGTGAATGCAGACCAAAGAAAGA 0 .TAGAGCAAGACAAGAAAATCCCTGTGGGCCTTGCTCAGAGCGGAGAAAGCATTTGTTTGTACAAGATCCGCAGACGTGTAAATG TTCCTGCAAAAACACAGACTCGCGTTGCAAGGCGAGGCAGCTTGAGTTAAACGAACGTACTTGCAGATGTGACAAGCCGAGGCG GTGAGCCGGGCAGGAGGAAGGAGCCTCCCTCAGCGTTTCGGGAACCAGATCTCTCACCAGG
229
MSREMQDVDLAEVKP VEKGETITGLLQEFDVQEQDIETLHGSVHVTLCGTPKGNRPVILTYHDIGMHKTCYNPLFNYEDMQE 5 ITQHFAVCHVDAPGQQDG SFPAGY YPSMDQ AEM PGV QQFGLKSIIGMGTGAGAYT TRFA røPEMVEG V INV PC AEGMDWMSKISGWTQALPDMWSHLFGKEEMQS-WEWHTYRQHIWDMNPGNLHLFINAYNSRRDLEIERPMPGTHTVTLQ CPAL WGDSSPAVDAVVECNSKLDPTKTTLLKMADCGGLPQISQPAKLAEAFKYFVQGMGYMPSASMTRLMRSRTASGSSVTS LDGTRSRSHTSEGTRSRSHTSEGTRSRSHTSEGAH DITPNSGAAGNSAGPKSME¥SC 230
TGAAGCTCGTCAGTTCACCATCCGCCCTCGGCTTCCGCGGGGCGCTGGGCCGCCAGCCTCGGCACCGTCCTTTCCTTTCTCCCT CGCGTTAGGCAGGTGACAGCAGGGACATGTCTCGGGAGATGCAGGATGTAGACCTCGCTGAGGTGAAGCCTTTGGTGGAGAAAG GGGAGACCATCACCGGCCTCCTGCAAGAGTTTGATGTCCAGGAGCAGGACATCGAGACTTTACATGGCTCTGTTCACGTCACGC TGTGTGGGACTCCCAAGGGAAACCGGCCTGTCATCCTCACCTACCATGACATCGGCATGAACCACAAAACCTGCTACAACCCCC TCTTCAACTACGAGGACATGCAGGAGATCACCCAGCACTTTGCCGTCTGCCACGTGGACGCCCCTGGCCAGCAGGACGGCGCAG CCTCCTTCCCCGCAGGGTACATGTACCCCTCCATGGATCAGCTGGCTGAAATGCTTCCTGGAGTCCTTCAACAGTTTGGGCTGA AAAGCATTATTGGCATGGGAACAGGAGCAGGCGCCTACACCCTAACTCGATTTGCTCTAAACAACCCTGAGATGGTGGAGGGCC TTGTCCTTATCAACGTGAACCCTTGTGCGGAAGGCTGGATGGACTGGGCCGCCTCCAAGATCTCAGGATGGACCCAAGCTCTGC CGGACATGGTGGTGTCCCACCTTTTTGGGAAGGAAGAAATGCAGAGTAACGTGGAAGTGGTCCACACCTACCGCCAGCACATTG TGAATGACATGAACCCCGGCAACCTGCACCTGTTCATCAATGCCTACAACAGCCGGCGCGACCTGGAGATTGAGCGACCAATGC CGGGAACCCACACAGTCACCCTGCAGTGCCCTGCTCTGTTGGTGGTTGGGGACAGCTCGCCTGCAGTGGATGCCGTGGTGGAGT GCAACTCAAAATTGGACCCAACAAAGACCACTCTCCTCAAGATGGCGGACTGTGGCGGCCTCCCGCAGATCTCCCAGCCGGCCA AGCTCGCTGAGGCCTTCAAGTACTTCGTGCAGGGCATGGGATACATGCCCTCGGCTAGCATGACCCGCCTGATGCGGTCCCGCA CAGCCTCTGGTTCCAGCGTCACTTCTCTGGATGGCACCCGCAGCCGCTCCCACACCAGCGAGGGCACCCGAAGCCGCTCCCACA CCAGCGAGGGCACCCGCAGCCGCTCGCACACCAGCGAGGGGGCCCACCTGGACATCACCCCCAACTCGGGTGCTGCTGGGAACA GCGCCGGGCCCAAGTCCATGGAGGTCTCCTGCTAGGCGGCCTGCCCAGCTGCCGCCCCCGGACTCTGATCTCTGTAGTGGCCCC CTCCTCCCCGGCCCCTTTTCGCCCCCTGCCTGCCATACTGCGCCTAACTCGGTATTAATCCAAAGCTTATTTTGTAAGAGTGAG CTCTGGTGGAGACAAATGAGGTCTATTACGTGGGTGCCCTCTCCAAAGGCGGGGTGGCGGTGGACCAAAGGAAGGAAGCAAGCA TCTCCGCATCGCATCCTCTTCCATTAACCAGTGGCCGGTTGCCACTCTCCTCCCCTCCCTCAGAGACACCAAACTGCCAAAAAC AAGACGCGTAGCAGCACACACTTCACAAAGCCAAGCCTAGGCCGCCCTGAGCATCCTGGTTCAAACGGGTGCCTGGTCAGAAGG CCAGCCGCCCACTTCCCGTTTCCTCTTTAACTGAGGAGAAGCTGATCCAGCTTTCCGGAAACAAAATCCTTTTCTTCATTTGGG GAGGGGGGTAATAGTGACATGCAGGCACCTCTTTTAAACAGGCAAAACAGGAAGGGGGAAAAGGTGGGATTCATGTCGAGGCTA GAGGCATTTGGAACAACAAATCTACGTAGTTAACTTGAAGAAACCGATTTTTAAAGTTGGTGCATCTAGAAAGCTTTGAATGCA GAAGCAAACAAGCTTGATTTTTCTAGCATCCTCTTAATGTGCAGCAAAAGCAGGCAACAAAATCTCCTGGCTTTACAGACAAAA ATATTTCAGCAAACGTTGGGCATCATGGTTTTTGAAGGCTTTAGTTCTGCTTTCTGCCTCTCCTCCACAGCCCCAACCTCCCAC CCCTGATACATGAGCCAGTGATTATTCTTGTTCAGGGAGAAGATCATTTAGATTTGTTTTGCATTCCTTAGAATGGAGGGCAAC ATTCCACAGCTGCCCTGGCTGTGATGAGTGTCCTTGCAGGGGCCGGAGTAGGAGCACTGGGGTGGGGGCGGAATTGGGGTTACT CGATGTAAGGGATTCCTTGTTGTTGTGTTGAGATCCAGTGCAGTTGTGATTTCTGTGGATCCCAGCTTGGTCCAGGAATTTTGA GAGATTGGCTTAAATCCAGTTTTCAATCTTCGACAGCTGGGCTGGAACGTGAACTCAGTAGCTGAACCTGTCTGACCCGGTCAC GTTCTTGGATCCTCAGAACTCTTTGCTCTTGTCGGGGTGGGGGTGGGAACTCACGTGGGGAGCGGTGGCTGAGAAAATGTAAGG ATTCTGGAATACATATTCCATGGACTTTCCTTCCCTCTCCTGCTTCCTCTTTTCCTGCTCCCTAACCTTTCGCCGAATGGGGCA GACAAACACTGACGTTTCTGGGTGGCCAGTGCGGCTGCCAGGTTCCTGTACTACTGCCTTGTACTTTTCATTTTGGCTCACCGT GGATTTTCTCATAGGAAGTTTGGTCAGAGTGAATTGAATATTGTAAGTCAGCCACTGGGACCCGAGGATTTCTGGGACCCCGCA GTTGGGAGGAGGAAGTAGTCCAGCCTTCCAGGTGGGCGTGAGAGGCAATGACTCGTTACCTGCCGCCCATCACCTTGGAGGCCT TCCCTGGCCTTGAGTAGAAAAGTCGGGGATCGGGGCAAGAGAGGCTGAGTACGGATGGGAAACTATTGTGCACAAGTCTTTCCA GAGGAGTTTCTTAATGAGATATTTGTATTTATTTCCAGACCAATAAATTTGTAACTTTGCAAAAAAAAAAAAAAAAAAAA
231
MI YILIIGI LPQSLAHPGFFTSIGQMTDLIHTEKDVTSLKDYIKAEEDKLEQI KWAEKLDRLTSTATKDPEGFVGHPVA FKLMKRNTEWSELENLVLKDMSDGFISNLTIQRPVLSNDEDQVGAAKALLRLQDTYNLDTDTISKGNLPGVKHKSF TAEDCF ELGKVAYTEADYYHTE MEQALRQ DEGEISTIDKVSVLDYLSYAVYQQGD DKALL TKKLLELDPEHQRANGNLKYFEYIM AKEKDVNKSASDDQSDQKTTPKKKGVAVDYLPERQKYEMLCRGEGIKMTPRRQKKLFCRYHDGNR P FILAPAKQEDEWDKPR IIRFHDIISDAEIEIVKDLAKPRLSRATVHDPETGKLTTAQYRVSKSA LSGYENPWSRI MRIQDLTG DVSTAEELQVA Y GVGGQYEPHFDFARKDEPDAFKELGTGNRIATWFYMSDVSAGGATVFPEVGASVWPKKGTAVFWYNLFASGEGDYSTRHAACP VL¥GNKWVSNK HERGQEFRRPCTLSELE
232
GAGCGGGCTGAGGGTAGGAAGTAGCCGCTCCGAGTGGAGGCGACTGGGGGCTGAAGAGCGCGCCGCCCTCTCGTCCCACTTTCC
AGGTGTGTGATCCTGTAAAATTAAATCTTCCAAGATGATCTGGTATATATTAATTATAGGAATTCTGCTTCCCCAGTCTTTGGC
TCATCCAGGCTTTTTTACTTCAATTGGTCAGATGACTGATTTGATCCATACTGAGAAAGATCTGGTGACTTCTCTGAAAGATTA TATTAAGGCAGAAGAGGACAAGTTAGAACAAATAAAAAAATGGGCAGAGAAGTTAGATCGGCTAACTAGTACAGCGACAAAAGA TCCAGAAGGATTTGTTGGGCATCCAGTAAATGCATTCAAATTAATGAAACGTCTGAATACTGAGTGGAGTGAGTTGGAGAATCT GGTCCTTAAGGATATGTCAGATGGCTTTATCTCTAACCTAACCATTCAGAGACCAGTACTTTCTAATGATGAAGATCAGGTTGG GGCAGCCAAAGCTCTGTTACGTCTCCAGGATACCTACAATTTGGATACAGATACCATCTCAAAGGGTAATCTTCCAGGAGTGAA ACACAAATCTTTTCTAACGGCTGAGGACTGCTTTGAGTTGGGCAAAGTGGCCTATACAGAAGCAGATTATTACCATACGGAACT 5 GTGGATGGAACAAGCCCTAAGGCAACTGGATGAAGGCGAGATTTCTACCATAGATAAAGTCTCTGTTCTAGATTATTTGAGCTA TGCGGTATATCAGCAGGGAGACCTGGATAAGGCACTTTTGCTCACAAAGAAGCTTCTTGAACTAGATCCTGAACATCAGAGAGC TAATGGTAACTTAAAATATTTTGAGTATATAATGGCTAAAGAAAAAGATGTCAATAAGTCTGCTTCAGATGACCAATCTGATCA GAAAACTACACCAAAGAAAAAAGGGGTTGCTGTGGATTACCTGCCAGAGAGACAGAAGTACGAAATGCTGTGGCGTGGGGAGGG TATCAAAATGACCCCTCGGAGACAGAAAAAACTCTTTTGCCGCTACCATGATGGAAACCGTAATCCTAAATTTATTCTGGCTCC
10 AGCTAAACAGGAGGATGAATGGGACAAGCCTCGTATTATTCGCTTCCATGATATTATTTCTGATGCAGAAATTGAAATCGTCAA AGACCTAGCAAAACCAAGGCTGAGCCGAGCTACAGTACATGACCCTGAGACTGGAAAATTGACCACAGCACAGTACAGAGTATC TAAGAGTGCCTGGCTCTCTGGCTATGAAAATCCTGTGGTGTCTCGAATTAATATGAGAATACAAGATCTAACAGGACTAGATGT TTCCACAGCAGAGGAATTACAGGTAGCAAATTATGGAGTTGGAGGACAGTATGAACCCCATTTTGACTTTGCACGGAAAGATGA GCCAGATGCTTTCAAAGAGCTGGGGACAGGAAATAGAATTGCTACATGGCTGTTTTATATGAGTGATGTGTCTGCAGGAGGΆGC
15 CACTGTTTTTCCTGAAGTTGGAGCTAGTGTTTGGCCCAAAAAAGGAACTGCTGTTTTCTGGTATAATCTGTTTGCCAGTGGAGA AGGAGATTATAGTACACGGCATGCAGCCTGTCCAGTGCTAGTTGGCAACAAATGGGTATCCAATAAATGGCTCCATGAACGTGG ACAAGAATTTCGAAGACCTTGTACGTTGTCAGAATTGGAATGACAAACAGGCTTCCCTTTTTCTCCTATTGTTGTACTCTTATG TGTCTGATATACACATTTCCATAGTCTTAACTTTCAGGAGTTTACAATTGACTAACACTCCATGATTGATTCAGTCATGAACCT CATCCCATGTTTCATCTGTGGACAAT'TGCTTACTTTGTGGGTTCTTTTAAAAGTAACACGAAATCATCATATTGCATAAAACCT
20 .TAAAGTTCTGTTGGTATCACAGAAGACAAGGCAGAGTTTAAAGTGAGGAATTTTATATTTAAAGAACTTTTTGGTTGGATAAAA ACATAATTTGAGCATCCAGTTTTAGTATTTCACTACATCTCAGTTGGTGGGTGTTAAGCTAGAATGGGCTGTGTGATAGGAAAC AAATGCCTTACAGATGTGCCTAGGTGTTCTGTTTACCTAGTGTCTTACTCTGTTTTCTGGATCTGAAGACTAGTAATAAACTAG GACACTAACTGGGTTCCATGTGATTGCCCTTTCATATGATCTTCTAAGTTGATTTTTTTCCTCCCAAGTCTTT'TTTAAAGAAAG TATACTGTATTTTACCAACCCCCTCTCTTTTCTTTTAGCTCCTCTGTGGTGAATTAAACGTACTTGAGTTAAAATATTTCGATT
25 TTTTTTTTTTTTTTAATGGAAAGTCCTGCATAACAACACTGGGCCTTCTTAACTAAAATGCTCACCACTTAGCCTGTTTTTTTA TCCCTTTTTTAAAATGACAGATGATTTTGTTCAGGAATTTTGCTGTTTTTCTTAGTGCTAATACCTTGCCTCTTATTCCTGCTA CAGCAGGGTGGTAATATTGGCATTCTGATTAAATACTGTGCCTTAGGAGACTGGAAGTTTAAAAATGTACAAGTCCTTTCAGTG ATGAGGGAATTGATTTTTTTTAAAAGTCTTTTTCTTAGAAAGCCAAAATGTTTGTTTTTTTAAGATTCTGAAATGTGTTGTGAC AACAATGACCTATTTATGATCTTAAATCTTTTTT
30 233
MSQNGAPGMQEESLQGSWVELHFS NGNGGSVPAS¥SIY GDMEKILLDAQHESGRSSSKSSHCDSPPRSQTPQDTNRASETDT HSIGEKNSSQSEEDDIERRKEVESILKKNSDWIWD SSRPENIPPKEFLFKHPKRTATLSMRTSVMKKGGIFSAEFLKVFLPS LLLSHLLAIG GIYIGRRLTTSTSTF
234
35 CCTCCGCTCAGTCCGGGAGCGCACGTGGGCCGCGGCGCTCCGACCTCCGCTTTCCCACCGCCCGCAGCTGAAGCACATCCCGCA GCCCGGCGCGGACTCCGATCGCCGCAGTTGCCCTCTGGCGCCATGTCGCAGAACGGAGCGCCCGGGATGCAGGAGGAGAGCCTG CAGGGCTCCTGGGTAGAACTGCACTTCAGCAATAATGGGAACGGGGGCAGCGTTCCAGCCTCGGTTTCTATTTATAATGGAGAC ATGGAAAAAATACTGCTGGACGCACAGCATGAGTCTGGACGGAGTAGCTCCAAGAGCTCTCACTGTGACAGCCCACCTCGCTCG CAGACACCACAAGATACCAACAGGGCTTCTGAAACAGATACCCATAGCATTGGAGAGAAAAACAGCTCACAGTCTGAGGAAGAT •40 GATATTGAAAGAAGGAAAGAAGTTGAAAGCATCTTGAAGAAAAACTCAGATTGGATATGGGATTGGTCAAGTCGGCCGGAAAAT ATTCCCCCCAAGGAGTTCCTCTTTAAACACCCGAAGCGCACGGCCACCCTCAGCATGAGGAACACGAGCGTCATGAAGAAAGGG' GGCATATTCTCTGCAGAATTTCTGAAAGTTTTCCTTCCATCTCTGCTGCTCTCTCATTTGCTGGCCATCGGATTGGGGATCTAT ATTGGAAGGCGTCTGACAACCTCCACCAGCACCTTTTGATGAAGAACTGGAGTCTGACTTGGTTCGTTAGTGGATTACTTCTGA GCTTGCAACATAGCTCACTGAAGAGCTGTTAGATCCTGGGGTGGCCACGTCACTTGTGTTTATTTGTTCTGTAAATGCTGCGTT
45 CCTAATTTAGTAAAATAAAAGAATAGACACTAAAATCATGTTGATCTATAATTACACCTATGGGATCAATAAGCATGTCAGACT GATTAATGTCTACTGTGAAAATTTGGTAGTAAATTTTCATTTGATATTAGATATAAATATCTGAATATAAATAATTTTAATATA CTAGTCATGATGTGTGTTGTATTTTAAAAATTATCTGCAACCTTAATTCAGCTGAAGTACTTTATATTTCAAAAGAATGAATAA CATTGATAATAAAATCGCTACTTTAAGGGGTTTGTCCAAAATAAATATTGTGGCCTTATATATCACACTATTGTAGAAAGTATT ATTTAATTTAAATGGATGCAGGTTGTCTACTAAAGAAAGATTATATATAACTATGCTAATTGTTCATAATCAACAGAAACCAAG
50 ATAGAGCTACAAACTCAGCTGTACAGTTCGTACACTAAACTCTTCTTGCTTTTGCATTATAAGGAATTAAGTCTCCGATTATTA GGTGATCACCCTGGATGATCAGTTTTCTGCTGAAGGCACCTACTCAGTATCTTTTCCTCTTTATCACTCTGCATTGGTGAATTT AATCCTCTCCTTTGTGTTCAACTTTTGTGTGCTTTTAAAATCAGCTTTATTCTAAGCAAATCTGTGTCTACTTTAAAAAACTGG AAATGGAAAAAAAAATAAATCTT
235
MQMSPALTC ¥ GLALVFGEGSAVHHPPSYVAHLASDFG¥RVFQQVAQASKDRWVFSPYGVASVLAMLQLTTGGETQQQIQAA
MGFKIDDKG PALRH YKELMGP NKDEISTTDAIFVQRDLKLVQGFMPHFFRLFRSTVKQ¥DFSEVERARFIINDWVKTHTK
GMISNL GKGAVDQ TRLVLV ALYFNGQ KTPFPDSSTHRR FHKSDGST¥SVPMMAQTNKFNYTEFTTPDGHYYDILELPYH GDTLSMFIAAPYEKEVPLSALTNI SAQLISH KGNMTRLPRL V PKFSLETEVDLRKPLENLGMTDMFRQFQADFTSLSDQE P HVAQALQKVKIEVNESGTVASSSTAVIVSARMAPEEIIMDRPFLFVVRHNPTGTVLF GQVMEP
236 . . .
GAATTCCTGCAGCTCAGCAGCCGCCGCCAGAGCAGGACGAACCGCCAATCGCAAGGCACCTCTGAGAACTTCAGGATGCAGATG TCTCCAGCCCTCACCTGCCTAGTCCTGGGCCTGGCCCTTGTCTTTGGTGAAGGGTCTGCTGTGCACCATCCCCCATCCTACGTG GCCCACCTGGCCTCAGACTTCGGGGTGAGGGTGTTTCAGCAGGTGGCGCAGGCCTCCAAGGACCGCAACGTGGTTTTCTCACCC TATGGGGTGGCCTCGGTGTTGGCCATGCTCCAGCTGACAACAGGAGGAGAAACCCAGCAGCAGATTCAAGCAGCTATGGGATTC AAGATTGATGACAAGGGCATGGCCCCCGCCCTCCGGCATCTGTACAAGGAGCTCATGGGGCCATGGAACAAGGATGAGATCAGC ACCACAGACGCGATCTTCGTCCAGCGGGATCTGAAGCTGGTCCAGGGCTTCATGCCCCACTTCTTCAGGCTGTTCCGGAGCACG GTCAAGCAAGTGGACTTTTCAGAGGTGGAGAGAGCCAGATTCATCATCAATGACTGGGTGAAGACACACACAAAAGGTATGATC AGCAACTTGCTTGGGAAAGGAGCCGTGGACCAGCTGACACGGCTGGTGCTGGTGAATGCCCTCTACTTCAACGGCCAGTGGAAG ACTCCCTTCCCCGACTCCAGCACCCACCGCCGCCTCTTCCACAAATCAGACGGCAGCACTGTCTCTGTGCCCATGATGGCTCAG ACCAACAAGTTCAACTATACTGAGTTCACCACGCCCGATGGCCATTACTACGACATCCTGGAACTGCCCTACCACGGGGACACC CTCAGCATGTTCATTGCTGCCCCTTATGAAAAAGAGGTGCCTCTCTCTGCCCTCACCAACATTCTGAGTGCCCAGCTCATCAGC CACTGGAAAGGCAACATGACCAGGCTGCCCCGCCTCCTGGTTCTGCCCAAGTTCTCCCTGGAGACTGAAGTCGACCTCAGGAAG CCCCTAGAGAACCTGGGAATGACCGACATGTTCAGACAGTTTCAGGCTGACTTCACGAGTCTTTCAGACCAAGAGCCTCTCCAC GTCGCGCAGGCGCTGCAGAAAGTGAAGATCGAGGTGAACGAGAGTGGCACGGTGGCCTCCTCATCCACAGCTGTCATAGTCTCA GCCCGCATGGCCCCCGAGGAGATCATCATGGACAGACCCTTCCTCTTTGTGGTCCGGCACAACCCCACAGGAACAGTCCTTTTC ATGGGCCAAGTGATGGAACCCTGACCCTGGGGAAAGACGCCTTCATCTGGGACAAAACTGGAGATGCATCGGGAAAGAAGAAAC TCCGAAGAAAAGAATTTTAGTGTTAATGACTCTTTCTGAAGGAAGAGAAGACATTTGCCTTTTGTTAAAAGATGGTAAACCAGA TCTGTCTCCAAGACCTTGGCCTCTCCTTGGAGGACCTTTAGGTCAAACTCCCTAGTCTCCACCTGAGACCCTGGGAGAGAAGTT TGAAGCACAACTCCCTTAAGGTCTCCAAACCAGACGGTGACGCCTGCGGGACCATCTGGGGCACCTGCTTCCACCCGTCTCTCT GCCCACTCGGGTCTGCAGACCTGGTT.CCCACTGAGGCCCTTTGCAGGATGGAACTACGGGGCTTACAGGAGCTTTTGTGTGCCT* GGTAGAAACTATTTCTGTTCCAGTCACATTGCCATCACTCTTGTACTGCCTGCCACCGCGGAGGAGGCTGGTGACAGGCCAAAG GCCAGTGGAAGAAACACCCTTTCATCTCAGAGTCCACTGTGGCACTGGCCACCCCTCCCCAGTACAGGGGTGCTGCAGGTGGCA GAGTGAATGTCCCCCATCATGTGGCCCAACTCTCCTGGCCTGGCCATCTCCCTCCCCAGAAACAGTGTGCATGGGTTATTTTGG AGTGTAGGTGACTTGTTTACTCATTGAAGCAGATTTCTGCTTCCTTTTATTTTTATAGGAATAGAGGAAGAAATGTCAGATGCG TGCCCAGCTCTTCACCCCCCAATCTCTTGGTGGGGAGGGGTGTACCTAAATATTTATCATATCCTTGCCCTTGAGTGCTTGTTA GAGAGAAAGAGAACTACTAAGGAAAATAATATTATTTAAACTCGCTCCTAGTGTTTCTTTGTGGTCTGTGTCACCGTATCTCAG GAAGTCCAGCCACTTGACTGGCACACACCCCTCCGGACATCCAGCGTGACGGAGCCCACACTGCCACCTTGTGGCCGCCTGAGA CCCTCGCGCCCCCCGCGCCCCCCGCGCCCCTCTTTTTCCCCTTGATGGAAATTGACCATACAATTTCATCCTCCTTCAGGGGAT CAAAAGGACGGAGTGGGGGGACAGAGACTCAGATGAGGACAGAGTGGTTTCCAATGTGTTCAATAGATTTAGGAGCAGAAATGC AAGGGGCTGCATGACCTACCAGGACAGAACTTTCCCCAATTACAGGGTGACTCACAGCCGCATTGGTGACTCACTTCAATGTGT CATTTCCGGCTGCTGTGTGTGAGCAGTGGACACGTGAGGGGGGGGTGGGTGAGAGAGACAGGCAGCTCGGATTCAACTACCTTA GATAATATTTCTGAAAACCTACCAGCCAGAGGGTAGGGCACAAAGATGGATGTAATGCACTTTGGGAGGCCAAGGCGGGAGGAT TGCTTGAGCCCAGGAGTTCAAGACCAGCCTGGGCAACATACCAAGACCCCCGTCTCTTTAAAAATATATATATTTTAAATATAC TTAAATATATATTTCTAATATCTTTAAATATATATATATATTTTAAAGACCAATTTATGGGAGAATTGCACACAGATGTGAAAT GAATGTAATCTAATAGAAGC
237 LARALLLCAVALSHTANPCCSHPCQNRGVCMSVGFDQYKCDCTRTGFYGENCSTPEFLTRIK FLKPTPNTVHYILTHFKGF WVV IPFLP-NAIMSYVLTSRSHLIDSPPTYNADYGYKS EAFSNLSYYTRALPPVPDDCPTPLGVKGKKQ PDSNEIVEKLL LRRKFIPDPQGSNMMFAFFAQHFTHQFFKTDHKRGPAFTNGLGHGVDNHIYGETLARQRKLRLFKDGKMKYQIIDGEMYPPTV KDTQAEMIYPPQVPEHLRFAVGQEVFGLVPGLMMYATIWLREHNRVCDVLKQEHPEWGDEQLFQTSRLI IGETIKIVIEDYVQ H SGYHFKLKFDPELLFNKQFQYQNRIAAEFNT YH HP LPDTFQIHDQKYNYQQFIYNSILLEHGITQFVESFTRQIAGRV AGGRNVPPAVQKVSQASIDQSRQMKYQSFNEYRKRFMLKPYESFEE TGEKEMSAELEALYGDIDAVELYPALLVEKPRPDAIF GETMVEVGAPFSLKGLMGNVICSPAYWKPSTFGGEVGFQIINTASIQSLIC VKGCPFTSFSVPDPELIKTVTINASSSRSGL DDINPTVLI-KERSTEL
238
CAATTGTCATACGACTTGCAGTGAGCGTCAGGAGCACGTCCAGGAACTCCTCAGCAGCGCCTCCTTCAGCTCCACAGCCAGACG CCCTCAGACAGCAAAGCCTACCCCCGCGCCGCGCCCTGCCCGCCGCTCGGATGCTCGCCCGCGCCCTGCTGCTGTGCGCGGTCC TGGCGCTCAGCCATACAGCAAATCCTTGCTGTTCCCACCCATGTCAAAACCGAGGTGTATGTATGAGTGTGGGATTTGACCAGT ATAAGTGCGATTGTACCCGGACAGGATTCTATGGAGAAAACTGCTCAACACCGGAATTTTTGACAAGAATAAAATTATTTCTGA AACCCACTCCAAACACAGTGCACTACATACTTACCCACTTCAAGGGATTTTGGAACGTTGTGAATAACATTCCCTTCCTTCGAA ATGCAATTATGAGTTATGTCTTGACATCCAGATCACATTTGATTGACAGTCCACCAACTTACAATGCTGACTATGGCTACAAAA GCTGGGAAGCCTTCTCTAACCTCTCCTATTATACTAGAGCCCTTCCTCCTGTGCCTGATGATTGCCCGACTCCCTTGGGTGTCA AAGGTAAAAAGCAGCTTCCTGATTCAAATGAGATTGTGGAAAAATTGCTTCTAAGAAGAAAGTTCATCCCTGATCCCCAGGGCT CAAACATGATGTTTGCATTCTTTGCCCAGCACTTCACGCATCAGTTTTTCAAGACAGATCATAAGCGAGGGCCAGCTTTCACCA ACGGGCTGGGCCATGGGGTGGACTTAAATCATATTTACGGTGAAACTCTGGCTAGACAGCGTAAACTGCGCCTTTTCAAGGATG GAAAAATGAAATATCAGATAATTGATGGAGAGATGTATCCTCCCACAGTCAAAGATACTCAGGCAGAGATGATCTACCCTCCTC AAGTCCCTGAGCATCTACGGTTTGCTGTGGGGCAGGAGGTCTTTGGTCTGGTGCCTGGTCTGATGATGTATGCCACAATCTGGC TGCGGGAACACAACAGAGTATGCGATGTGCTTAAACAGGAGCATCCTGAATGGGGTGATGAGCAGTTGTTCCAGACAAGCAGGC TAATACTGATAGGAGAGACTATTAAGATTGTGATTGAAGATTATGTGCAACACTTGAGTGGCTATCACTTCAAACTGAAATTTG ACCCAGAACTACTTTTCAACAAACAATTCCAGTACCAAAATCGTATTGCTGCTGAATTTAACACCCTCTATCACTGGCATCCCC TTCTGCCTGACACCTTTCAAATTCATGACCAGAAATACAACTATCAACAGTTTATCTACAACAACTCTATATTGCTGGAACATG GAATTACCCAGTTTGTTGAATCATTCACCAGGCAAATTGCTGGCAGGGTTGCTGGTGGTAGGAATGTTCCACCCGCAGTACAGA AAGTATCACAGGCTTCCATTGACCAGAGCAGGCAGATGAAATACCAGTCTTTTAATGAGTACCGCAAACGCTTTATGCTGAAGC CCTATGAATCATTTGAAGAACTTACAGGAGAAAAGGAAATGTCTGCAGAGTTGGAAGCACTCTATGGTGACATCGATGCTGTGG AGCTGTATCCTGCCCTTCTGGTAGAAAAGCCTCGGCCAGATGCCATCTTTGGTGAAACCATGGTAGAAGTTGGAGCACCATTCT CCTTGAAAGGACTTATGGGTAATGTTATATGTTCTCCTGCCTACTGGAAGCCAAGCACTTTTGGTGGAGAAGTGGGTTTTCAAA TCATCAACACTGCCTCAATTCAGTCTCTCATCTGCAATAACGTGAAGGGCTGTCCCTTTACTTCATTCAGTGTTCCAGATCCAG AGCTCATTAAAACAGTCACCATCAATGCAAGTTCTTCCCGCTCCGGACTAGATGATATCAATCCCACAGTACTACTAAAAGAAC GTTCGACTGAACTGTAGAAGTCTAATGATCATATTTATTTATTTATATGAACCATGTCTATTAATTTAATTATTTAATAATATT TATATTAAACTCCTTATGTTACTTAACATCTTCTGTAACAGAAGTCAGTACTCCTGTTGCGGAGAAAGGAGTCATACTTGTGAA GACTTTTATGTCACTACTCTAAAGATTTTGCTGTTGCTGTTAAGTTTGGAAAACAGTTTTTATTCTGTTTTATAAACCAGAGAG AAATGAGTTTTGACGTCTTTTTACTTGAATTTCAACTTATATTATAAGAACGAAAGTAAAGATGTTTGAATACTTAAACACTAT CACAAGATGGCAAAATGCTGAAAGTTTTTACACTGTCGATGTTTCCAATGCATCTTCCATGATGCATTAGAAGTAACTAATGTT TGAAATTTTAAAGTACTTTTGGTTATTTTTCTGTCATCAAACAAAAACAGGTATCAGTGCATTATTAAATGAATATTTAAATTA GACATTACCAGTAATTTCATGTCTACTTTTTAAAATCAGCAATGAAACAATAATTTGAAATTTCTAAATTCATAGGGTAGAATC ACCTGTAAAAGCTTGTTTGATTTCTTAAAGTTATTAAACTTGTACATATACCAAAAAGAAGCTGTCTTGGATTTAAATCTGTAA AATCAGATGAAATTTTACTACAATTGCTTGTTAAAATATTTTATAAGTGATGTTCCTTTTTCACCAAGAGTATAAACCTTTTTA GTGTGACTGTTAAAACTTCCTTTTAAATCAAAATGCCAAATTTATTAAGGTGGTGGAGCCACTGCAGTGTTATCTCAAAATAAG AATATTTTGTTGAGATATTCCAGAATTTGTTTATATGGCTGGTAACATGTAAAATCTATATCAGCAAAAGGGTCTACCTTTAAA ATAAGCAATAACAAAGAAGAAAACCAAATTATTGTTCAAATTTAGGTTTAAACTTTTGAAGCAAACTTTTTTTTATCCTTGTGC ACTGCAGGCCTGGTACTCAGATTTTGCTATGAGGTTAATGAAGTACCAAGCTGTGCTTGAATAACGATATGTT'ΓTCTCAGATTT TCTGTTGTACAGTTTAATTTAGCAGTCCATATCACATTGCAAAAGTAGCAATGACCTCATAAAATACCTCTTCAAAATGCTTAA ATTCATTTCACACATTAATTTTATCTCAGTCTTGAAGCCAATTCAGTAGGTGCATTGGAATCAAGCCTGGCTACCTGCATGCTG TTCCTTTTCTTTTCTTCTTTTAGCCATTTTGCTAAGAGACACAGTCTTCTCATCACTTCGTTTCTCCTATTTTGTTTTACTAGT TTTAAGATCAGAGTTCACTTTCTTTGGACTCTGCCTATATTTTCTTACCTGAACTTTTGCAAGTTTTCAGGTAAACCTCAGCTC AGGACTGCTATTTAGCTCCTCTTAAGAAGATTAAAAGAGAAAAAAAAAGGCCCTTTTAAAAATAGTATACACTTATTTTAAGTG AAAAGCAGAGAATTTTATTTATAGCTAATTTTAGCTATCTGTAACCAAGATGGATGCAAAGAGGCTAGTGCCTCAGAGAGAACT GTACGGGGTTTGTGACTGGAAAAAGTTACGTTCCCATTCTAATTAATGCCCTTTCTTATTTAAAAACAAAACCAAATGATATCT
AAGTAGTTCTCAGCAATAATAATAATGACGATAATACTTCTTTTCCACATCTCATTGTCACTGACATTTAATGGTACTGTATAT TACTTAATTTATTGAAGATTATTATTTATGTCTTATTAGGACACTATGGTTATAAACTGTGTTTAAGCCTACAATCATTGATTT TTTTTTGTTATGTCACAATCAGTATATTTTCTTTGGGGTTACCTCTCTGAATATTATGTAAACAATCCAAAGAAATGATTGTAT TAAGATTTGTGAATAAATTTTTAGAAATCTGATTGGCATATTGAGATATTTAAGGTTGAATGTTTGTCCTTAGGATAGGCCTAT GTGCTAGCCCACAAAGAATATTGTCTCATTAGCCTGAATGTGCCATAAGACTGACCTTTTAAAATGTTTTGAGGGATCTGTGGA TGCTTCGTTAATTTGTTCAGCCACAATTTATTGAGAAAATATTCTGTGTCAAGCACTGTGGGTTTTAATATTTTTAAATCAAAC GCTGATTACAGATAATAGTATTTATATAAATAATTGAAAAAAATTTTCTTTTGGGAAGAGGGAGAAAATGAAATAAATATCATT AAAGATAACTCAGGAGAATCTTCTTTACAATTTTACGTTTAGAATGTTTAAGGTTAAGAAAGAAATAGTCAATATGCTTGTATA AAACACTGTTCACTGTTTTTTTTAAAAAAAAAACTTGATTTGTTATTAACATTGATCTGCTGACAAAACCTGGGAATTTGGGTT GTGTATGCGAATGTTTCAGTGCCTCAGACAAATGTGTATTTAACTTATGTAAAAGATAAGTCTGGAAATAAATGTCTGTTTATT TTTGTACTATTTA
239
MDPNCSCEAGGSCACAGSCKCKKCKCTSCKKSCCSCCP GCAKCAQGCICKGASEKCSCCA
240 ' "' '"
CTCCAGTCTCACCTCGGCTTGCAATGGACCCCAACTGCTCCTGCGAGGCTGGTGGCTCCTGCGCCTGCGCCGGCTCCTGCAAGT GCAAAAAGTGCAAATGCACCTCCTGCAAGAAGAGCTGCTGCTCCTGTTGCCCCCTGGGCTGTGCCAAGTGTGCCCAGGGCTGCA TCTGCAAAGGGGCGTCAGAGAAGTGCAGCTGCTGTGCCTGATGTCGGGACAGCCCTGCTGTCAGATGAAAACAGAATGACACGT AAAATCCGAGGTTTTTTTTTTCTACAACTCCGACTCATTTGCTACATTCCTTTTTTTCTGTGAAATATGTGAATAATAATTAAA CACTTAGACTTGAAAAAAAAAAAAAAAAAAA
241 MDPNCSCSPVGSCACAGSCKCKECKCTSCKKSCCSCCPVGCAKCAQGCICKGTSDKCSCCA
242
CCGCTGCGTGTTTTCCTCTTGATCGGGAACTCCTGCTTCTCCTTGCCTCGAAATGGACCCCAACTGCTCCTGCTCGCCTGTTGG CTCCTGTGCCTGTGCCGGCTCCTGCAMTGCAAAGAGTGCAAATGCACCTCCTGCAAGAAGAGCTGCTGCTCCTGCTGCCCTGT GGGCTGTGCMAAGTGTGCCCAGGGCTGCATCTGCAAAGGGACGTCAGACAAGTGCAGCTGCTGTGCCTGATGCCAGGACAGCTG TGCTCTCAGATGTAAATAGAGCAACCTATATAAACCTGGATTTTTTTTTTTTTTTTTTTGTACAACCCTGACCCGTTTGCTACA TCTTTTTTTCTATGA TATGTG TGGC TAMTTCATCTAGACTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
243
MDPNCSCAAGVSCTCASSCKCKECKCTSCKKSCCSCCPVGCAKCAQGCICKGASEKCSCCA
244 ACTCCGCCTTCCACGTGCACCCACTGCCTCTTCCCTTCTCGCTTGGGAACTCTAGTCTCGCCTCGGGTTGCAATGGACCCCAAC TGCTCCTGTGCCGCTGGTGTCTCCTGCACCTGCGCCAGCTCCTGCAAGTGCAAAGAGTGCAAATGCACCTCCTGCAAGAAGAGC TGCTGCTCCTGCTGCCCTGTGGGCTGTGCCAAGTGTGCCCAAGGCTGCATCTGCAAAGGGGCATCGGAGAAGTGCAGCTGCTGC GCCTGATGTCGGGACAGCCCTGCTCCCAAGTACAAATAGAGTGACCCGTAAAATCTAGGATTTTTTGTTTTTTGCTACAATCTT GACCCCTTTGCTACATTCCCTTTTTTCTGTGAAATATGTGAATAATAATTAAACACTTAG 246
TTTAAAGTCAAAATTGTTTTTATTGTCAGTCACATATTTAGTATAAAAAGAAATGCAGCAAATGGCTCAGTGTTGTATTTTTAA AAAAATCCAGGTTGTGCAGGTTGTTCTATTTACATCTGGGAGAAGAGCTGTTCCCACATCAGGCACAGCAGCTGCACTTCTCCG ATGCCCCTTTGCAGACGCAGCCCTGGGACACTTGGCACAGCCACGGGGAGCAGGAACAGCAGCTCTTCTTGGAGGAGGTGCATT TGCACTCTTTGCACTTGCAGGAGCCGGCGCACGTGCAGGAGCCA 247 -
MGTQK¥TPALIFAITVATIGSFQFGYNTGVINAPEKIIKEFINKTLTDKGNAPPSEVLLTS WSLSVAIFSVGGMIGSFSVGLF WRFGRRNSMLIVW LAVTGGCFMGLCKVAKSVEMLILGRLVIGLFCGLCTGF¥PMYIGEISPTALRGAFGTLNQLGIWGI V AQIFGLEFILGSEELWPLLLGFTILPAILQSAA PFCPESPRFLLINRKEEENAKQI QRL GTQDVSQDIQEMKDESARMSQE KQVTVLELFR¥SSYRQPIIISIV QLSQQ SGINAVFYYSTGIFKDAG¥QEPIYATIGAGWNTIFTWSLFLVERAGRRTLHM IGLGG FCSTMTVSLLLKDNYNGMSFVCIGAILVFVAFFEIGPGPIPWFIVAELFSQGPRPAAMAVAGCSNWTSNFLVGLLF PSAAHYLGAYVFIIFTGF ITFLAFTFFKVPETRGRTFEDITRAFEGQAHGADRSGKDGVMEMNSIEPAKETTTNV
248
GTGGGGTGGGGTGGGGCTGGGGGCTTGTCGCCCTTTCAGGCTCCACCCTTTGCGGAGATTATAAATAGTCATGATCCCAGCGAG 5 ACCCAGAGATGCCTGTAATGGTGAGACTTTGGATCCTTCCTGAGGACGTGGAGAAAACTTTCTGCTGAGAAGGACATTTTGAAG GTTTTGTTGGCTGAAAAAGCTGTTTCTGGAATCACCCCTAGATCTTTCTTGAAGACTTGAATTAGATTACAGCGATGGGGACAC AGAAGGTCACCCCAGCTCTGATATTTGCCATCACAGTTGCTACAATCGGCTCTTTCCAATTTGGCTACAACACTGGGGTCATCA ATGCTCCTGAGAAGATCATAAAGGAATTTATCAATAAAACTTTGACGGACAAGGGAAATGCCCCACCCTCTGAGGTGCTGCTCA CGTCTCTCTGGTCCTTGTCTGTGGCCATATTTTCCGTCGGGGGTATGATCGGCTCCTTTTCCGTCGGACTCTTCGTCAACCGCT
10 TTGGCAGGCGCAATTCAATGCTGATTGTCAACCTGTTGGCTGTCACTGGTGGCTGCTTTATGGGACTGTGTAAAGTAGCTAAGT CGGTTGAAATGCTGATCCTGGGTCGCTTGGTTATTGGCCTCTTCTGCGGACTCTGCACAGGTTTTGTGCCCATGTACATTGGAG AGATCTCGCCTACTGCCCTGCGGGGTGCCTTTGGCACTCTCAACCAGCTGGGCATCGTTGTTGGAATTCTGGTGGCCCAGATCT TTGGTCTGGAATTCATCCTTGGGTCTGAAGAGCTATGGCCGCTGCTACTGGGTTTTACCATCCTTCCTGCTATCCTACAAAGTG CAGCCCTTCCATTTTGCCCTGAAAGTCCCAGATTTTTGCTCATTAACAGAAAAGAAGAGGAGAATGCTAAGCAGATCCTCCAGC * 15 GGTTGTGGGGCACCCAGGATGTATCCCAAGACATCCAGGAGATGAAAGATGAGAGTGCAAGGATGTCACAAGAAAAGCAAGTCA CCGTGCTAGAGCTCTTTAGAGTGTCCAGCTACCGACAGCCCATCATCATTTCCATTGTGCTCCAGCTCTCTCAGCAGCTCTCTG GGATCAATGCTGTGTTCTATTACTCAACAGGAATCTTCAAGGATGCAGGTGTTCAAGAGCCCATCTATGCCACCATCGGCGCGG GTGTGGTTAATACTATCTTCACTGTAGTTTCTCTATTTGTGGTGGAAAGGGCAGGAAGAAGGACTCTGCATATGATAGGCCTTG GAGGGATGGCTTTTTGTTCCACGCTCATGACTGTTTCTTTGTTATTAAAGGATAACTATAATGGGATGAGCTTTGTCTGTATTG
20 GGGCTATCTTGGTCTTTGTAGCCTTCTTTGAAATTGGACCAGGCCCCATTCCCTGGTTTATTGTGGCCGAACTCTTCAGCCAGG
. GCCCCCGCCCAGCTGCGATGGCAGTGGCCGGCTGCTCCAACTGGACCTCCAACTTCCTAGTCGGATTGCTCTTCCCCTCCGCTG
CTCACTATTTAGGAGCCTACGTTTTTATTATCTTCACCGGCTTCCTCATTACCTTCTTGGCTTTTACCTTCTTCAAAGTCCCTG
AGACCCGTGGCAGGACTTTTGAGGATATCACACGGGCCTTTGAAGGGCAGGCACACGGTGCAGATAGATCTGGAAAGGACGGCG
TCATGGAGATGAACAGCATCGAGCCTGCTAAGGAGACCACCACCAATGTCTAAGTCGTGCCTCCTTCCACCTCCCTCCCGGCAT
25 GGGAAAGCCACCTCTCCCTCAACAAGGGAGAGACCTCATCAGGATGAACCCAGGACGCTTCTGAATGCTGCTACTTAATTCCTT TCTCATCCCACGCACTCCATGAGCACCCCAAGGCTGCGGTTTGTTGGATCTTCAATGGCTTTTTAAATTTTATTTCCTGGACAT CCTCTTCTGCTTAGGAGAGACCGAGTGAACCTACCTTCATTTCAGGAGGGATTGGCCGCTTGGCACATGACAACTTTGCCAGCT' TTTCCTCCCTTGGGTTCTGATATTGCCGCACTAGGGGATATAGGAGAGGAAAAGTAAGGTGCAGTTCCCCCAACCTCAGACTTA CCAGGAAGCAGATACATATGAGTGTGGAAGCCGGAGGGTGTTTATGTAAGAGCACCTTCCTCACTTCCATACAGCTCTACGTGG
30 CAAATTAACTTGAGTTTTATTTATTTTATCCTCTGGTTTAATTACATAATTTTTTTTTTTTTACTTTAAGTTTCAGGATACATG TGCCGAATGTGCAGGTTTGTTACATAGGTATATATATGCCATGATGGAAATATTTATTTTTTTAAGCGTAATTTTGCCAAATAA TAAAAACAGAAGGAAATTGAGATTAGAGGGAGGTGTTTAAAGAGAGGTTATAGAGTAGAAGATTTGATGCTGGAGAGGTTAAGG TGCAATAAGAATTTAGGGAGAAATGTTGTTCATTATTGGAGGGTAAATGATGTGGTGCCTGAGGTCTGTACGTTACCTCTTAAC AATTTCTGTCCTTCAGATGGAAACTCTTTAACTTCTCGTAAAAGTCATATACCTATATAATAAAGCTACTGATTTCCTTGGAGC
35 •TTTTTTCTTTAAGATAATAGTTTACATGTAGTAGTACTTGAAATCTAGGATTATTAACTAATATGGGCATTGTAGTTAATGATG GTTGATGGGTTCTAATTTTGGATGGAGTCCAGGGAAGAGAAAGTGATTTCTAGAAAGCCTGTTCCCCTCACTGGATGAAATAAC TCCTTCTTGTAGTAGTCTCATTACTTTTGAAGTAATCCCGCCACCTATCTCGTGGGAGAGCCATCCAAATAAGAAACCTAAAAT AATTGGTTCTTGGTAGAGATTCATTATTTTTCCACTTTGTTCTTTAGGAGATTTTAGGTGTTGATTTTCTGTTGTATTTTAACT CATACCTTTAAAGGAATTCCCCAAAGAATGTTTATAGCAAACTTGGAATTTGTAACCTCAGCTCTGGGAGAGGATTTTTTTCTG
40 AGCGATTATTATCTAAAGTGTGTTGTTGCTTTAGGCTCACGGCACGCTTGCGTATGTCTGTTACCATGTCACTGTGGTCCTATG CCGAATGCCCTCAGGGGACTTGAATCTTTCCAATAAACCAGGTTTAGACAGTATGAGTCAATGTGCAGTGTAGCCCACACTTGA GAGGATGAATGTATGTGCACTGTCACTTTGCTCTGGGTGGAAGTACGTTATTGTTGACTTATTTTCTCTGTGTTTGTTCCTACA GCCCCTTTTTCATATGTTGCTCAGTCTCCCTTTCCCTTCTTGGTGCTTACACATCTCAGACCCTTTAGCCAAACCCTTGTCAGT GACAGTATTTTGGTTCTTAGTTCTCACTGTTCCCTCTGCTCCTGGAGCCTTTGAATAAAAATGCACGTAGCTGAGGCCGGATGC
45 GGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCTAGGCGGGCGGTCAGGGGTTCGAGACCAGTCTGGCCAACATCGTGA AACCCTGTCTCTACTAAAAATGCAAAAATTAGCCGGGCGTGGTGGCGGGCGCCTGTAATCCCAGCTACTTGGGAAGCTGAGGCG GGAGAATCATGTGAACCCGGGACGCAGGGGTTGCAGTGAGCGGAGATCGCATCATTGCACTCTAGCCTGGGCCACAGGGCGAGA CTCCGTCTCAAAAAAAAAAAAATGCACATAGCTATCGAGTGTGCTTTAGCTTGAAAAGGTGACCTTGCAACTTCATGTCAACTT TCTGGCTCCTCAAACAGTAGGTTGGCAGTAAGGCAGGGTCCCATTTCTCACTGAGAAGATTGTGAATATTTCCATATGGATTTT
50 CTATTGTTACTCTGGTTCTTTGTTTTAAAATAAAAATTCTGAATGTACACG 249
MIASHLLAYFFTELNHDQVQKVDQYLYH RLSDET EISKRFRKEME GLGATTHPTAAVK-- PTFVRSTPDGTEHGEF A D LGGTNFRVLWVKVTDNGLQKVEMENQIYAIPEDIMRGSGTQLFDHIAEC A FMDK QIKDKKLPLGFTFSFPCHQTKLDESFL VSWTKGFKSSGVEGRDWALIRKAIQRRGDFDIDIVAVWDTVGTMMTCGYDDHNCEIGLIVGTGSNACYMEE--RHIDMVEGDE GRMCIME GAFGDDGSLNDIRTEFDQEIDMGSLNPGKQLFEKMISGMYMGELVRLILVKMAKEE LFGGKLSPELLNTGRFET KDISDIEGEKDGIRRA.REVLMRLG DPTQEDCVATHRICQIVSTRSASLCAATLAAVLQRIKENKGEERLRSTIGVDGSVYKKH •PHFAKRLHKTVRRL¥PGCD¥RFLRSEDGSGKGAAMVTA¥AYRLADQHRARQKTLEHLQLSHDQLLEVKRRMKVEMERGLSKETH ASAPVKM PTYVCATPDGTEKGDFLALDLGGTNFRV LVR¥RNGK GGVEMHNKIYAIPQEVMHGTGDELFDHIVQCIADFLEY MGMKG¥SLPLGFTFSFPCQQNS DESILLK TKGFKASGCEGEDVVTLLKEAIHRREEFDLDWAW DT¥GT TCGFEDPHC EVG IVGTGSNACYMEEMRWELVEGEEGMCVmE GAFGDNGCLDDFRTEFDVAVDE S NPGKQRFEK ISGMYLGEIVRN ILiDFTKRGLLFRGRISERL TRGIFET FLSQIESDCLA LQVRAI QHLGLESTCDDSIIVKEVCTWARRAAQLCGAGMAA VVDRIRENRGLDALKVTVGVDGT YRLHPHFAKVMHETVKDLAPKCDVSFLQSEDGSGKGAA ITAVACRIREAGQR
250
GTTGCATGAAACTCCGGCGCAGGAGTCCCGGGCTGCCGCTGGCAACATCGTGTCACCCAGCTAAGAAAATCCGCGGGCCCGAGC CACGGGCCTGTGAATCGGAGAGGTCCCACTGCCCGAGTGGAGCCGGGCTGAGATTCTTCTCAAGTTGAGCCTCAGTGATCCTGT GGCCGAAGTTAGCGCCTTGACGTGGGACAACCGGACACGTCGCCAGGAGAGAACTGAGGCGCCTTCTAGCAGTTGTGACGCCAA AATCACGTCTCCGGAGACCCGCGCCCTCCGCCAGCCGGGCGCACCCTCGCCGGTAGCCTTCTTTGTGCGCCGTCCGGACTCCCA GCTCCCGGCCCGGCAGCCGAGCCCCAGCACAAAGCAGTCGGACCGCGCCGCCCGCCTCCCCTCTCGCGTCTCCGCCTCGGTTTC CCAACTCTGCGCCGTCGGGCCGCGGCAGGATGATTGCCTCGCATCTGCTTGCCTACTTCTTCACGGAGCTCAACCATGACCAAG TGCAGAAGGTTGACCAGTATCTCTACCACATGCGCCTCTCTGATGAGACCCTCTTGGAGATCTCTAAGCGGTTCCGCAAGGAGA TGGAGAAAGGGCTTGGAGCCACCACTCACCCTACTGCAGCAGTGAAGATGCTGCCCACCTTTGTGAGGTCCACTCCAGATGGGA CAGAACACGGAGAGTTCCTGGCTCTGGATCTTGGAGGGACCAACTTCCGTGTGCTTTGGGTGAAAGTAACGGACAATGGGCTCC AGAAGGTGGAGATGGAGAATCAGATCTATGCCATCCCTGAGGACATCATGCGAGGCAGTGGCACCCAGCTGTTTGACCACATTG CCGAATGCCTGGCTAACTTCATGGATAAGCTACAAATCAAAGACAAGAAGCTCCCACTGGGTTTTACCTTCTCGTTCCCCTGCC ACCAGACTAAACTAGACGAGAGTTTCCTGGTCTCATGGACCAAGGGATTCAAGTCCAGTGGAGTGGAAGGCAGAGACGTTGTGG CTCTGATCCGGAAGGCCATCCAGAGGAGAGGGGACTTTGATATCGACATTGTGGCTGTGGTGAATGACACAGTTGGGACCATGA TGACCTGTGGTTATGATGACCACAACTGTGAGATTGGTCTCATTGTGGGCACGGGCAGCAACGCCTGCTACATGGAAGAGATGC GCCACATCGACATGGTGGAAGGCGATGAGGGGCGGATGTGTATCAATATGGAGTGGGGGGCCTTCGGGGACGATGGCTCGCTCA ACGACATTCGCACTGAGTTTGACCAGGAGATTGACATGGGCTCACTGAACCCGGGAAAGCAACTGTTTGAGAAGATGATCAGTG GGATGTACATGGGGGAGCTGGTGAGGCTTATCCTGGTGAAGATGGCCAAGGAGGAGCTGCTCTTTGGGGGGAAGCTCAGCCCAG AGCTTCTCAACACCGGTCGCTTTGAGACCAAAGACATCTCAGACATTGAAGGGGAGAAGGATGGCATCCGGAAGGCCCGTGAGG TCCTGATGCGGTTGGGCCTGGACCCGACTCAGGAGGACTGCGTGGCCACTCACCGGATCTGCCAGATCGTGTCCACACGCTCCG CCAGCCTGTGCGCAGCCACCCTGGCCGCCGTGCTGCAGCGCATCAAGGAGAACAAAGGCGAGGAGCGGCTGCGCTCTACTATTG GGGTCGACGGTTCCGTCTACAAGAAACACCCCCATTTTGCCAAGCGTCTACATAAGACCGTGCGGCGGCTGGTGCCCGGCTGCG ATGTCCGCTTCCTCCGCTCCGAGGATGGCAGTGGCAAAGGTGCAGCCATGGTGACAGCAGTGGCTTACCGGCTGGCCGATCAAC ACCGTGCCCGCCAGAAGACATTAGAGCATCTGCAGCTGAGCCATGACCAGCTGCTGGAGGTCAAGAGGAGGATGAAGGTAGAAA TGGAGCGAGGTCTGAGCAAGGAGACTCATGCCAGTGCCCCCGTCAAGATGCTGCCCACCTACGTGTGTGCTACCCCGGACGGCA CAGAGAAAGGGGACTTCTTGGCCTTGGACCTTGGAGGAACAAATTTCCGGGTCCTGCTGGTCCGTGTTCGGAATGGGAAGTGGG GTGGAGTGGAGATGCACAACAAGATCTACGCCATCCCGCAGGAGGTCATGCACGGCACCGGGGACGAGCTCTTTGACCACATTG TCCAGTGCATCGCGGACTTCCTCGAGTACATGGGCATGAAGGGCGTGTCCCTGCCTCTGGGTTTTACCTTCTCCTTCCCCTGCC AGCAGAACAGCCTGGACGAGAGCATCCTCCTCAAGTGGACAAAAGGCTTCAAGGCATCTGGCTGCGAGGGCGAGGACGTGGTGA CCCTGCTGAAGGAAGCGATCCACCGGCGAGAGGAGTTTGACCTGGATGTGGTTGCTGTGGTGAACGACACAGTCGGAACTATGA TGACCTGTGGCTTTGAAGACCCTCACTGTGAAGTTGGCCTCATTGTTGGCACGGGCAGCAATGCCTGCTACATGGAGGAGATGC GCAACGTGGAACTGGTGGAAGGAGAAGAGGGGCGGATGTGTGTGAACATGGAATGGGGGGCATTCGGGGACAATGGATGCCTAG ATGACTTCCGCACAGAATTTGATGTGGCTGTGGATGAGCTTTCACTCAACCCCGGCAAGCAGAGGTTCGAGAAAATGATCAGTG GAATGTACCTGGGTGAGATTGTCCGTAACATTCTCATCGATTTCACCAAGCGTGGACTGCTCTTCCGAGGCCGCATCTCAGAGC GGCTCAAGACAAGGGGCATCTTTGAAACCAAGTTCTTGTCTCAGATTGAGAGTGACTGCCTGGCCCTGCTGCAAGTCCGAGCCA TCCTGCAACACTTAGGGCTTGAGAGCACCTGTGACGACAGCATCATTGTTAAGGAGGTGTGCAGTGTGGTGGCCCGGCGGGCAG CCCAGCTCTGTGGCGCAGGCATGGCCGCTGTGGTGGACAGGATACGAGAAAACCGTGGGCTGGACGCTCTCAAAGTGACAGTGG GTGTGGATGGGACCCTCTACAAGCTACATCCTCACTTTGCCAAAGTCATGCATGAGACAGTGAAGGACCTGGCTCCGAAATGTG ATGTGTCTTTCCTGCAGTCAGAGGATGGCAGCGGGAAGGGGGCGGCGCTCATCACTGCTGTGGCCTGCCGCATCCGTGAGGCTG GACAGCGATAGAACCCCTGAAATCGGAAGGGACTTCCTCTTTCTCTCCTTCTTCCCTGTTTTAAATTATAAGATGTCATCCCCT TGTGTCAGAGACAGACCCCTTGGCTTTTGCTTGGCAGAGAGGACCCCACTGGACTGGGTTTTGTCTCTGCATCTCATTGTAGAG CTTGGTGGCTGAGCTTGGCCCTATTAAGATAAATAGAGTTCCAAATAAGGATTTGTTCACATGCATCATAACCATTCCCATTGG TTCTCCTAAAACATGAAAATTATCTCCCTTAGTAATCCCCCTTGCCAAATTCCATGTCCCTGTATAATTCTACAGGATGGGGAC ACTAATGAAGATACGGTTGCTTCACCTTGGAGCCTGAACATGACATTTCTAAGTGGGGTGCATCCCCCAGCACTGATGTTGTTA CTGATTCTCCTGTCAGAGATCTGGGAGGTCTCCACTGAGGATGTGAGCCTGATTATCCTATAGGCAGACGTGGGGAGGGTGGAG GGGTGACAGTGGAGGAAAATCCATGGATATCCACGCAGCAGCCCCTCTTTAACCTCATCTACAAGCATTTGCCCTGTGGATTCC AGCATTTGCCATTCCTGGAATCAAGGAATCCTGAGTCTGGGCAATGAAACCAAAGCCAGGAGTTGACGCATCCTGCAGTTGGGC CAGCTGTCGCATCTCAGCGGGGCGCACATGTTATCCACAAGCAATGGACCTTTGGGGAAGGGGGAGTTTTTAGTTTGTTTTACA AATTTTTCCTGCAAAAGTGGAATCACTGTATTTTCATTTTAATTTATATTTGAAATTTTATTTAGTTCTTGAGTAGATCTGCTT CTTCATCTTGACATGTAATGAATGGTCAGTTGTACGTAATGTATTTATATGTTAATTTGTTATGTATATAGATGTGCAAGTCTT GTCAGAATTGGCCTCAGTGTAGTTAAAGGGCAGAAGGGGAAGATACTGACTAGTCATAGAAATACCTCATTCGCCTGTGGGAAG AGAAGGGAAGCCTCTTCAGGGTGAGTGAATGGCAAAGCGGTTGCTTCTCCG
251 MTSKLAVA LAAFLISAALCEGAVLPRSAKE RCQCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELCLDPKENW VQRWEKFLKRAENS •
252'
AGCAGAGCACACAAGCTTCTAGGACAAGAGCCAGGAAGAAACCACCGGAAGGAACCATCTCACTGTGTGTAAACATGACTTCCA AGCTGGCCGTGGCTCTCTTGGCAGCCTTCCTGATTTCTGCAGCTCTGTGTGAAGGTGCAGTTTTGCCAAGGAGTGCTAAAGAAC TTAGATGTCAGTGCATAAAGACATACTCCAAACCTTTCCACCCCAAATTTATCAAAGAACTGAGAGTGATTGAGAGTGGACCAC ACTGCGCCAACACAGAAATTATTGTAAAGCTTTCTGATGGAAGAGAGCTCTGTCTGGACCCCAAGGAAAACTGGGTGCAGAGGG TTGTGGAGAAGTTTTTGAAGAGGGCTGAGAATTCATAAAAAAATTCATTCTCTGTGGTATCCAAGAATCAGTGAAGATGCCAGT GAAACTTCAAGCAAATCTACTTCAACACTTCATGTATTGTGTGGGTCTGTTGTAGGGTTGCCAGATGCAATACAAGATTCCTGG TTAAATTTGAATTTCAGTAAACAATGAATAGTTTTTCATTGTACCATGAAATATCCAGAACATACTTATATGTAAAGTATTATT TATTTGAATCTACAAAAAACAACAAATAATTTTTAAATATAAGGATTTTCCTAGATATTGCACGGGAGAATATACAAATAGCAA AATTGAGCCAAGGGCCAAGAGAATATCCGAACTTTAATTTCAGGAATTGAATGGGTTTGCTAGAATGTGATATTTGAAGCATCA CATAAAAATGATGGGACAATAAATTTTGCCATAAAGTCAAATTTAGCTGGAAATCCTGGATTTTTTTCTGTTAAATCTGGCAAC CCTAGTCTGCTAGCCAGGATCCACAAGTCCTTGTTCCACTGTGCCTTGGTTTCTCCTTTATTTCTAAGTGGAAAAAGTATTAGC CACCATCTTACCTCACAGTGATGTTGTGAGGACATGTGGAAGCACTTTAAGTTTTTTCATCATAACATAAATTATTTTCAAGTG TAACTTATTAACCTATTTATTATTTATGTATTTATTTAAGCATCAAATATTTGTGCAAGAATTTGGAAAAATAGAAGATGAATC ATTGATTGAATAGTTATAAAGATGTTATAGTAAATTTATTTTATTTTAGATATTAAATGATGTTTTATTAGATAAATTTCAATC' AGGGTTTTTAGATTAAACAAAGAAACAATTGGGTAeCCAGTTAAATTTTCATTTCAGATAAACAACAAATAATTTTTTAGTATA AGTACATTATTGTTTATCTGAAAGTTTTAATTGAACTAACAATCCTAGTTTGATACTCCCAGTCTTGTCATTGCCAGCTGTGTT GGTAGTGCTGTGTTGAATTACGGAATAATGAGTTAGAACTATTAAAACAGCCAAAACTCCACAGTCAATATTAGTAATTTCTTG CTGGTTGAAACTTGTTTATTATGTACAAATAGATTCTTATAATATTATTTAAATGACTGCATTTTTAAATACAAGGCTTTATAT TTTTAACTTTAAGATGTTTTTATGTGCTCTCCAAATTTTTTTTACTGTTTCTGATTGTATGGAAATATAAAAGTAAATATGAAA CATTTAAAATATAATTTGTTGTCAAAGTAAAAAAAAAAAAAAA
253
MGKVKVGWGFGRIGRLVTRAAFNSGKVDIVAI1.DPFIDLNYMVYMFQYDSTHG FHGTVKAENGKL¥INGNPITIFQERDPSK IKWGDAGAEYWESTGVFTTMEKAGAHLQGGA RVIISAPSADAPMF¥MGWHEKYDNS KIISNASCTTNCLAPLAKVIHDNF GIVEGLMTTVHAITATQKTVDGPSGK WRDGRGALQNIIPASTGAAKAVGKVIPELNGKLTGMAFR¥PTANVSVVDLTCRLEKP AKYDDIKKVVKQASEGPLKGILGYTEHQWSSDFNSDTHSSTFDAGAGIALNDHFV LISWYDNEFGYSNRVVDLMAHMASKE
254
CTCTCTGCTCCTCCTGTTCGACAGTCAGCCGCATCTTCTTTTGCGTCGCCAGCCGAGCCACATCGCTCAGACACCATGGGGAAG GTGAAGGTCGGAGTCAACGGATTTGGTCGTATTGGGCGCCTGGTCACCAGGGCTGCTTTTAACTCTGGTAAAGTGGATATTGTT GCCATCAATGACCCCTTCATTGACCTCAACTACATGGTTTACATGTTCCAATATGATTCCACCCATGGCAAATTCCATGGCACC GTCAAGGCTGAGAACGGGAAGCTTGTCATCAATGGAAATCCCATCACCATCTTCCAGGAGCGAGATCCCTCCAAAATCAAGTGG GGCGATGCTGGCGCTGAGTACGTCGTGGAGTCCACTGGCGTCTTCACCACCATGGAGAAGGCTGGGGCTCATTTGCAGGGGGGA GCCAAAAGGGTCATCATCTCTGCCCCCTCTGCTGATGCCCCCATGTTCGTCATGGGTGTGAACCATGAGAAGTATGACAACAGC CTCAAGATCATCAGCAATGCCTCCTGCACCACCAACTGCTTAGCACCCCTGGCCAAGGTCATCCATGACAACTTTGGTATCGTG GAAGGACTCATGACCACAGTCCATGCCATCACTGCCACCCAGAAGACTGTGGATGGCCCCTCCGGGAAACTGTGGCGTGATGGC CGCGGGGCTCTCCAGAACATCATCCCTGCCTCTACTGGCGCTGCCAAGGCTGTGGGCAAGGTCATCCCTGAGCTGAACGGGAAG CTCACTGGCATGGCCTTCCGTGTCCCCACTGCCAACGTGTCAGTGGTGGACCTGACCTGCCGTCTAGAAAAACCTGCCAAATAT GATGACATCAAGAAGGTGGTGAAGCAGGCGTCGGAGGGCCCCCTCAAGGGCATCCTGGGCTACACTGAGCACCAGGTGGTCTCC TCTGACTTCAACAGCGACACCCACTCCTCCACCTTTGACGCTGGGGCTGGCATTGCCCTCAACGACCACTTTGTCAAGCTCATT TCCTGGTATGACAACGAATTTGGCTACAGCAACAGGGTGGTGGACCTCATGGCCCACATGGCCTCCAAGGAGTAAGACCCCTGG ACCACCAGCCCCAGCAAGAGCACAAGAGGAAGAGAGAGACCCTCACTGCTGGGGAGTCCCTGCCACACTCAGTCCCCCACCACA CTGAATCTCCCCTCCTCACAGTTGCCATGTAGACCCCTTGAAGAGGGGAGGGGCCTAGGGAGCCGCACCTTGTCATGTACCATC AATAAAGTACCCTGTGCTCAACC
255
MSLSNK T DKLDVKGKRVVMR¥DFWPMK QITNNQRIKAAVPSIKFCLDNGAKSVV MSHLGRPDG¥P PDKYSLEP¥AVE KSLLGKDVLFLKDCVGPEVEKACA PAAGSVILLEN RFHVEEEGKGKDASG-.KVKAEPAKIEAFRASLSKLGDVYV DAFGT AHRAHSSMVGVNLPQKAGGFL KKELNYFAKALESPERPFLAILGGAK¥ADKIQ I1TOMLDKVNEMIIGGG FTFLKVLNME IGTSLFDEEGAKIVKDLMSKAEK GVKITLPVDFVTADKFDENAKTGQAT¥ASGIPAG MGLDCGPESSKKYAEAVTRAKQIVW NGPVGVFEWEAFARGTKA MDEVVKATSRGCITIIGGGDTATCCAKWNTEDKVSHVSTGGGASLELLEGKV PGVDALSNI
256
AAGCCTCCGGAGCGCACGTCGGCAGTCGGCTCCCTCGTTGACCGAATCACCGACCTCTCTCCCCAGCTGTATTTCCAAAATGTC GCTTTCTAACAAGCTGACGCTGGACAAGCTGGACGTTAAAGGGAAGCGGGTCGTTATGAGAGTCGACTTCAATGTTCCTATGAA GAACAACCAGATAACAAACAACCAGAGGATTAAGGCTGCTGTCCCAAGCATC AATTCTGCTTGGACAATGGAGCCAAGTCGGT AGTCCTTATGAGCCACCTAGGCCGGCCTGATGGTGTGCCCATGCCTGACAAGTACTCCTTAGAGCCAGTTGCTGTAGAACTCAA ATCTCTGCTGGGCAAGGATGTTCTGTTCTTGAAGGACTGTGTAGGCCCAGAAGTGGAGAAAGCCTGTGCCAACCCAGCTGCTGG GTCTGTCATCCTGCTGGAGAACCTCCGCTTTCATGTGGAGGAAGAAGGGAAGGGAAAAGATGCTTCTGGGAACAAGGTTAAAGC CGAGCCAGCCAAAATAGAAGCTTTCCGAGCTTCACTTTCCAAGCTAGGGGATGTCTATGTCAATGATGCTTTTGGCACTGCTCA CAGAGCCCACAGCTCCATGGTAGGAGTCAATCTGCCACAGAAGGCTGGTGGGTTTTTGATGAAGAAGGAGCTGAACTACTTTGC AAAGGCCTTGGAGAGCCCAGAGCGACCCTTCCTGGCCATCCTGGGCGGAGCTAAAGTTGCAGACAAGATCCAGCTCATCAATAA TATGCTGGACAAAGTCAATGAGATGATTATTGGTGGTGGAATGGCTTTTACCTTCCTTAAGGTGCTCAACAACATGGAGATTGG CACTTCTCTGTTTGATGAAGAGGGAGCCAAGATTGTCAAAGACCTAATGTCCAAAGCTGAGAAGAATGGTGTGAAGATTACCTT GCCTGTTGACTTTGTCACTGCTGACAAGTTTGATGAGAATGCCAAGACTGGCCAAGCCACTGTGGCTTCTGGCATACCTGCTGG CTGGATGGGCTTGGACTGTGGTCCTGAAAGCAGCAAGAAGTATGCTGAGGCTGTCACTCGGGCTAAGCAGATTGTGTGGAATGG TCCTGTGGGGGTATTTGAATGGGAAGCTTTTGCCCGGGGAACCAAAGCTCTCATGGATGAGGTGGTGAAAGCCACTTCTAGGGG CTGCATCACCATCATAGGTGGTGGAGACACTGCCACTTGCTGTGCCAAATGGAACACGGAGGATAAAGTCAGCCATGTGAGCAC TGGGGGTGGTGCCAGTTTGGAGCTCCTGGAAGGTAAAGTCCTTCCTGGGGTGGATGCTCTCAGCAATATTTAGTACTTTCCTGC CTTTTAGTTCCTGTGCACAGCCCCTAAGTCAACTTAGCATTTTCTGCATCTCCACTTGGCATTAGCTAAAACCTTCCATGTCAA GATTCAGCTAGTGGCCAAGAGATGCAGTGCCAGGAACCCTTAAACAGTTGCACAGCATCTCAGCTCATCTTCACTGCACCCTGG ATTTGCATACAT CTTCAAGATCCCATTTGAATTTTTTAGTGACTAAACCATTGTGCATTCTAGAGTGCATATATTTATATTTT GCCTGTTAAAAAGAAAGTGAGCAGTGTTAGCTTAGTTCTCTTTTGATGTAGGTTATTATGATTAGCTTTGTCACTGTTTCACTA CTCAGCATGGAAACAAGATGAAATTCCATTTGTAGGTAGTGAGACAAAATTGATGATCCATTAAGTAAACAATAAAAGTGTCCA TTG
257
MSILKIHAREIFDSRGNPTVEVDLFTSKG FRAA¥PSGASTGIYEALELRDNDKTRYMGKGVSKAVEHINKTIAPALVSKKL V TEQEKIDKLMIEMDGTENKSKFGANAILG¥SLAVCKAGA¥EKG¥PLYRHIADLAGNSEVI-HPVPAFN¥INGGSHAGNKLAMQEF MILPVGAANFREAMRIGAEVYHNLK VIKEKYGKDAT VGDEGGFAPNILENKEGLE KTAIGKAGYTDKVVIGMDVAASEFF RSGKYDLDFKSPDDPSRYISPDQLAD YKSFIKDYPWSIEDPFDQDDWGAWQKFTASAGIQWGDDLTVTNPKRIAKAV EKS CNCLLLKV1.QIGSVTESLQACKLAQA GWGVMVSHRSGETEDTFIAD WGLCTGQIKTGAPCRSER AKY QLLRIEEELGS AKFAGRNFRNPLAK
258 TAGCTAGGCAGGAAGTCGGCGCGGGCGGCGCGGACAGTATCTGTGGGTACCCGGAGCACGGAGATCTCGCCGGCTTTACGTTCA CCTCGGTGTCTGCAGCACCCTCCGCTTCCTCTCCTAGGCGACGAGACCCAGTGGCTAGAAGTTCACCATGTCTATTCTCAAGAT CCATGCCAGGGAGATCTTTGACTCTCGCGGGAATCCCACTGTTGAGGTTGATCTCTTCACCTCAAAAGGTCTCTTCAGAGCTGC TGTGCCCAGTGGTGCTTCAACTGGTATCTATGAGGCCCTAGAGCTCCGGGACAATGATAAGACTCGCTATATGGGGAAGGGTGT 5 CTCAAAGGCTGTTGAGCACATCAATAAAACTATTGCGCCTGCCCTGGTTAGCAAGAAACTGAACGTCACAGAACAAGAGAAGAT TGACAAACTGATGATCGAGATGGATGGAACAGAAMTAAATCTAAGTTTGGTGCGAACGCCATTCTGGGGGTGTCCCTTGCCGT ' ' CTGCAAAGCTGGTGCCGTTGAGAAGGGGGTCCCCCTGTACCGCCACATCGCTGACTTGGCTGGCAACTCTGAAGTCATCCTGCC AGTCCCGGCGTTCAATGTCATCAATGGCGGTTCTCATGCTGGCAACAAGCTGGCCATGCAGGAGTTCATGATCCTCCCAGTCGG TGCAGCAAACTTCAGGGAAGCCATGCGCATTGGAGCAGAGGTTTACCACAACCTGAAGAATGTCATCAAGGAGAAATATGGGAA
10 AGATGCCACCAATGTGGGGGATGAAGGCGGGTTTGCTCCCAACATCCTGGAGAATAAAGAAGGCCTGGAGCTGCTGAAGACTGC TATTGGGAAAGCTGGCTACACTGATAAGGTGGTCATCGGCATGGACGTAGCGGCCTCCGAGTTCTTCAGGTCTGGGAAGTATGA CCTGGACTTCAAGTCTCCCGATGACCCCAGCAGGTACATCTCGCCTGACCAGCTGGCTGACCTGTACAAGTCCTTCATCAAGGA CTACCCAGTGGTGTCTA*TCGAAGATCCCTTTGACCAGGATGACTGGGGAGCTTGGCAGAAGTTCACAGCCAGTGCAGGAATCCA GGTAGTGGGGGATGATCTCACAGTGACCAACCCAAAGAGGATCGCCAAGGCCGTGAACGAGAAGTCCTGCAACTGCCTCCTGCT
15 CAAAGTCAACCAGATTGGCTCCGTGACCGAGTCTCTTCAGGCGTGCAAGCTGGCCCAGGCCAATGGTTGGGGCGTCATGGTGTC TCATCGTTCGGGGGAGACTGAAGATACCTTCATCGCTGACCTGGTTGTGGGGCTGTGCACTGGGCAGATCAAGACTGGTGCCCC TTGCCGATCTGAGCGCTTGGCCAAGTACAACCAGCTCCTCAGAATTGAAGAGGAGCTGGGCAGCAAGGCTAAGTTTGCCGGCAG GAACTTCAGAAACCCCTTGGCCAAGTAAGCTGTGGGCAGGCAAGCCCTTCGGTCACCTGTTGGCTACACAGACCCCTCCCCTCG TGTCAGCTCAGGCAGCTCGAGGCCCCCGACCAACACTTGCAGGGGTCCCTGCTAGTTAGCGCCCCACCGCCGTGGAGTTCGTAC
20 CGCTTCCTTAGAACTTCTACAGAAGCCAAGCTCCCTGGAGCCCTGTTGGCAGCTCTAGCTTTGCAGTCGTGTAATTGGCCCAAG TCATTGTTTTTCTCGCCTCACTTTCCACCAAGTGTCTAGAGTCATGTGAGCCTCGTGTCATCTCCGGGGTGGCCACAGGCTAGA TCCCCGGTGGTTTTGTGCTCAAAATAAAAAGCCTCAGTGACCCATGAG
259
MPHSYPALSAEQKKELSDIALRI¥APGKGILAADESVGSMAKR SQIGVENTEENRRLYRQVLFSADDRVKKCIGGVIFFHETL 25 YQKDDNGVPFVRTIQDKGIWGIK¥DKGVVPLAGTDGETTTQG DG SERCAQYKKDGADFAK RCVLKISERTPSA AILENA VLARYASICQQNGIVPIVEPEILPDGDHDL RCQWTEKV MVYKALSDHHWLEGT KP MVTPGHACPI YTPEEIAMA TVTALRRT¥PPAVPGVTF SGGQSEEEASFNLNAINRCP PRPWA TFSYGRALQASALNAWRGQRDNAGAATEEFIKRAEVNG LAAQGKYEGSGEDGGAAAQSLYIA HAY
260
30 CCGAGCTGTGCTTGTGGCTGCGGCTGCTAACTGGCTGCGCACAGGGAGCTGTCACCATGCCTCACTCGTACCCAGCCCTTTCTG CTGAGCAGAAGAAGGAGTTGTCTGACATTGCCCTGCGGATTGTAGCCCeGGGCAAAGGCATTCTGGCTGCGGATGAGTCTGTAG GCAGCATGGCCAAGCGGCTGAGCCAAATTGGGGTGGAAAACACAGAGGAGAACCGCCGGCTGTACCGCGAGGTCCTGTTCAGTG CTGATGACCGTGTGAAAAAGTGCATTGGAGGCGTCATTTTCTTCCATGAGACCCTCTACCAGAAAGATGATAATGGTGTTCCCT TCGTCCGAACCATCCAGGATAAGGGCATCGTCGTGGGCATCAAGGTTGACAAGGGTGTGGTGCCTCTAGCTGGGACTGATGGAG
35 AAACCACCACTCAAGGGCTGGATGGGCTCTCAGAACGCTGTGCCCAATACAAGAAGGATGGTGCTGACTTTGCCAAGTGGCGCT GTGTGCTGAAAATCAGTGAGCGTACACCCTCTGCACTTGCCATTCTGGAGAACGCCAACGTGCTGGCCCGTTATGCCAGTATCT GCCAGCAGAATGGCATTGTGCCTATTGTGGAACCTGAAATATTGCCTGATGGAGACCACGACCTCAAACGTTGTCAGTATGTTA CAGAGAAGGTCTTGGCTGCTGTGTACAAGGCCCTGAGTGACCATCATGTATACCTGGAGGGGACCCTGCTCAAGCCCAACATGG TGACCCCGGGCCATGCCTGTCCCATCAAGTATACCCCAGAGGAGATTGCCATGGCAACTGTCACTGCCCTGCGTCGCACTGTGC
40 CCCCAGCTGTCCCAGGAGTGACCTTCCTGTCTGGGGGTCAGAGCGAAGAAGAGGCATCATTCAACCTCAATGCCATCAACCGCT GCCCCCTTCCCCGACCCTGGGCGCTTACCTTCTCCTATGGGCGTGCCCTGCAAGCCTCTGCACTCAATGCCTGGCGAGGGCAAC GGGACAATGCTGGGGCTGCCACTGAGGAGTTCATCAAGCGGGCTGAGGTGAATGGGCTTGCAGCCCAGGGCAAGTATGAAGGCA GTGGAGAAGATGGTGGAGCAGCAGCACAGTCACTCTACATTGCCAACCATGCCTACTGAGTATCCACTCCATACCACAGCCCTT GGCCCAGCCATCTGCACCCACTTTTGCTTGTAGTCATGGCCAGGGCCAAATAGCTATGCAGAGCAGAGATGCCTTCACCTGGCA
45 CCAACTTGTCTTCCTTTCTCTCTTCCCTTCCCCTCTCTCATTGCTGCACCTGGGACCATAGGATGGGAGGATAGGGAGCCCCTC ATGACTGAGGGCAGAAGAAATTGCTAGAAGTCAGAACAGGATGGCTGGGTCTCCCCCTACCTCTTCCAGCTCCCACAATTTTCC CATGATGAGGTAGCTTCTCCCTGGGCTCTCCTTCTTGCCTGCCCTGTCTCCTGGGATCAGAGGGTAGTACAGAAGCCCTGACTC ATGCCTTGAGTACATACCATACAGCAAATAAATGGTAGCAAAACAAAAAAAAAAAAAAAAAAAAAAAAAA
261 PSRKFFVGGIM(MNGRKQSLGELIGTLNAAKVPADTEWCAPPTAYIDFARQKLDPKIAVAAQNCYKVTNGAFTGEISPGMI KDCGATWVVLGHSERRHVFGESDE IGQKVAHALAEGLGVIACIGEKLDEREAGITEKVVFEQTKVIAD VKDWSKWLAYEPV WAIGTGKTATPQQAQEVHEKLRGWLKS VSDAVAQSTRIIYGGSVTGATCKELASQPDVDGFLVGGASLKPEFVDIINAKQ
262 GCGCGACACTGACCTTCAGCGCCTCGGCTCGGCCATGGCGCCCTCCAGGAAGTTCTTCGTTGGGGGAAACTGGAAGATGAACGG GCGGAAGCAGAGTCTGGGGGAGCTCATCGGCACTCTGAACGCGGCCAAGGTGCCGGCCGACACCGAGGTGGTTTGTGCTCCCCC TACTGCCTATATCGACTTCGCCCGGCAGAAGCTAGATCCCAAGATTGCTGTGGCTGCGCAGAACTGCTACAAAGTGACTAATGG GGCTTTTACTGGGGAGATCAGCCCTGGCATGATCAAAGACTGCGGAGCCACGTGGGTGGTCCTGGGACACTCAGAGAGAAGGCA TGTCTTTGGGGAGTCAGATGAGCTGATTGGGCAGAAAGTGGCCCATGCTCTGGCAGAGGGACTCGGAGTAATCGCCTGCATTGG GGAGAAGCTAGATGAAAGGGAAGCTGGCATCACTGAGAAGGTTGTTTTCGAGCAGACAAAGGTCATCGCAGATAACGTGAAGGA CTGGAGCAAGGTCGTCCTCGCCTATGAGCCTGTGTGGGCCATTGGTACTGGCAAGACTGCAACACCCCAACAGGCCCAGGAAGT ACACGAGAAGCTCCGAGGATGGCTGAAGTCCAACGTCTCTGATGCGGTGGCTCAGAGCACCCGTATCATTTATGGAGGCTCTGT GACTGGGGCAACCTGCAAGGAGCTGGCCAGCCAGCCTGATGTGGATGGCTTCCTTGTGGGTGGTGCTTCCCTCAAGCCCGAATT CGTGGACATCATCAATGCCAAACAATGAGCCCCATCCATCTTCCCTACCCTTCCTGCCAAGCCAGGGACTAAGCAGCCCAGAAG CCCAGTAACTGCCCTTTCCCTGCATATGCTTCTGATGGTGTCATCTGCTCCTTCCTGTGGCCTCATCCAAACTGTATCTTCCTT TACTGTTTATATCTTCACCCTGTAATGGTTGGGACCAGGCCAATCCCTTCTCCACTTACTATAATGGTTGGAACTAAACGTCAC CAAGGTGGCTTCTCCTTGGCTGAGAGATGGAAGGCGTGGTGGGATTTGCTCCTGGGTTCCCTAGGCCCTAGTGAGGGCAGAAGA GAAACCATCCTCTCCCTTCTTACACCGTGAGGCCAAGATCCCCTCAGAAGGCAGGAGTGCTGCCCTCTCCCATGGTGCCCGTGC CTCTGTGCTGTGTATGTGAACCACCCATGTGAGGGAATAAACCTAGCACTAGG 263 SK LRAVILGPPGSGKGTVCQRIAQNFGLQHLSSGHF RENIKASTEVGEMAKQYIEKSLLVPDHVITR MMSELENRRGQH LLDGFPRT GQAEALDKICEVDLVISLNIPFETLKDR SRRWIHPPSGRVYN DFNPPH¥HGIDDVTGEPLVQQEDDKPEAVA AR RQYKDVAKP¥IELYKSRGVLHQFSGTETNKIWPYVYTLFSNKITPIQSKEAY * ■
264 CGGCGCTGGGCTGAGGGGAGGGGTTGTCTTAAAAGTCTCTCCTTCCCCCTGTAGGGGCGGCCGGCGAGTCCCAGTGAGAGCGGA GGGTGCCAGAGGTAGGGGGCCGAGAAACAAAGTTCCCGGGGCTTCCTCCGGGGCCGCGGTCGGGGCTGCGCGTTTGACCGCCCC CCTCCTCGCGAAGCAATGGCTTCCAAACTCCTGCGCGCGGTCATCCTCGGGCCGCCCGGCTCGGGCAAGGGCACCGTGTGCCAG AGGATCGCCCAGAACTTTGGTCTCCAGCATCTCTCCAGCGGCCACTTCTTGCGGGAGAACATCAAGGCCAGCACCGAAGTTGGT GAGATGGCAAAGCAGTATATAGAGAAAAGTCTTTTGGTTCCAGACCATGTGATCACACGCCTAATGATGTCCGAGTTGGAGAAC AGGCGTGGACAGCACTGGCTCCTTGATGGTTTTCCTAGGACATTAGGACAAGCCGAAGCCCTGGACAAAATCTGTGAAGTGGAT CTAGTGATCAGTTTGAATATTCeATTTGAAACACTTAAAGATCGTCTCAGCCGCCGTTGGATTCACCCTCCTAGCGGAAGGGTA TATAACCTGGACTTCAATCCACCTCATGTACATGGTATTGATGACGTCACTGGTGAACCGTTAGTCCAGCAGGAGGATGATAAA CCCGAAGCAGTTGCTGCCAGGCTAAGACAGTACAAAGACGTGGCAAAGCCAGTCATTGAATTATACAAGAGCCGAGGAGTGCTC CACCAATTTTCCGGAACGGAGACGAACAAAATCTGGCCCTACGTTTACACACTTTTCTCAAACAAGATCACACCTATTCAGTCC AAAGAAGCATATTGACCCTGCCCAATGGAAGAACCAGGAAGATGTGGTCATTCATTCAATAGTGTGTGTAGTATTGGTGCTGTG TCCAAATTAGAAGCTAGCTGAGGTAGCTTGCAGCATCTTTTCTAGTTGAAATGGTGAACTGATAGGAAAACAAATGAGTAGAAA GAGTTCATGAAGAGGCCCTCCTCTGCCTTTCAAAAGGCTGGTCACCTACACATGTTTAAGGTGTCTCTGCACATGTCTCAAGCC CATCACAAGAAAGCAAGTACAGTGTGGATTTCAAATGGTGTGTAACTTCAGCTCCAGCTGGTTTTTGACAGCTGTTGCTGTGGT AATATTTTTGACATGTGATGGTGATAGTCTCTGGTTCTCCCCATCCCCACAAAGGCTGTTGAACCACAGCACCAGGAAGCCTGA GAATGAATCCTGAGGGCTCTAGCCCAGGCTTTGTCCCAGGCTTTCTGGTGTGTGCCCTCCTGGTAACAGTGAAATTGAAGCTAC TTACTCATAGTGGTTGTTTCTCTGGTCTTGAGTGACTGTGTCCACAGTTCATTTTTTTCCGGTAGGAATAACTCCTTTTCTACA TCCACGCTCCATAGAGTCTCTCCTTTTCAGACATCCTGGGATGAAAGAATTTGGCT.TTTTTTTTTCTTTTTTTTTTGGACATCT GTTTTCACTCTTAGGCTTTTAAACAATAGTTATTGCTTTTATCCCTCTCAGATTCTAATAACTGAGAGCGATGGGGCTATATTG AATCTCTGTATGCACTGAGAACTGAGCTATGAAGAGAATCTTATTAAACTGCTGGTCTGACTTTATGGATTGACACTGTTCCTT TCTTTTATTGTGAAAAAAAAAAAAAAA
265 MDPNCSCAAGDSCTCAGSCKCKECKCTSC SCCSCCPVGCAKCAQGCICKGASDKCSCCA 266
ATGGATCCCAACTGCTCCTGCGCCGCCGGTGACTCCTGCACCTGCGCCGGCTCCTGCAAATGCAAAGAGTGCAAATGCACCTCC TGCAAGAAAAGCTGCTGCTCCTGCTGCCCTGTGGGCTGTGCCAAGTGTGCCCAGGGCTGCATCTGCAAAGGGGCGTCGGACAAG TGCAGCTGCTGCGCCTGA ■ 267
MRIAVICFC LGITCAIPVKQADSGSSEEKQLYNKYPDAVATWLNPDPSQKQNLLAPQTLPSKSNESHDHMDDMDDEDDDDHVD SQDSIDSNDSDDVDDTDDSHQSDESHHSDESDELVTDFPTD PATEVFTP PTVDTYDGRGDSVVYGLRSKSKKFRRPDIQYP DATDEDITSHMESEELNGAYKAIPVAQDLNAPSDWDSRGKDSYETSQLDDQSAETHSHKQSRLYKRKANDESNEHSD¥IDSQEL SK¥SREFHSHEFHSHEDMLVVDPKSKEEDKHLKFRISHELDSASSEV 268
GCAGAGCACAGCATCGTCGGGACCAGACTCGTCTCAGGCCAGTTGCAGCCTTCTCAGCCAAACGCCGACCAAGGAAAACTCACT ACCATGAGAATTGCAGTGATTTGCTTTTGCCTCCTAGGCATCACCTGTGCCATACCAGTTAAACAGGCTGATTCTGGAAGTTCT GAGGAAAAGCAGCTTTACAACAAATACCCAGATGCTGTGGCCACATGGCTAAACCCTGACCCATCTCAGAAGCAGAATCTCCTA GCCCCACAGACCCTTCCAAGTAAGTCCAACGAAAGCCATGACCACATGGATGATATGGATGATGAAGATGATGATGACCATGTG GACAGCCAGGACTCCATTGACTCGAACGACTCTGATGATGTAGATGACACTGATGATTCTCACCAGTCTGATGAGTCTCACCAT TCTGATGAATCTGATGAACTGGTCACTGATTTTCCCACGGACCTGCCAGCAACCGAAGTTTTCACTCCAGTTGTCCCCACAGTA GACACATATGATGGCCGAGGTGATAGTGTGGTTTATGGACTGAGGTCAAAATCTAAGAAGTTTCGCAGACCTGACATCCAGTAC CCTGATGCTACAGACGAGGACATCACCTCACACATGGAAAGCGAGGAGTTGAATGGTGCATACAAGGCCATCCCCGTTGCCCAG GACCTGAACGCGCCTTCTGATTGGGACAGCCGTGGGAAGGACAGTTATGAAACGAGTCAGCTGGATGACCAGAGTGCTGAAACC CACAGCCACAAGCAGTCCAGATTATATAAGCGGAAAGCCAATGATGAGAGCAATGAGCATTCCGATGTGATTGATAGTCAGGAA CTTTCCAAAGTCAGCCGTGAATTCCACAGCCATGAATTTCACAGCCATGAAGATATGCTGGTTGTAGACCCCAAAAGTAAGGAA GAAGATAAACACCTGAAATTTCGTATTTCTCATGAATTAGATAGTGCATCTTCTGAGGTCAATTAAAAGGAGAAAAAATACAAT TTCTCACTTTGCATTTAGTCAAAAGAAAAAATGCTTTATAGCAAAATGAAAGAGAACATGAAATGCTTCTTTCTCAGTTTATTG GTTGAATGTGTATCTATTTGAGTCTGGAAATAACTAATGTGTTTGATAATTAGTTTAGTTTGTGGCTTCATGGAAACTCCCTGT AAACTAAAAGCTTCAGGGTTATGTCTATGTTCATTCTATAGAAGAAATGCAAACTATCACTGTATTTTAATATTTGTTATTCTC TCATGAATAGAAATTTATGTAGAAGCAAACAAAATACTTTTACCCACTTAAAAAGAGAATATAACATTTTATGTCACTATAATC TTTTGTTTTTTAAGTTAGTGTATATTTTGTTGTGATTATCTTTTTGTGGTGTGAATAAATCTTTTATCTTGAATGTAATAAGAA TTTGGTGGTGTCAATTGCTTATTTGTTTTCCCACGGTTGTCCAGCAATTAATAAAACATAACCTTTTTTACTGCCTAAAAAAAA AAAAAAAAAAAA 269
MWTLVS ¥ALTAGLVAGTRCPDGQFCP¥ACCLDPGGASYSCCRPL DK PTTLSRHLGGPCQVDAHCSAGHSCIFTVSGTSSCC PFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNS¥GAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHG AFCDVHTRCITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQDTV CD IQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQ GTCE QGPHQVPWMEKAPAHLS PDPQALKRDVPCDNVSSCPSSDTCCQ TSGEWGCCPIPEAVCCSDHQHCCPQGYTC¥AEGQCQRGS EIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCVKARSCEKEWSAQP ATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKC RREAPRWDAPLRDPA LRQLL
270 GTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGGACCCTGGTGAGCTGGG TGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAG GAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCΪGGGTGGCCCCTGCCAGGTTG ATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCAT GCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACT CCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGG GGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACA CCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCA GCTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTGCT GCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGT GCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGG TGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGTG AGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCT GGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCT GTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACC ACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGA AGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCT GCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGG CTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCC CTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGG GCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCA GGGGTACCAAGTGTTTGCGCAGGGAGGCCCeGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGAGGGA CAGTACTGAAGACTCTGCAGCCCTCGGGACCCCACTCGGAGGGTGCCCTCTGCTCAGGCCTCCCTAGCACCTCCCCCTAACCAA ATTCTCCCTGGACCCCATTCTGAGCTCCCCATCACCATGGGAGGTGGGGCCTCAATCTAAGGCCTTCCCTGTCAGAAGGGGGTT * GTGGCAAAAGCCACATTACAAGCTGCCATCCCCTCCCCGTTTCAGTGGACCCTGTGGCCAGGTGCTTTTCCCTATCCACAGGGG TGTTTGTGTGTGTGCGCGTGTGCGTTTCAATAAAGTTTGTACACTTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
271
MKHVLNLY LGWLT LSIFVR¥MESLEGLLESPSPGTSWTTRSQ A TEPTKG PDHPSRSM 272
GCACGAGGGCGCTTTTGTCTCCGGTGAGTTTTGTGGCGGGAAGCTTCTGCGCTGGTGCTTAGTAACCGACTTTCCTCCGGACTC CTGCACGACCTGCTCCTACAGCCGGCGATCCACTCCCGGCTGTTCCCCCGGAGGGTCCAGAGGCCTTTCAGAAGGAGAAGGCAG CTCTGTTTCTCTGCAGAGGAGTAGGGTCCTTTCAGCCATGAAGCATGTGTTGAACCTCTACCTGTTAGGTGTGGTACTGACCCT ACTCTCCATCTTCGTTAGAGTGATGGAGTCCCTAGAAGGCTTACTAGAGAGCCCATCGCCTGGGACCTCCTGGACCACCAGAAG CCAACTAGCCAACACAGAGCCCACCAAGGGCCTTCCAGACCATCCATCCAGAAGCATGTGATAAGACCTCCTTCCATACTGGCC ATATTTTGGAACACTGACCTAGACATGTCCAGATGGGAGTCCCATTCCTAGCAGACAAGCTGAGCACCGTTGTAACCAGAGAAC TATTACTAGGCCTTGAAGAACCTGTCTAACTGGATGCTCATTGCCTGGGCAAGGCCTGTTTAGGCCGGTTGCGGTGGCTCATGC CTGTAATCCTAGCACTTTGGGAGGCTGAGGTGGGTGGATCACCTGAGGTCAGGAGTTCGAGACCAGCCTCGCCAACATGGCGAA ACCCCATCTCTACTAAAAATACAAAAGTTAGCTGGGTGTGGTGGCAGAGGCCTGTAATCCCAGTTCCTTGGGAGGCTGAGGCGG GAGAATTGCTTGAACCCGGGGACGGAGGTTGCAGTGAACCGAGATCGCACTGCTGTACCCAGCCTGGGCCACAGTGCAAGACTC CATCTCAAAAAAAAAAAGAAAAGAAAAAGCCTGTTTAATGCACAGGTGTGAGTGGATTGCTTATGGCTATGAGATAGGTTGATC TCGCCCTTACCCCGGGGTCTGGTGTATGCTGTGCTTTCCTCAGCAGTATGGCTCTGACATCTCTTAGATGTCCCAACTTCAGCT GTTGGGAGATGGTGATATTTTCAACCCTACTTCCTAAACATCTGTCTGGGGTTCCTTTAGTCTTGAATGTCTTATGCTCAATTA TTTGGTGTTGAGCCTCTCTTCCACAAGAGCTCCTCCATGTTTGGATAGCAGTTGAAGAGGTTGTGTGGGTGGGCTGTTGGGAGT GAGGATGGAGTGTTCAGTGCCCATTTCTCATTTTACATTTTAAAGTCGTTCCTCCAACATAGTGTGTATTGGTCTGAAGGGGGT GGTGGGATGCCAAAGCCTGCTCAAGTTATGGACATTGTGGCCACCATGTGGCTTAAATGATTTTTTCTAACTAATAAAGTGGAA TATATATTTCAAAAAAAAAAAAAAAAAA
273
MSIEKIWAREILDSRGNPTVEVDLYTAKGLFRAAVPSGASTGIYEALELRDGDKQRYLGKGVL AVDHINSTIAPALISSGLSV VEQEKLDNLMLELDGTENKSKFGAAILGVSLAVCKAGAAERELPLYRHIAQLAGNSDLILPVPAFNVINGGSHAGNKLAMQEF MILPVGAESFRDAMRLGAE¥YHTLKG¥IKDKYGKDAT VGDEGGFAPNILENSEALELVKEAIDKAGYTEKIVIGMDVAASEFY RDGKYDLDFKSPTDPSRYITGDQLGALYQDF¥RDYPVVSIEDPFDQDDWAAWSKFTANVGIQIVGDDLTVTNPKRIERAVEEKA CNCL LKV-.QIGS¥TEAIQACKLAQEKGWGVMVSHRSGETEDTFIADLVVGLCTGQIKTGAPCRSERLAKY QLMRIEEE GDE ARFAGHNFR PSV 274
ACCCGCGCTCGTACGTGCGCCTCCGCCGGCAGCTCCTGACTCATCGGGGGCTCCGGGTCACATGCGCCCGCGCGGCCCTATAGG CGCCTCCTCCGCCCGCCGCCCGGGAGCCGCAGCCGCCGCCGCCACTGCCACTCCCGCTCTCTCAGCGCCGCCGTCGCCACCGCC ACCGCCACCGCCACTACCACCGTCTGAGTCTGCAGTCCCGAGATCCCAGCCATCATGTCCATAGAGAAGATCTGGGCCCGGGAG ATCCTGGACTCCCGCGGGAACCCCACAGTGGAGGTGGATCTCTATACTGCCAAAGGTCTTTTCCGGGCTGCAGTGCCCAGTGGA GCCTCTACGGGCATCTATGAGGCCCTGGAGCTGAGGGATGGAGACAAACAGCGTTACTTAGGCAAAGGTGTCCTGAAGGCAGTG GACCACATCAACTCCACCATCGCGCCAGCCCTCATCAGCTCAGGTCTCTCTGTGGTGGAGCAAGAGAAACTGGACAACCTGATG CTGGAGTTGGATGGGACTGAGAACAAATCCAAGTTTGGGGCCAATGCCATCCTGGGTGTGTCTCTGGCCGTGTGTAAGGCAGGG GCAGCTGAGCGGGAACTGCCCCTGTATCGCCACATTGCTCAGCTGGCCGGGAACTCAGACCTCATCCTGCCTGTGCCGGCCTTC AACGTGATCAATGGTGGCTCTCATGCTGGCAACAAGCTGGCCATGCAGGAGTTCATGATCCTCCCAGTGGGAGCTGAGAGCTTT CGGGATGCCATGCGACTAGGTGCAGAGGTCTACCATACACTCAAGGGAGTCATCAAGGACAAATACGGCAAGGATGCCACCAAT GTGGGGGATGAAGGTGGCTTTGCCCCCAATATCCTGGAGAACAGTGAAGCCTTGGAGCTGGTGAAGGAAGCCATCGACAAGGCT GGCTACACGGAAAAGATCGTTATTGGCATGGATGTTGCTGCCTCAGAGTTTTATCGTGATGGCAAATATGACTTGGACTTCAAG TCTCCCACTGATCCTTCCCGATACATCACTGGGGACCAGCTGGGGGCACTCTACCAGGACTTTGTCAGGGACTATCCTGTGGTC TCCATTGAGGACCCATTTGACCAGGATGATTGGGCTGCCTGGTCCAAGTTCACAGCCAATGTAGGGATCCAGATTGTGGGTGAT GACCTGACAGTGACCAACCCAAAACGTATTGAGCGGGCAGTGGAAGAAAAGGCCTGCAACTGTCTGCTGCTCAAGGTCAACCAG ATCGGCTCGGTCACTGAAGCCATCCAAGCGTGCAAGCTGGCCCAGGAGAATGGCTGGGGGGTCATGGTGAGTCATCGCTCAGGA GAGACTGAGGACACATTCATTGCTGACCTGGTGGTGGGGCTGTGCACAGGCCAGATCAAGACTGGTGCCCCGTGCCGTTCTGAA CGTCTGGCTAAATACAACCAGCTCATGAGAATTGAGGAAGAGCTGGGGGATGAAGCTCGCTTTGCCGGACATAACTTCCGTAAT CCCAGTGTGCTGTGATTCCTCTGCTTGCCTGGAGACGTGGAAGCTCTGTCTCATCCTCCTGGAACCTTGCTGTCCTGATCTGTG ATAGTTCACCCCCTGAGATCCCCTGAGCCCCAGGGTGCCCAGAACTTCCCTGATTGACCTGCTCCGCTGCTCCTTGGCTTACCT GACCTCTTGCTGTCTCTGCTCGCCCTCCTTTCTGTGCCCTACTCATTGGGGTTCCGCACTTTCCACTTCTTCCTTTCTCTTTCT CTCTTCCCTCAGAAACTAGAAATGTGAATGAGGATTATTATAAAAGGGGGTCCGTGGAAGAATGATCAGCATCTGTGATGGGAG CGTCAGGGTTGGTGTGCTGAGGTGTTAGAGAGGGAGCATGTGTCACTTGTGCTTTGCTCTTGTCCCACGTGTCTTCCACTTTGC ATATGAGCCGTGAACTGTGCATAGTGCTGGGATGGAGGGGAGTGTTGGGCATGTGATCACGCCTGGCTAATAAGGCTTTAGTGT ATTTATTTATTTATTTATTTTATTTGTTTTTCATTCATCCCATTAATCATTTCCCCATAACTCAATGGCCTAAAACTGGCCTGA CTTGGGGGAACGATGTGTCTGTATTTCATGTGGCTGTAGATCCCAAGATGACTGGGGTGGGAGGTCTTGCTAGAATGGGAAGGG TCATAGAAAGGGCCTTGACATCAGTTCCTTTGTGTGTACTCACTGAAGCCTGCGTTGGTCCAGAGCGGAGGCTGTGTGCCTGGG GGAGTTTTCCTCTATACATCTCTCCCCAACCCTAGGTTCCCTGTTCTTCCTCCAGCTGCACCAGAGCAACCTCTCACTCCCCAT GCCACGTTCCACAGTTGCCACCACCTCTGTGGCATTGAAATGAGCACCTCCATTAAAGTCTGAATCAGTGC
275
MPLNRT SMSS PG EDWEDEFD ENAVLFE¥AWE¥ANKVGGIYTVLQTKAKVTGDEWGDUYFLVGPYTEQGVRTQVELLEAPT PALKRT DSMNSKGCKVYFGRWLIEGGPLWLLDVGASAA ERKGEL DICNIGVPWYDREA DAVLFGFLTTWF GEFLAQ SEEKPHWAHFHE LAGVGLCLCRARR PVATIFTTHAT LGRY CAGAVDFY LENFNVDKEAGERQIYHRYCMERAAAHCA HVFTTVSQITAIEAQH LKRKPDIVTPNGLNVKKFSAMHEFQNLHAQSKARIQEFVRGHFYGHLDFNLDKTLYFFIAGRYEFSN KGADVF EALARNYLLRWGSEQTWAFFIMPARTMFN¥ETLKGQA¥RKQLWDTATVKEKFGRKLYESI-LVGS PDMNKML DKEDFTMMKRAIFATQRQSFPPVCTHM DDSSDPI TTIRRIGLFNSSADRVKVIFHPEFLSSTSPLLPVDYEEFVRGCHLGV FPSYYEP GYTPAECTVMGIPSISTNLSGFGCFMEEHIADPSAYGIYILDRRFRSLDDSCSQLTSF YSFCQQSRRQRIIQRNR TER SDLLDWKY GRYYMSARHMALSKAFPEHFTYEPNEADAAQGYRYPRPASVPPSPS SRHSSPHQSEDEEDPRNGPLEEDG ERYDEDEEAAKDRRNIRAPEWPRRASCTSSTSGRKRNSVDTATSSSLSTPSEPLSPTSS GEERN
276
CGCTTCGGGCAGGGGTGCGGTCTTGCAATAGGAAGCCGAGCGTCTTGCAAGCTTCCCGTCGGCACCAGCTACTCGGCCCCGCAC CCTACCTGGTGCATTCCCTAGACACCTCCGGGGTCCCTACCTGGAGATCCCCGGAGCCCCCCTTCCTGCGCCAGCCATGCCTTT AAACCGCACTTTGTCCATGTCCTCACTGCCAGGACTGGAGGACTGGGAGGATGAATTCGACCTGGAGAACGCAGTGCTCTTCGA AGTGGCCTGGGAGGTGGCTAACAAGGTGGGTGGCATCTACACGGTGCTGCAGACGAAGGCGAAGGTGACAGGGGACGAATGGGG CGACAACTACTTCCTGGTGGGGCCGTACACGGAGCAGGGCGTCAGGACCCAGGTGGAACTGCTGGAGGCCCCCACCCCGGCCCT GAAGAGGACACTGGATTCCATGAACAGCAAGGGCTGCAAGGTGTATTTCGGGCGCTGGCTGATCGAGGGAGGCCCTCTGGTGGT GCTCCTGGACGTGGGTGCCTCAGCTTGGGCCCTGGAGCGCTGGAAGGGAGAGCTCTGGGATATCTGCAACATCGGAGTGCCGTG GTACGACCGCGAGGCCAACGACGCTGTCCTCTTTGGCTTTCTGACCACCTGGTTCCTGGGTGAGTTCCTGGCACAGAGTGAGGA GAAGCCACATGTGGTTGCTCACTTCCATGAGTGGTTGGCAGGCGTTGGACTCTGCCTGTGTCGTGCCCGGCGACTGCCTGTAGC AACCATCTTCACCACCCATGCCACGCTGCTGGGGCGCTACCTGTGTGCCGGTGCCGTGGACTTCTACAACAACCTGGAGAACTT CAACGTGGACAAGGAAGCAGGGGAGAGGCAGATCTACCACCGATACTGCATGGAAAGGGCGGCAGCCCACTGCGCTCACG CTT CACTACTGTGTCCCAGATCACCGCCATCGAGGCACAGCACTTGCTCAAGAGGAAACCAGATATTGTGACCCCCAATGGGCTGAA TGTGAAGAAGTTTTCTGCCATGCATGAGTTCCAGAACCTCCATGCTCAGAGCAAGGCTCGAATCCAGGAGTTTGTGCGGGGCCA TTTTTATGGGCATCTGGACTTCAACTTGGACAAGACCTTATACTTCTTTATCGCCGGCCGCTATGAGTTCTCCAACAAGGGTGC TGACGTCTTTCTGGAGGCATTGGCTCGGCTCAACTATCTGCTCAGAGTGAACGGCAGCGAGCAGACAGTGGTTGCCTTCTTCAT CATGCCAGCGCGGACCAACAATTTCAACGTGGAAACCCTCAAAGGCCAAGCTGTGCGCAAACAGCTTTGGGACACGGCCAACAC GGTGAAGGAAAAGTTCGGGAGGAAGCTTTATGAATCCTTACTGGTTGGGAGCCTTCCCGACATGAACAAGATGCTGGATAAGGA AGACTTCACTATGATGAAGAGAGCCATCTTTGCAACGCAGCGGCAGTCTTTCCCCCCTGTGTGCACCCACAATATGCTGGATGA CTCCTCAGACCCCATCCTGACCACCATCCGCCGAATCGGCCTCTTCAATAGCAGTGCCGACAGGGTGAAGGTGATTTTCCACCC GGAGTTCCTCTCCTCCACAAGCCCCCTGCTCCCTGTGGACTATGAGGAGTTTGTCCGTGGCTGTCACCTTGGAGTCTTCCCCTC CTACTATGAGCCTTGGGGCTACACACCGGCTGAGTGCACGGTTATGGGAATCCCCAGTATCTCCACCAATCTCTCCGGCTTCGG CTGCTTCATGGAGGAACACATCGCAGACCCCTCAGCTTACGGTATCTACATTCTTGACCGGCGGTTCGGCAGCCTGGATGATTC CTGCTCGCAGCTCACCTCCTTCCTCTACAGTTTCTGTCAGCAGAGCCGGCGGCAGCGTATCATCCAGCGGAACCGCACGGAGCG CCTCTCCGACCTTCTGGACTGGAAATACCTAGGCCGGTACTATATGTCTGCGCGCCACATGGCGCTGTCCAAGGCCTTTCCAGA GCACTTCACCTACGAGCCCAACGAGGCGGATGCGGCCCAGGGGTACCGCTACCCACGGCCAGCCTCGGTGCCACCGTCGCCCTC GCTGTCACGACACTCCAGCCCGCACCAGAGTGAGGACGAGGAGGATCCCCGGAACGGGCCGCTGGAGGAAGACGGCGAGCGCTA CGATGAGGACGAGGAGGCCGCCAAGGACCGGCGCAACATCCGTGCACCAGAGTGGCCGCGCCGAGCGTCCTGCACCTCCTCCAC CAGCGGCCGCAAGCGCAACTCTGTGGACACGGCCACCTCCAGCTCACTCAGCACCCCGAGCGAGCCCCTCAGCCCCACCAGCTC CCTGGGCGAGGAGCGTAACTAAGTCCGCCCCACCACACTCCCCGCCTGTCCTGCCTCTCTGCTCCAGAGAGAGGATGCAGAGGG GTGCTGCTCCTAAACCCCCGATCCAGATCTGCACGGGGTGCGGCCCCGCAGTGCCCCCACCCAGTCCGCCAAACACTCCACCCC CTCCAGCTCCAGTTTCCAAGTTCCTGCACTCCTGAATCCACAAAGCCGTGCCTTTCTCTGGCTCCAGAATATGCATAATCAGCG CCCTGGAGTCCCCTGGGCCTGGACCGCTTCCCAGAGGCCAGGAAATCTGCCATTACTCTGCGGTGGTGCCAGAGGTTTTAGGAA ACCTGGCATGGTGCTTTCAGGTCTGGGGCTTTTAGAGCCCCCCGTGTGGCTTACAAATTCTACAGCATACAGAGCAGGCCACGC TCAGGCCCGGCATGCGGGCCACCAAGTTCTGGAAACCACGTGGTGTCCCTGCGAATGGGGCGATCAAGTCCAGAGCCGGGGCAC TTTCAGAGTTTGAAGGTAACTGAGAGCAGATGGTCCTCCATTTCAACTCCAGAAGTGGGGCTCTGGGAGGGATGTTCTAGCCCT CCCTGGCTGTCAGAGCCAGGCTCTGCCTGGAGGATCCCTCCATCCGGCTCCTGTCATCCCCTACACTTTGGCCAAGCAAGAGGT GGTAGAACCACTTGGCTGCTCATTCCTTCTGGAGGACACACAGTCTCAGTCCAGATGCCTTCCTGTCTTTCTGGTCCTTTCTGG ACCAGATCCTACTCTTCCTTTCTAAATCTGAGATCTCCCTCCAGGGAATCCGCCTGCAGAGGACAGAGCTGGCTGTCTTCCCCC ACCCCTAACCTGGCTTATTCCCAACTGCTCTGCCCACTGTGAAACCACTAGGTTCTAGGTCCTGGCTTCTAGATCTGGAACCTT ACCACGTTACTGCATACTGATCCCTTTCCCATGATCCAGAACTGAGGTCACTGGGTTCTAGAACCCCCACATTTACCTCGAGGC TCTTCCATCCCCAAACTGTGCCCTGCCTTCAGCTTTGGTGAAAGGGAGGGCCCCTCATGTGTGCTGTGCTGTGTCTGCACCGCT TGGTTTGCAGTTGAGAGGGGAGGGCAGGAGGGGTGTGATTGGAGTGTGTCCGGAGATGAGATGAAAAAAATACATCTATATTTA AGA
277
MESKGASSCRLFCLLISATVFRPGLG YTV SAYGDTIIIPCRLDVPQNMFGKWKYEKPDGSPVFIAFRSSTKKSVQYDDVP EYKDRNLSENYT SISNARISDEKRFVC LVTED VFEAPTIVKVFKQPSKPEIVSKA F ETEQL KLGDGISEDSYPDGN1 TWYRNGVLHPLEGAWIIFKKEMDPVTQ YTMTSTLEYKTTKADIQMPFTCSVTYYGPSGQKTIHSEQAVFDIYYPTEQVTIQ •V PPKNAIKEGDNITLKCLGNGNPPPEEFLFY PGQPEGIRSSNTYTL DVRRNATGDYKCS IDKKSMIASTAITVHYLDLSL • NPSGE¥TRQIGDALPVSCTISASRATVVMKDNIRLRSSPSFSSLHYQDAGNYVCETALQEVEGLKKRES TLIVEGKPQIKM TKKTDPSGLSKTIICHVEGFPKPAIQ TITGSGSVINQTEESPYINGRYYSKIIISPEENVTLTCTAENQ ERTVWSLNVSAIS IPEHDEADEISDENREKWDQAKLIVGIWG LL LVAGVVY LYMKKSKTASKHV DLGMEENKK EENNHKTEA
278 CGGGACGACGCCCCCTCCTGCGGCGTGGACTCCGTCAGTGGCCCACCAAGAAGGAGGAGGAATATGGAATCCAAGGGGGCCAGT TCCTGCCGTCTGCTCTTCTGCCTCTTGATCTCCGCCACCGTCTTCAGGCCAGGCCTTGGATGGTATACTGTAAATTCAGCATAT GGAGATACCATTATCATACCTTGCCGACTTGACGTACCTCAGAATCTCATGTTTGGCAAATGGAAATATGAAAAGCCCGA'TGGC TCCCCAGTATTTATTGCCTTCAGATCCTCTACAAAGAAAAGTGTGCAGTACGACGATGTACCAGAATACAAAGACAGATTGAAC CTCTCAGAAAACTACACTTTGTCTATCAGTAATGCAAGGATCAGTGATGAAAAGAGATTTGTGTGCATGCTAGTAACTGAGGAC AACGTGTTTGAGGCACCTACAATAGTCAAGGTGTTCAAGCAACCATCTAAACCTGAAATTGTAAGCAAAGCACTGTTTCTCGAA ACAGAGCAGCTAAAAAAGTTGGGTGACTGCATTTCAGAAGACAGTTATCCAGATGGCAATATCACATGGTACAGGAATGGAAAA GTGCTACATCCCCTTGAAGGAGCGGTGGTCATAATTTTTAAAAAGGAAATGGACCCAGTGACTCAGCTCTATACCATGACTTCC ACCCTGGAGTACAAGACAACCAAGGCTGACATACAAATGCCATTCACCTGCTCGGTGACATATTATGGACCATCTGGCCAGAAA ACAATTCATTCTGAACAGGCAGTATTTGATATTTACTATCCTACAGAGCAGGTGACAATACAAGTGCTGCCACCAAAAAATGCC ATCAAAGAAGGGGATAACATCACTCTTAAATGCTTAGGGAATGGCAACCCTCCCCCAGAGGAATTTTTGTTTTACTTACCAGGA CAGCCCGAAGGAATAAGAAGCTCAAATACTTACACACTGATGGATGTGAGGCGCAATGCAACAGGAGACTACAAGTGTTCCCTG ATAGACAAAAAAAGCATGATTGCTTCAACAGCCATCACAGTTCACTATTTGGATTTGTCCTTAAACCCAAGTGGAGAAGTGACT AGACAGATTGGTGATGCCCTACCCGTGTCATGCACAATATCTGCTAGCAGGAATGCAACTGTGGTATGGATGAAAGATAACATC AGGCTTCGATCTAGCCCGTCATTTTCTAGTCTTCATTATCAGGATGCTGGAAAC.TATGTCTGCGAAAC.TGCTCTGCAGGAGGTT GAAGGACTAAAGAAAAGAGAGTCATTGACTCTCATTGTAGAAGGCAAACCTCAAATAAAAATGACAAAGAAAACTGATCCCAGT GGACTATCTAAAACAATAATCTGCCATGTGGAAGGTTTTCCAAAGCCAGCCATTCAGTGGACAATTACTGGCAGTGGAAGCGTC ATAAACCAAACAGAGGAATCTCCTTATATTAATGGCAGGTATTATAGTAAAATTATCATTTCCCCTGAAGAGAATGTTACATTA ACTTGCACAGCAGAAAACCAACTGGAGAGAACAGTAAACTCCTTGAATGTCTCTGCTATAAGTATTCCAGAACACGATGAGGCA GACGAGATAAGTGATGAAAACAGAGAAAAGGTGAATGACCAGGCAAAACTAATTGTGGGAATCGTTGTTGGTCTCCTCCTTGCT GCCCTTGTTGCTGGTGTCGTCTACTGGCTGTACATGAAGAAGTCAAAGACTGCATCAAAACATGTAAACAAGGACCTCGGTAAT ATGGAAGAAAACAAAAAGTTAGAAGAAAACAATCACAAAACTGAAGCCTAAGAGAGAAACTGTCCTAGTTGTCCAGAGATAAAA ATCATATAGACCAATTGAAGCATGAACGTGGATTGTATTTAAGACATAAACAAAGACATTGACAGCAATTCATGGTTCAAGTAT TAAGCAGTTCATTCTACCAAGCTGTCACAGGTTTTCAGAGAATTATCTCAAGTAAAACAAATGAAATTTAATTAGAAACAATAA GAACAAGTTTTGGCAGCCATGATAATAGGTCATATGTTGTGT.TTGGTTCAATTTTTTTTCCGTAAATGTCTGCACTGAGGATTT CTTTTTGGTTTGCCTTTTATGTAAATTTTTTACGTAGCTATTTTTATACACTGTAAGCTTTGTTCTGGGAGTTGCTGTTAATCT GATGTATAATGTAATGTTTTTATTTCAATTGTTTATATGGATAATCTGAGCAGGTACATTTCTGATTCTGATTGCTATCAGCAA TGCCCCAAACTTTCTCATAAGCACCTAAAACCCAAAGGTGGCAGCTTGTGAAGATTGGGGACACTCATATTGCCCTAATTAAAA ACTGTGATTTTTATCACAAGGGAGGGGAGGCCGAGAGTCAGACTGATAGACACCATAGGAGCCGACTCTTTGATATGCCACCAG CGAACTCTCAGAAATAAATCACAGATGCATATAGACAGACATACATAATGGTACTCCCAAACTGACAATTTTACCTATTCTGAA AAAGACATAAAACAGAATT
279
MER¥KMINVQRLLEAAEFLERRERECEHGYASSFPS PSPRLQHSKPPRRLSRAQKHSSGTSNTSTARSTHNELEKNRRAHLR LC ER KVLIP GPDCTRHTTLG LNKAKAHIKKLEEAERKSQHQLENLEREQRF KWR EQLQGPQEMERIRMDSIGSTISSD RSDSEREEIEVDVESTEFSHGEVDNISTTSISDIDDHSSLPSIGSDEGYSSASVKLSFTS 280
AGATTATGATCGCCTGAGGCCCCTCTCCTACCCAGATACCGATGTTATACTGATGTGTTTTTCCTTTTTTTTTTTTTTTTTTTA AGTAATTAAGGGTAGTTAAATTATTTAAAGTATACAAAGTCCAAACAGCCAGGGGTAAGGTCTCCAAGAGGCCTTCCCAGGGTA AGGGAGTGCGGAGAGGCCCCGGTCGCCACCCGCGGTGCCCATGGAGCGGGTGAAGATGATCAACGTGCAGCGTCTGCTGGAGGC TGCCGAGTTTTTGGAGCGCCGGGAGCGAGAGTGTGAACATGGCTACGCCTCTTCATTCCCGTCCATGCCGAGCCCCCGACTGCA GCATTCAAAGCCCCCACGGAGGTTGAGCCGGGCACAGAAACACAGCAGCGGGACGAGCAACACCAGCACTGCCAACAGATCTAC ACACAATGAGCTGGAAAAGAATCGACGAGCTCATCTGCGCCTTTGTTTAGAACGCTTAAAAGTTCTGATTCCACTAGGACCAGA CTGCACCCGGCACACAACACTTGGTTTGCTGAACAAAGCCAAAGCACACATCAAGAAACTTGAAGAAGCTGAAAGAAAAAGCCA GCACCAGCTCGAGAATTTGGAACGAGAACAGAGATTTTTAAAGTGGCGACTGGAACAGCTGCAGGGTCCTCAGGAGATGGAACG AATACGAATGGACAGCATTGGATCAACTATTTCTTCAGATCGTTCTGATTCAGAGCGAGAGGAGATTGAAGTGGATGTTGAAAG. CACAGAGTTCTCCCATGGAGAAGTGGACAATATAAGTACCACCAGCATCAGTGACATTGATGACCACAGCAGCCTGCCGAGTAT TGGGAGTGACGAGGGTTACTCCAGTGCCAGTGTCAAACTTTCATTCACTTCATAGAACCCAGCATGACATAACAGTGCAGGGCA AAATATTCACTGGGCCAATTCAATACAAACAATCTCTTAAATTGGGTTCATGATGCAGTCTCCTCTTTAAAACAAAACAAAACA AAACAAAACTATACTTGAACAAAAGGGTCAGAGGACCTGTATTTAAGCAAATACTTAGCAAAAAGTGGGGCAGAGCTCCCAAGG AGAACAAATATTCAGAATATTCATATTGGAAAAATCACAATTTTTAATGGCAGCAGAAAACTTGTGTGAAATTTTCTTGATTTG AGTTGATTGAGAAGAGGACATTGGAGATGCCATCCTCTTTCTCTTTTCTCGTTTGCTCATACTACATTGAGTAGACACATTTAA GGATGGGGTTATGAACCCTTCCTGAGCTTTATGGTCCTAAAAGCAAAATAAAAACTATTCGAATGAAAAGACAAGAAAATCAGG TATTAATCTTGGATAGCTAATAATGAGCTATTAAAACTCAGCCTGGGACAGTTTATCATGAAGCCTGTGGATGATCAATCCTTT ATTATTATTTTTTTTTTTTGAAAAAAGCTCATTTCATGCTCTGCAAAAGGAGAGACTCCCATGAAGCCTTTTGAAAGGGATCAT
Figure imgf000352_0001
Αnn mπnm n*mm mm7s. nτs π 7.nnn n τy.n rπ π τi rι CAGCACTTGTCTCATTTTAATGTAAAGATTTGCTTCCATTTTCCTACAGGCAGTCTCTCTCTTCCTCACAGTCCCACTGTGCAG GTGCTATTGTTACTCTTACGAATATTTTCAGTAATGTTATTTTCTTCTAAGTGAAATTTCTAGCCTGCACTTTGATGTCATGTG TTCCCTTTGTCTTTCAAACTCCAAGGTTCCCCTGTGGC.CCTCTCCCTTACCCTGGGAAGGCCTCTTGGAGACCTTACCCCTGGC TGTTTGGACTTTGTATACTTTAAATAATTTAACTACCCTTAATTACTTAAAAAAAAAAAAAAAA 282
ATCGCAACCTGGGCCTCAGGATGCTGCTGCAGTGATGGCGCCAACCCGTGGCAGTCCCAGAGCTGGAGGCAGGAGGATGGATCC TCATCTCCATGGGAAGTGTCAGCGTGTGGCTGCCAGGGAAGCGTGGCAGGCGCCTGGCCTTGGGTCCATCTACATAGTTGCGTG TTTCAACAATGTCCATTTATCCTTCACCCCGAGGCGTGTTTTGGGGGCTGCAAACACCTCCCGGTAGAGGCTGGACCTGAGGAC CCTTCCCACCTGTGCCCGTCCCTTCCTGAAGTCCTAGCCACAGCCCATCCTCCATGAGTCCCGGCAGCTCTGGGTCATGCCCTT CCCTGGTCACCCATCTGCCCCTCACCTCGTCATCCAGGGACCCAGACCCTGCACCTTCCATGTGGGCCCACAGATCCTTGGCAG GTACCTGAGGTGCACCATTGAGTGTCGGATTTGGGGTTAGCATCCAGAAAGAAGAATGCGCATGACGCTCTGTGAAGGCTGGAA CTCAGGTCTTCAGGGAGAGAAAGGAAGACTGGATTGCACCTTGATGCCTCCTGAGGAGGCGGCCCCCCTCTTGAGGTGGGCGTG GGCCCGGCCCAGCCTTATCCAAGTCGCTCTGTCCACCTCCCCCTTCCTGGCCCCCACCCCACTCCTGTGCCTCCCAGGAGCCCT CCCTGTGCTCCACCTGCCTCCGCAGAAGGAAGCCTCTTTCTCTGTTTCCCTGGGTGAGGGGGCTGGCAGGTGGCTAACCCCATT TAGCATCTCCAGGCCCTGCCATGGTGTCTCATCTTGCTGTTATCTCTAGCTCTTTCCCTCCTCCCATTTCCTTTAGTAGTTGAA TTTTGCAAAGCTTGTAGCAGTAGCTCAGTTGCCTGCAGCATCCTTGTGTGTAGATAAATTAGTCGACAGAAACTCAGCACTGGG GACAGGATTGCAAAGTCGGGGACATAGATGCAGACAGTTGTTGAGATTTGGGGATAGCCGGGCTTGTGAGCGGTGCCCATTTCC AGATGAAGCCTTTCAGCCCTTGTGAGTCCCCGGCCCTTGGTGCGATGTCTGTGAGTTTGACCTGCCCAGCGTGTGGGCTGGCTC AATGCTGAATAAAGTGGGTTTGTGTCAAAAAAAAAAAAAAAAAAAAAAAAAA 283
MDQKSLWAGVWLLL QGGSAYKLVCYFT WSQDRQEPGKFTPENIDPFLCSHLIYSFASIE NKVIIKDKSEVMLYQTINSLK TKNPKLKI LSIGGYLFGSKGFHPM¥DSSTSRLEFINSIILF RNHNFDGLDVSWIYPDQKENTHFTVLIHELAEAFQKDFTKS TKERL LTAGVSAGRQMIDNSYQVEKLAKDLDFIN LSFDFHGSWEKPLITGHNSPLSKGWQDRGPSSYYNVEYAVGYWIHKGM PSEK¥VMGIPTYGHSFTLASAETTVGAPASGPGAAGPITESSGF AYYEICQFLKGAKITRLQDQQVPYAVKGNQWVGYDDVKS METK¥QFLKNLNLGGAMIWSIDMDDFTGKSCNQGPYP VQAVKRSLGSL
284
AGAAGAAGCTGGCCAAGGATATGGGAGCAACCACCATGGACCAGAAGTCTCTCTGGGCAGGTGTAGTGGTCTTGCTGCTTCTCC AGGGAGGATCTGCCTACAAACTGGTTTGCTACTTTACCAACTGGTCCCAGGACCGGCAGGAACCAGGAAAATTCACCCCTGAGA ATATTGACCCCTTCCTATGCTCTCATCTCATCTATTCATTCGCCAGCATCGAAAACAACAAGGTTATCATCAAGGACAAGAGTG AAGTGATGCTCTACCAGACCATCAACAGTCTCAAAACCAAGAATCCCAAACTGAAAATTCTCTTGTCCATTGGAGGGTACCTGT TTGGTTCCAAAGGGTTCCACCCTATGGTGGATTCTTCTACATCACGCTTGGAATTCATTAACTCCATAATCCTGTTTCTGAGGA ACCATAACTTTGATGGACTGGATGTAAGCTGGATCTACCCAGATCAGAAAGAAAACACTCATTTCACTGTGCTGATTCATGAGT TAGCAGAAGCCTTTCAGAAGGACTTCACAAAATCCACCAAGGAAAGGCTTCTCTTGACTGCGGGCGTATCTGCAGGGAGC3CAAA TGATTGATAACAGCTATCAAGTTGAGAAACTGGCAAAAGATCTGGATTTCATCAACCTCCTGTCCTTTGACTTCCATGGGTCTT GGGAAAAGCCCCTTATCACTGGCCACAACAGCCCTCTGAGCAAGGGGTGGCAGGACAGAGGGCCAAGCTCCTACTACAATGTGG AATATGCTGTGGGGTACTGGATACATAAGGGAATGCCATCAGAGAAGGTGGTCATGGGCATCCCCACATATGGGCACTCGTTCA CACTGGCCTCTGCAGAAACCACCGTGGGGGCCCCTGCCTCTGGCCCTGGAGCTGCTGGACCCATCACAGAGTCTTCAGGCTTCC TGGCCTATTATGAGATCTGCCAGTTCCTGAAAGGAGCCAAGATCACGCGCCTCCAGGATCAGCAGGTTCCCTACGCAGTCAAGG GGAACCAGTGGGTGGGCTATGATGATGTGAAGAGTATGGAGACCAAGGTTCAGTTCTTAAAGAATTTAAACCTGGGAGGAGCCA TGATCTGGTCTATTGACATGGATGACTTCACTGGCAAATCCTGCAACCAGGGCCCTTACCCTCTTGTCCAAGCAGTCAAGAGAA GCCTTGGCTCCTTGTGAAGGATTAACTTACAGAGAAGCAGGCAAGATGACCTTGCTGCCTGGGGCCTGCTCTCTCCCAGGAATT CTCATGTGGGATTCCCCTTGCCAGGCTGGCCTTTGGATCTCTCTTCCAAGCCTTTCCTGACTTCCTCTTAGATCATAGATTGGA CCTGGTTTTGTTTTCCTGCAGCTGTTGACTTGTTGCCCTGAAGTACAATAAAAAAAATTCATTTTGCTCCAGTA
285 MS SENSVFAYESSVHSTVLLSLNDQRKKDVLCDVTIFVEGQRFRAHRSVLAACSSYFHSRIVGQADGE NITLPEEVTVKGF EPLIQFAYTAKLILSKENVDEVCKCVEFLSVHNIEESCFQFLKFKFLDSTADQQECPRKKCFSSHCQKTDLK SLLDQRD ETD- EVEEF ENK VQTPQCKLRRYQGNAKASPPLQDSASQTYES CLEKDAALALPSLCPKYRKFQKAFGTDRVRTGESSVKDIHAS VQPNERSENECLGGVPECRDLQVMLKCDESKLAMEPEETKKDPASQCPTE SEVTPFPHNSSIDPHGLYS SLLHTYDQYGDLN FAGMQNTTVTEKP SGTDVQEKTFGESQDLP KSDLGTREDSS¥ASSDRSSVEREVAEHAKGFWSDICSTDTPCQMQLSPAV AKDGSEQ1SQKRSECPWLGIRISESPEPGQRTFTTLSSWCPFIST--STEGCSSNLEIGNDDYVSEPQQEPCPYACVIS GDDS ETDTEGDSESCSAREQECEVKLPFNAQRIISLSR DFQSLLKMHKLTPEQLDCIHDIRRRSKNRIAAQRCRKRKLDCIQNESE IEKLQSEKESL KERDHILSTLGETKQNLTGLCQKVCKEAALSQEQIQILAKYSAADCPLSFLISE DKSTPDGE ALPSIFSL SDRPPAVLPPCARGNSEPGYARGQESQQMSTATSEQAGPAEQCRQSGGISDFCQQMTDKCTTDE
286
TCGCCCCCGCCGGGCGCTCTCGCTTCAGTCAGTCGGGCCGCGCCGCGCCTCAGCTCTGGTTGATGATAATTAGAAGCATGCTTT CCACTGAACTTCCCGACAACATTTGTTATGCAGAATGTCTCTGAGTGAGAACTCGGTTTTTGCCTATGAATCTTCTGTGCATAG CACCAATGTTTTACTCAGCCTTAATGACCAGCGGAAGAAAGATGTGCTGTGCGATGTCACCATCTTTGTGGAGGGACAGCGGTT CCGCGCTCACCGGTCCGTGCTGGCGGCATGCAGCAGTTACTTCCACTCAAGAATCGTAGGCCAGGCTGATGGAGAGCTGAACAT TACTCTTCCAGAAGAGGTGACAGTTAAAGGATTTGAACCTTTAATTCAGTTTGCCTACACTGCTAAACTGATTTTAAGTAAAGA GAATGTGGATGAAGTGTGCAAATGTGTGGAGTTTTTAAGTGTACATAATATTGAGGAATCCTGCTTTCAGTTTCTGAAATTTAA GTTTTTGGACTCCACTGCAGACCAGCAAGAATGCCCAAGAAAAAAATGCTTTTCATCACACTGTCAGAAAACAGACCTTAAACT TTCACTTTTGGACCAGAGGGATCTAGAAACTGATGAAGTGGAGGAATTTCTGGAAAATAAAAATGTTCAGACTCCTCAGTGTAA ACTCCGCAGGTATCAAGGAAATGCAAAAGCCTCACCTCCTCTACAAGACAGTGCCAGTCAGACATATGAGTCCATGTGCTTAGA GAAGGATGCTGCTCTGGCCTTGCCTTCTTTATGCCCCAAATACAGAAAATTCCAAAAAGCATTTGGAACTGACAGAGTCCGTAC TGGGGAATCTAGTGTCAAAGACATTCATGCTTCTGTTCAGCCAAATGAAAGGTCTGAAAATGAATGCCTGGGAGGAGTCCCGGA GTGTAGAGATTTGCAGGTGATGTTAAAATGTGACGAAAGTAAATTAGCAATGGAACCTGAAGAAACGAAGAAAGATCCTGCTTC TCAGTGCCCAACTGAAAAATCAGAAGTGACTCCTTTCCCCCACAATTCTTCCATAGACCCTCATGGACTTTATTCTTTGTCTCT TTTACACACATATGACCAATATGGTGACTTGAATTTTGCTGGTATGCAAAACACAACAGTGTTAACAGAAAAGCCTTTGTCAGG TACAGACGTCCAAGAAAAAACATTTGGTGAAAGTCAGGATTTACCTTTGAAATCCGACTTGGGCACCAGGGAAGATAGTAGTGT TGCATCTAGTGATAGGAGTAGTGTGGAGCGAGAAGTGGCAGAACACCTAGCAAAAGGCTTCTGGAGTGACATTTGCAGCACGGA CACTCCTTGCCAAATGCAGTTATCACCTGCTGTGGCCAAAGATGGCTCAGAACAGATCTCACAGAAACGGTCTGAGTGTCCGTG GTTAGGTATCAGGATTAGTGAGAGCCCAGAACCAGGTCAAAGGACTTTCACAACATTAAGTTCTGTCAACTGCCCTTTTATAAG TACTCTGAGTACTGAAGGCTGTTCAAGCAATTTGGAAATTGGAAACGATGATTATGTTTCAGAACCCCAGCAAGAACCTTGCCC ATATGCTTGTGTCATTAGCTTGGGAGACGACTCTGAGACGGACACCGAAGGAGACAGTGAATCCTGTTCAGCCAGAGAACAAGA ATGTGAGGTAAAACTGCCATTCAATGCACAACGGATAATTTCACTGTCTCGAAATGATTTTCAGTCCTTGTTGAAAATGCACAA GCTTACTCCAGAACAGCTGGATTGTATCCATGATATTCGAAGAAGAAGTAAAAACAGAATTGCTGCACAGCGCTGTCGCAAGAG AAAACTTGACTGTATACAGAATCTTGAATCAGAAATTGAGAAGCTGCAAAGTGAAAAGGAGAGCTTGTTGAAGGAAAGAGATCA CATTTTGTCAACTCTGGGCGAGACAAAGCAGAACCTAACTGGACTTTGCCAGAAAGTTTGTAAAGAAGCAGCTCTGAGTCAAGA ACAAATACAGATACTCGCCAAGTACTCAGCTGCAGATTGCCCACTTTCATTTTTAATTTCTGAAAAAGATAAAAGTACTCCTGA TGGTGAACTGGCGTTACCATCAATTTTCAGTTTATCTGACCGGCCTCCAGCAGTGCTGCCTCCCTGTGCCAGAGGAAACAGTGA GCCTGGCTACGCGCGAGGGCAGGAGTCCCAGCAGATGTCCACAGCCACCTCTGAGCAAGCTGGGCCTGCGGAACAGTGTCGTCA GAGTGGTGGGATCTCAGATTTCTGTCAGCAGATGACTGATAAATGTACTACTGATGAGTAAACTTGCATTCACTTCCTTCAAAC CATCTAATTTTCTCCTGAAGTTTTGGCAGCGTCTTGAAAGCCTAATATGACCATCTGTTGCTCAACAATACTGTTTTTTTCCTT
TAGTAGTTTACCACAAGGGAATTTCCTTTAAGTCAACCATGATTTCTCCTTGATTTCTACAAGAGACAAAGAAATGATTTTGCC
■ TCCTGGATATCAGAAAAATCCATGTGAAAATGTAGTAAACCTTTAAAACTCATGTTTTAAAGAATAATAACTCTAGTAATAACT
CTTCCTGCTATTCAGAATAAGTAGGAGAATGAAAACTGCAGCATATCAGACAGCAATTTAACAGCTTGAAACATCTACAGATAG
TTCCTAGTAAAAGAAGTGGCCTGCAGAAGTTTAATAATTTGACTTTTTTCTAATATTTTAGTTTGAAAGAAAATTTCTTCCCAA GCAATGCTAATAGAGTTCTATTCTTAGAAGCAGGGTGTCAGCTACTGGGAATATTTTTGTAGAGCTGCATTGTGAAAAAAAGAT GGTCTTACCTGAATCTTAGGGCTTTGTTCTTCGGCTCCTAAAATCAGGCTTTAAGCTACATTGGGAAGATTTAGTAAATAGGCA AGTGGTTGGCCTAAGACGGGGGCTGCTTCTCCTCTTCAGTATGGACTCTAGAAAGTCTGGCTACATGAATAGATTTAAGTGTCA CTTTCCCTCCCTGCCCCCCGCTTCAGTCTCTACCATATCTGGTCCCATCATGGACTTCCTATTTCCTGGCATTTTTGTCCCTTT GGAAGAAGAAATAGGACTCAGAATACAGTGGCATGAGTGATTACACTGGCAGCATTATCTCAGGCTCCCTAGAATCTGGAGAGC TTACCAACATGTAAAGCTGTTCATTTTTCCACCGTGGGTCACCAATGCCAGAAAACCAGACATCACGGGGAAAGAATGTTGCTT ACTTTTTACCAGGAGTGCAGTTCATTTTTTTCACCCTGTTTTTGAAGTCGTATTATTCACTTGTAAAAATGATTGTAACAGATA AAAAATGTATCTGCAGCAACTCTGCAGGTTTGTGAAATAGGATGAAACTCAATCTTTTTCTATTGTGGGTTTGCATTTGAAAAG CAGGTTGAATCCTTGCTCTCTTCTCCAAATTTGGTGTGGTATAAAGACACACAAA CATTTTAACTTGGACATTTAAAGATCAG TCTTAGTGTTTGTTCAGTCCTGTTACAAAATAGATAACTGAGCACCTATCGCATAACATTTTGCGGTGGCTTTTAGCCATGCTG GGGTTAGATGTGTTTGAGAGTCAAATGAAAGCTATGGATCTTCTCAGCAATTAAAAAAAATGCATATATTCACATTCACAGAAA CATTGGCAGAACCCAGTTTTAATGGTACAGAGGAGTAGTTTATAGTGTTGATTTCACCAAAATCAGAGGGCTGAAAGAGACACT TCTATAGACTGCATCCTGAGCCTAGTGCAGGGCTTGTCTAGCTAATGTGGGCAGCCACCACCCACTGTGTATGAACAAGTCTGA AGCAAGTTGGCCTTGCCCTTGAGAGTATATGGGGACCAGTCTTCATGTCTTGGAGTAATTTGTCAAATGTTACCCTTTTTGATC AGGGTGTAGGGGGAGGATATTGCTAGTATATTTTCAGTGGTTTGTATGTTCTCTCTGTCACTGACTTATTTGTAAGAGAAAATT AGTTGGACTTGTTTATTTTCTAGTAGCTTTTATAAGTACACTCAAGAATTTGTCAGGGAGAATAATTCTGATAGTGCATCCCAT ACTGCAAAAGAATTTGTGTGTGTGTGTGTGTGTGTGTGTGTGTATGTGTATGTATACATATATATCTCTCCATATAGGTATTTC TTTGATACTTGTAATTTTAAATTTCAGCTTCACGATATAAAATAATATAAGAACTTCTGGTTTACAAAATGTAAAATCTTAAGC CAATGGAACCCTTGATTTCCTACCTCAGTGTACACTCAACTATTGGTTGTATCAGTTTGTGTATGTGCAAATGTCAAATAATCT TTTGCTTTAATTGCTACTGTACTTGCTTTGAAAGATTACCTACTATTTTATGATAAAATGTAGTTGTCTCCAGAGCTTAAATAT AATTTGTAAAGCACTTGGTTTAAATTTCTCTCTACCTATAAACAGTTTAGCATTAAGGGTTTCTATTAATGACACAGAATTATT GGCCAAGTGTAATTTCTTAAAATTTAGCATTACTTTAAATAGCCAGCATGTAATACAAGTAACTACACTACCTCATATCTACAT GATTTTCAAGTTGTAATGCAGATGGACAGATAAAAAAGATTTTACGTTTGTCTTTTGGCCATAAGTGGGAAAGTTTTCTGTATA TTGCATAGCATTACACATTTATGCCTATTTTAACATTAACTTCTAAAGAAGTTTTTTCTAAGAAAATGTTTCAAGGCAATATTT TTTTTGAGGCTGCCGAAGACAAATGACAGGATTATGAGTATACAGTGTATGCCTTTTCCTTCATGCAGAATTTTGAAATGTTTT CAGTTTGTATATTGCATATTCACATGATCATTGCTCACTATTTTATGAACTGGCCTTCTCAATGTTTGATGATTTTTTAAAAGC TGTTATGTTGAATTCAGTAAAATAACATTACCTTATTTTTTTTCTTATTCAAATTCTGGAACTATAGCAAATAATTCGTTAAAT TGTCATATTCAAAACAAATGTGGATACAGTCTTGGTTCTCCATCTGTAATTTTTTTTAACAGTTTGCTATAGCTTACTGCTTAA CTAATTTTAAATAAGGAAATAAGTATGTTAGAα'GCAGTAGACGATACAGGTTGCATGTGGACACTCAGTCACATTAACAACTTG GGAAAAAAATGGCAATGTTACGGTGAATTCTCAGGTGAACTTTTTTCAGTTATAAAACATCTATTTTGAATCTGTAAATATTTT AAATGTTTTATTAAGGCATGTAATAAACTATTCTTTGAAACTTGTTGGGTAGAATGAAAATTAAAGCCATAATGGTAAAAGATG GCATACTGATTATAAAAGAAGCAGAAAAACATTGATTTTTTTATATCTTTCATAATATAATTTTCTAACAATGCAATAAAACCA CTAAACTTTTGTGTC
287
MVKIVTVKTQAYQDQKPGTSGLRKR¥KVFQSSANYAENFIQSIISTVEPAQRQEAT WGGDGRFYMKEAIQ IARIAAA GIG RLVIGQNGILSTPA¥SCIIRKI AIGGIILTASHNPGGP-.GDFGIKFNISNGGPAPEAITDKIFQISKTIEEYAVCPD KVD G VLGKQQFDLENKFKPFTVEIVDSVEAYATMLRSIFDFSA KELLSGPNRLKICIDAMHGVVGPYVKKI CEE GAPANSAVNCV PLEDFGGHHPDPNLTYAADLVETMKSGEHDFGAAFDGDGDRNMILGKHGFFVNPSDSVAVIAANIFSIPYFQQTGVRGFARSMP TSGALDR¥ASAT IA YETPTGWKFFGNLMDASKLSLCGEESFGTGSDHIREKDGL AVLA SILATRKQSVEDI KDR¥QKH G FFTRYDYEEVEAEGA MMKDLEALMFDRSFVGKQFSA DKVYTVEKADNFEYSDPVDGSISR QGLRLIFTDGSR1VFRL SGTGSAGATIRLYIDSYEKDVAKINQDPQVMLAP ISIALKVSQLQERTGRTAPTVIT 288
GGGCCGGCCGCCCCTCCGCCAGCCAAGTCCGCCGCTCTGACCCCCGGCAGCAAGTCGCCACCATGGTGAAGATCGTGACAGTTA AGACCCAGGCGTACCAGGACCAGAAGCCGGGCACGAGCGGGCTGCGGAAGCGGGTGAAGGTGTTCCAGAGCAGCGCCAACTACG CGGAGAACTTCATCCAGAGTATCATCTCCACCGTGGAGCCGGCGCAGCGGCAGGAGGCCACGCTGGTGGTGGGCGGGGACGGCC GGTTCTACATGAAGGAGGCCATCCAGCTCATCGCTCGCATCGCTGCCGCCAACGGGATCGGTCGCTTGGTTATCGGACAGAATG GAATCCTCTCCACCCCTGCTGTATCCTGCATCATTAGAAAAATCAAAGCCATTGGTGGGATCATTCTGACAGCCAGTCACAACC CAGGGGGCCCCAATGGAGATTTTGGAATCAAATTCAATATTTCTAATGGAGGTCCTGCTCCAGAAGCAATAACTGATAAAATTT TCCAAATCAGCAAGACAATTGAAGAATATGCAGTTTGCCCTGACCTGAAAGTAGACCTTGGTGTTCTGGGAAAGCAGCAGTTTG ACTTGGAAAATAAGTTCAAACCCTTCACAGTGGAAATTGTGGATTCGGTAGAAGCTTATGCTACAATGCTGAGAAGCATCTTTG ATTTCAGTGCACTGAAAGAACTACTTTCTGGGCCAAACCGACTGAAGATCTGTATTGATGCTATGCATGGAGTTGTGGGACCGT ATGTAAAGAAGATCCTCTGTGAAGAACTCGGTGCCCCTGCGAACTCGGCAGTTAACTGCGTTCCTCTGGAGGACTTTGGAGGCC ACCACCCTGACCCCAACCTCACCTATGCAGCTGACCTGGTGGAGACCATGAAGTCAGGAGAGCATGATTTTGGGGCTGCCTTTG ATGGAGATGGGGATCGAAACATGATTCTGGGCAAGCATGGGTTCTTTGTGAACCCTTCAGACTCTGTGGCTGTCATTGCTGCCA ACATCTTCAGCATTCCGTATTTCCAGCAGACTGGGGTCCGCGGCTTTGCACGGAGCATGCCCACGAGTGGTGCTCTGGACCGGG TGGCTAGTGCTACAAAGATTGCTTTGTATGAGACCCCAACTGGCTGGAAGTTTTTTGGGAATTTGATGGACGCGAGCAAACTGT CCCTTTGTGGGGAGGAGAGCTTCGGGACCGGTTCTGACCACATCCGTGAGAAAGATGGACTGTGGGCTGTCCTTGCCTGGCTCT CCATCCTAGCCACCCGCAAGCAGAGTGTGGAGGACATTCTCAAAGATCATTGGCAAAAGCATGGCCGGAATTTCTTCACCAGGT ATGATTACGAGGAGGTGGAAGCTGAGGGCGCAAACAAAATGATGAAGGACTTGGAGGCCCTGATGTTTGATCGCTCCTTTGTGG GGAAGCAGTTCTCAGCAAATGACAAAGTTTACACTGTGGAGAAGGCCGATAACTTTGAATACAGCGACCCAGTGGATGGAAGCA TTTCAAGAAATCAGGGCTTGCGCCTCATTTTCACAGATGGTTCTCGAATCGTCTTCCGACTGAGCGGCACTGGGAGTGCCGGGG CCACCATTCGGCTGTACATCGATAGCTATGAGAAGGACGTTGCCAAGATTAACCAGGACCCCCAGGTCATGTTGGCCCCCCTTA TTTCCATTGCTCTGAAAGTGTCCCAGCTGCAGGAGAGGACGGGACGCACTGCACCCACTGTCATCACCTAAGAAGACAGGCCTG' ATGTGGTACGTCCCTCCACCCCCGGACCCATCCAAGTCATCTGATTGAAGAGCATGACAGAAACAAAATGTATTCACCAAGCAT TTTAGGATTTGACTTTTTCACTAACCAGTTGACGAGCAGTGCATTTACAAGGCACTGCCAAACAAGATGCCCTTGGGAGCTGTG AGGGAAAGAGGACCTGCGGGCTTAGATCAATCTCAATTCCTTTTCATGCCCTCCTGCATTGCTGCTGCGTGGGTATTTGTCTCC 5 TTAGCCATCAGGTACAGTTTACACTACAATGTAAGCTATAGGTGGAGCATCAGCAGTGAGTGAGGCCATTCTTCATCCTTAGGA TGTGGCAATGAAATGATGGTGCAAGTTCCTTTCTCTTTTGTGAATCTTTCCCCCCATTTCCTGTTTACATGTAACCCAACAAAA TGCAATTTCTAGTGCCTTCTGTCCAATCAGTTCTTTCCTCTGAGTGAGACGTACTTGGCTACAGATTTCTGCCTTGTTTTGCGA CATTGTCCCATTCACACAGATATTTTGGGATAATAAAGGAAAATAAGCTACA
289
10 MGSTVPRSASVLLLLLLLRRAEQPCGAELTFELPDNA QCFYEDIAQGTKST EFQVITGGHYDVDCRLEDPDGKVLYKEMKKQ YDSFTFTASKNGTYKFCFSNEFSTFTHKTVYFDFQVGETHLCFLVDRVSA TQMESACVSIHEA KSVIDYQTHFRLREAQGRS • < RAED TRVAYWS¥GEALILLWSIGQVFLLKSFFSDKRTTTTRVGS .
290 • • . ■
GCACTGAGCCGCCGCCGCTTCCGGAAGCGCAGACCCGCTGGTGCCACGTTTATCCCCTTACATCCTCCTAGGACCCGGTCGGTA
15 GTCGTCGCCCCAGCCCGCCGGGGGCAAGCGCCCAGGTCCGCGGCCCTCGAGACGGGACCGAGAGCATCATGGGCAGCACTGTCC CGCGCTCCGCCTCCGTGCTGCTTCTGCTGCTGCTCCTGCGCCGGGCCGAGCAGCCCTGCGGGGCCGAGCTCACCTTCGAGCTGC CGGACAACGCCAAGCAGTGCTTCTACGAGGACATCGCTCAGGGCACCAAGTCGACCCTGGAGTTCCAGGTGATTACTGGTGGTC ACTATGATGTAGATTGTCGATTAGAAGATCCTGATGGTAAAGTGTTATACAAAGAGATGAAGAAACAGTATGATAGTTTTACCT TCACAGCCTCCAAAAATGGGACATACAAATTTTGCTTCAGCAATGAATTTTCTACTTTCACACATAAAACTGTATATTTTGATT
20 TTCAAGTTGGAGAGACCCACCTCTGTTTCCTAGTAGACCGAGTCAGTGCTCTTACCCAGATGGAATCTGCCTGTGTTTCAATTC
ACGAAGCTCTGAAGTCTGTCATCGATTATCAGACTCATTTCCGTTTAAGAGAAGCTCAAGGCCGAAGCCGAGCAGAGGATCTAA
ATACAAGAGTGGGCTATTGGTCAGTAGGAGAAGCCCTCATTCTTCTGGTGGTTAGCATAGGGCAGGTATTTCTTTTGAAAAGCT
TTTTCTCAGATAAAAGAACCACCACAACTCGTGTTGGATCATAACTACGTTTTGAGAATTGATGCACCATTGCCACTGTAATAT
• TGCTGTCCTCTAATTAATTTTAGGTACTGAAGAACTTAATATTGGCAACATTTTTAAATCCTTACTCATACACTTGTTGGGAGG
25 GATGTACAATGCATATTCCCAAACTGTGGAAAGGACACCTTTTTTTATTTGTAAAGGTGGAAAAACTTTGGAACTCATTTTGGG CTATTCATGTTAAATATTCAACACCAATGATCTACTCTGTTCGCAGTTGTTTATATCTACTCTTCGCACACTAAACTTTGGTAT TTTGATTCCTTTTAACCATTTAAGACTACTTTTCTTATAGGTAGTTGATATTTTAAAAACTTTAGATTTAATGTCTACATGTGT TAGGGAGGAAGAAAATTGCCTTTTAATTGTTAATAAGAAAACCAAATGTGATGAACTGTAGCCCAAGCCCTATTCTGCACTGTT CAGTTTTATGGAGGAAAAATAAATCTACCATAGGAATGTTAGTTAATATTGATAATCAATTTTGAAAATACAGTGGACTGAAAA
30 GCAATTTTATTCTTTCGAAGATTTCATTTAAATCTCTGTACTATGCATTTTTGTTTCAGTTTGTAAATGTGTAACATTTATAGT TAAATAGGACAAAGCAGGCCCTATGACTATTGTTTTCAAAAAATTAATATATAAATAATTCAGAGGGGTTT.TTCATTTACTTTT GAAAAGAAATTTCTTTAACAGGATTGCACCTATCAATTTCTTGTAGAATAAAAAAAAATCTTTCAACAAA
29l"
M GFTPDEMSRGGDAAAAVAAWAAAAAAASAGNGTGAGTGAEVPGAGAVSAAGPPGAAGPGPGQ CCJ-REDGERCGRAAGNAS •35 FSKRIQKSISQKKVKIELDKSARHLYICDYHKN IQSVRERRKRKGSDDDGGDSP¥QDIDTPEVDLYQ QV TLRRYKRHFKLP • RPGLNKAQLVEIVGCHFRSIPWEKDTLTYFIYSVKNDK KSDLK¥DSGVH
292
CCCCCATGTGACAGTGACGGGGTCCCCGCTCCAGGAGACGCTCGAGTCTGCGTCCCGGCCCTCAGCACTGTCCACTGTTTCGGT GCCAGCAGAGACCAGCAGGCCCGGGACAGTTGGTGTTTGGCCGTGCCGCTGTCTAACTTGGTGTGCAGAGTGAATTGCCGCTGC
40 CGGAGCGGAGAGAGGCGGAGCGGCCAGGAGAGAGGGGATTTCTGTCAGCGCCGGCCTCGGGAGCTCGGAGACATGAACGGCTTC ACGCCTGACGAGATGAGCCGCGGCGGGGATGCGGCCGCCGCAGTGGCCGCAGTGGTCGCTGCCGCGGCGGCCGCCGCCTCGGCG GGGAACGGGACCGGCGCGGGCACCGGGGCTGAGGTGCCGGGCGCGGGGGCGGTCTCAGCGGCTGGGCCCCCGGGGGCGGCCGGG CCGGGCCCCGGGCAACTGTGCTGCCTGCGGGAGGATGGTGAGCGGTGCGGCCGGGCGGCAGGCAACGCCAGCTTCAGCAAGAGG ATCCAGAAGAGCATCTCCCAGAAGAAGGTGAAGATCGAGCTGGATAAGAGCGCAAGGCATCTTTACATATGTGATTATCATAAA
45 AACTTAATTCAGAGTGTTCGAAACAGAAGAAAGAGAAAAGGGAGTGATGATGATGGAGGTGATTCACCTGTTCAAGATATTGAT ACCCCAGAGGTTGATTTATACCAATTACAAGTAAATACACTTAGGAGATACAAAAGACACTTCAAGCTACCAACCAGACCAGGA CTTAATAAAGCACAACTTGTTGAGATAGTTGGTTGCCACTTTAGGTCTATTCCAGTGAATGAAAAAGACACCTTAAGATATTTC ATCTACTCAGTGAAGAATGACAAGAACAAATCAGATCTCAAGGTTGATAGTGGTGTTCACTAGGAGACGTGGAATTGAGACTAA TAACTTGGATGTTAACACTGTTTACTGTTTTTTCACATGTAGAAATGTTCTTTGTGTATTTTTTCTACAGAGGATTTTCTCTGA TTTTATTTTCTTTGTTTCTGACTCTAATAATTAGTTGGAAACTCATATAAAATGAGCTTTCCTAAATTAAATCTATTTTAAATA AAGGTTATTACTATTAAAAAAAAAAAAAAAAAA
293 MPSAGTLPWVQGIICNA PCFRYPTPGEAPGVVGNFNKSIVARLFSDARRLL YSQKDTSMKDMRKVLRTLQQIKKSSSNLKL QDF VDNETFSGFLYHN SLPKSTVDKM RAD¥ILH VF QGYQLH TSLCNGSKSEEMIQLGDQEVSELCGLPREKLAAAERV LRSmDILKPILRTLNSTSPFPSKELAEATKTLLHSLGTLAQE FSMRSWSDMRQEVMFLT V SSSSSTQIYQAVSRIVCGHP EGGGLKIKS 1 YEDIWYKALFGGNGTEEDAETFYDNSTTPYCND MKNLESSPLSRII KA KPLLVGKILYTPDTPATRQVM AEWKTFQELAVFHDLEGM EELSPKI TFMENSQEMDLVRM LDSRDNDHFWEQQLDG DWTAQDI¥AFLAKHPEDVQSSNGS WTWREAFNETNQAIRTISRFMECVN NK EPIATEVWLINKSMEL DERKF AGIVFTGITPGSIELPHHVKYKIR DIDNVE RTNKIKDGY DPGPRADPFEDMRY GGFAY QDWEQAIIRV TGTEKKTGVYMQQMPYPGYVDDIFLRVMSRSMPLFMT AW IYSVAVIIKGIVYEKEAR KETMRI GLDNSI WFSWFISSLIP VSAG LWILKLGNL PYSDPSWFVFLSVFAVVTILQ CFLISTLFSRA LAAACGGIIYFTLYLPYVLC¥AWQDY¥GFT KIFASLLSPVAFGFGCEYFALFEEQGIGVQ DNLFESPVEE DGFNLTTSVSm FDTFLYGVMTWYIEAVFPGQYGIPRP YFPCTKSY FGEESDEKSHPGSNQKRISEICMEEEPTHLKLGVS IQNLVKVYRDGMKVAVDGLALNFYEGQITSFLGHNGAGKTTTMSILTGLFPPTSGTAYILGKDIRSEMSTIRQNLGVCPQH VL
FDM TVEEHI FYARLKGLSEKHVKAEMEQMA DVG PSSKLKSKTSQLSGGMQRK SVA AFVGGSKWILDEPTAGVDPYSR
RGIWE KYRQGRTII STHHMDEADVLGDRIAIISHGKLCCVGSSLF K QLGTGYY TLVKKDVESSLSSCR1\ISSST¥SYL
KKEDSVSQSSSDAGLGSDHESDT TIDVSAISNLIRKHVSEARLVEDIGHELTYV PYEAAKEGAFVELFHEIDDRLSDLGISS
• YGISETTLEEIFLKVAEESGVDAETSDGT PARRNRRAFGDKQSCLRPFTEDDAADPNDSDIDPESRETD LSGMDGKGSYQ¥K G KLTQQQFVAL KRLLIARRSRKGFFAQIV PAVFVCIALVFS IVPPFGKYPS ELQP MYNEQYTFVSNDAPEDTGT EL LNALTKDPGFGTRCMEGWPIPDTPCQAGEEEWTTAPVPQTIMDLFQNG TMQNPSPACQCSSDKIKKMLPVCPPGAGGLPPPQ RKQNTADILQD TGR ISDY VKTYVQIIAKS KNKIWVNEFRYGGFSLGVSNTQALPPSQEV DATKQMKKHLKLAKDSSADR F NSLGRFMTGLDTR 1WKWFMKGWHAISSF NVI NAILRANLQKGENPSHYGITAFNHPLNLTKQQ SEVAPMTTSVDVL ¥SICVIFAMSFVPASFWFLIQERVSKA HLQFISG¥KPVIYWLSNFVWDMCNYWPATLVIIIFICFQQKSYVSSTN PV AL L LYGWSITP MYPASF¥FKIPSTAYW TSVNLFIGINGSVATFVLELFTDNKL INDILKSVFIjIFPHFC GRGLIDMVK
NQAMADALERFG*ENRFVSP SWDLVGRNLFAMA¥EGWFFLITV IQYRFFIRPRPV AKLSPL-.DEDED¥RRERQRILDGGGQ
NDILEIKELTKIYRRKRKPAVDRICVGIPPGECFG GV GAGKSSTFKMLTGDTTVTRGDAFLNRNSI SNIHEVHQNMGYCP
QFDAITE LTGREHVEFFALLRGVPEKEVGKVGEWAIRKLGLVKYGEKYAGNYSGGNKRKLSTAMALIGGPPVVF DEPTTGMD
.P RRFLMCALSVVKEGRS LTSHSMEECEALCTRMAIMV GRFRCLGSVQHLKNRFGDGYTIV¥RIAGSNPDLKPVQDFFG LAFPGSVPKEKHR MLQYQ PSSLSS AR1FSILSQSKKRLHIEDYSVSQTTLDQVFV FA DQSDDDH KDLSLHK QTVVDV AVLTSFLQDEKV ESYV
294
CAAACATGTCAGCTGTTACTGGAAGTGGCCTGGCCTCTATTTATCTTCCTGATCCTGATCTCTGTTCGGCTGAGCTACCCACCC TATGAACAACATGAATGCCATTTTCCAAATAAAGCCATGCCCTCTGCAGGAACACTTCCTTGGGTTCAGGGGATTATCTGTAAT GCCAACAACCCCTGTTTCCGTTACCCGACTCCTGGGGAGGCTCCCGGAGTTGTTGGAAACTTTAACAAATCCATTGTGGCTCGC CTGTTCTCAGATGCTCGGAGGCTTCTTTTATACAGCCAGAAAGACACCAGCATGAAGGACATGCGCAAAGTTCTGAGAACATTA CAGCAGATCAAGAAATCCAGCTCAAACTTGAAGCTTCAAGATTTCCTGGTGGACAATGAAACCTTCTCTGGGTTCCTGTATCAC AACCTCTCTCTCCCAAAGTCTACTGTGGACAAGATGCTGAGGGCTGATGTCATTCTCCACAAGGTATTTTTGCAAGGCTACCAG TTACATTTGACAAGTCTGTGCAATGGATCAAAATCAGAAGAGATGATTCAACTTGGTGACCAAGAAGTTTCTGAGCTTTGTGGC CTACCAAGGGAGAAACTGGCTGCAGCAGAGCGAGTACTTCGTTCCAACATGGACATCCTGAAGCCAATCCTGAGAACACTAAAC TCTACATCTCCCTTCCCGAGCAAGGAGCTGGCCGAAGCCACAAAAACATTGCTGCATAGTCTTGGGACTCTGGCCCAGGAGCTG TTCAGCATGAGAAGCTGGAGTGACATGCGACAGGAGGTGATGTTTCTGACCAATGTGAACAGCTCCAGCTCCTCCACCCAAATC TACCAGGCTGTGTCTCGTATTGTCTGCGGGCATCCCGAGGGAGGGGGGCTGAAGATCAAGTCTCTCAACTGGTATGAGGACAAC AACTACAAAGCCCTCTTTGGAGGCAATGGCACTGAGGAAGATGCTGAAACCTTCTATGACAACTCTACAACTCCTTACTGCAAT GATTTGATGAAGAATTTGGAGTCTAGTCCTCTTTCCCGCATTATCTGGAAAGCTCTGAAGCCGCTGCTCGTTGGGAAGATCCTG TATACACCTGACACTCCAGCCACAAGGCAGGTCATGGCTGAGGTGAACAAGACCTTCCAGGAACTGGCTGTGTTCCATGATCTG GAAGGCATGTGGGAGGAACTCAGCCCCAAGATCTGGACCTTCATGGAGAACAGCCAAGAAATGGACCTTGTCCGGATGCTGTTG GACAGCAGGGACAATGACCACTTTTGGGAACAGCAGTTGGATGGCTTAGATTGGACAGCCCAAGACATCGTGGCGTTTTTGGCC AAGCACCCAGAGGATGTCCAGTCCAGTAATGGTTCTGTGTACACCTGGAGAGAAGCTTTCAACGAGACTAACCAGGCAATCCGG ACCATATCTCGCTTCATGGAGTGTGTCAACCTGAACAAGCTAGAACCCATAGCAACAGAAGTCTGGCTCATCAACAAGTCCATG GAGCTGCTGGATGAGAGGAAGTTCTGGGCTGGTATTGTGTTCACTGGAATTACTCCAGGCAGCATTGAGCTGCCCCATCATGTC AAGTACAAGATCCGAATGGACATTGACAATGTGGAGAGGACAAATAAAATCAAGGATGGGTACTGGGACCCTGGTCCTCGAGCT GACCCCTTTGAGGACATGCGGTACGTCTGGGGGGGCTTCGCCTACTTGCAGGATGTGGTGGAGCAGGCAATCATCAGGGTGCTG ACGGGCACCGAGAAGAAAACTGGTGTCTATATGCAACAGATGCCCTATCCCTGTTACGTTGATGACATCTTTCTGCGGGTGATG AGCCGGTCAATGCCCCTCTTCATGACGCTGGCCTGGATTTACTCAGTGGCTGTGATCATCAAGGGCATCGTGTATGAGAAGGAG GCACGGCTGAAAGAGACCATGCGGATCATGGGCCTGGACAACAGCATCCTCTGGTTTAGCTGGTTCATTAGTAGCCTCATTCCT CTTCTTGTGAGCGCTGGCCTGCTAGTGGTCATCCTGAAGTTAGGAAACCTGCTGCCCTACAGTGATCCCAGCGTGGTGTTTGTC TTCCTGTCCGTGTTTGCTGTGGTGACAATCCTGCAGTGCTTCCTGATTAGCACACTCTTCTCCAGAGCCAACCTGGCAGCAGCC TGTGGGGGCATCATCTACTTCACGCTGTACCTGCCCTACGTCCTGTGTGTGGCATGGCAGGACTACGTGGGCTTCACACTCAAG ATCTTCGCTAGCCTGCTGTCTCCTGTGGCTTTTGGGTTTGGCTGTGAGTACTTTGCCCTTTTTGAGGAGCAGGGCATTGGAGTG CAGTGGGACAACCTGTTTGAGAGTCCTGTGGAGGAAGATGGCTTCAATCTCACCACTTCGGTCTCCATGATGCTGTTTGACACC TTCCTCTATGGGGTGATGACCTGGTACATTGAGGCTGTCTTTCCAGGCCAGTACGGAATTCCCAGGCCCTGGTATTTTCCTTGC ACCAAGTCCTACTGGTTTGGCGAGGAAAGTGATGAGAAGAGCCACCCTGGTTCCAACCAGAAGAGAATATCAGAAATCTGCATG GAGGAGGAACCCACCCACTTGAAGCTGGGCGTGTCCATTCAGAACCTGGTAAAAGTCTACCGAGATGGGATGAAGGTGGCTGTC GATGGCCTGGCACTGAATTTTTATGAGGGCCAGATCACCTCCTTCCTGGGCCACAATGGAGCGGGGAAGACGACCACCATGTCA ATCCTGACCGGGTTGTTCCCCCCGACCTCGGGCACCGCCTACATCCTGGGAAAAGACATTCGCTCTGAGATGAGCACCATCCGG CAGAACCTGGGGGTCTGTCCCCAGCATAACGTGCTGTTTGACATGCTGACTGTCGAAGAACACATCTGGTTCTATGCCCGCTTG AAAGGGCTCTCTGAGAAGCACGTGAAGGCGGAGATGGAGCAGATGGCCCTGGATGTTGGTTTGCCATCAAGCAAGCTGAAAAGC AAAACAAGCCAGCTGTCAGGTGGAATGCAGAGAAAGCTATCTGTGGCCTTGGCCTTTGTCGGGGGATCTAAGGTTGTCATTCTG GATGAACCCACAGCTGGTGTGGACCCTTACTCCCGCAGGGGAATATGGGAGCTGCTGCTGAAATACCGACAAGGCCGCACCATT ATTCTCTCTACACACCACATGGATGAAGCGGACGTCCTGGGGGACAGGATTGCCATCATCTCCCATGGGAAGCTGTGCTGTGTG GGCTCCTCCCTGTTTCTGAAGAACCAGCTGGGAACAGGCTACTACCTGACCTTGGTCAAGAAAGATGTGGAATCCTCCCTCAGT TCCTGCAGAAACAGTAGTAGCACTGTGTCATACCTGAAAAAGGAGGACAGTGTTTCTCAGAGCAGTTCTGATGCTGGCCTGGGC AGCGACCATGAGAGTGACACGCTGACCATCGATGTCTCTGCTATCTCCAACCTCATCAGGAAGCATGTGTCTGAAGCCCGGCTG GTGGAAGACATAGGGCATGAGCTGACCTATGTGCTGCCATATGAAGCTGCTAAGGAGGGAGCCTTTGTGGAACTCTTTCATGAG ATTGATGACCGGCTCTCAGACCTGGGCATTTCTAGTTATGGCATCTCAGAGACGACCCTGGAAGAAATATTCCTCAAGGTGGCC GAAGAGAGTGGGGTGGATGCTGAGACCTCAGATGGTACCTTGCCAGCAAGACGAAACAGGCGGGCCTTCGGGGACAAGCAGAGC TGTCTTCGCCCGTTCACTGAAGATGATGCTGCTGATCCAAATGATTCTGACATAGACCCAGAATCCAGAGAGACAGACTTGCTC AGTGGGATGGATGGCAAAGGGTCCTACCAGGTGAAAGGCTGGAAACTTACACAGCAACAGTTTGTGGCCCTTTTGTGGAAGAGA CTGCTAATTGCCAGACGGAGTCGGAAAGGATTTTTTGCTCAGATTGTCTTGCCAGCTGTGTTTGTCTGCATTGCCCTTGTGTTC AGCCTGATCGTGCCACCCTTTGGCAAGTACCCCAGCCTGGAACTTCAGCCCTGGATGTACAACGAACAGTACACATTTGTCAGC AATGATGCTCCTGAGGACACGGGAACCCTGGAACTCTTAAACGCCCTCACCAAAGACCCTGGCTTCGGGACCCGCTGTATGGAA GGAAACCCAATCCCAGACACGCCCTGCCAGGCAGGGGAGGAAGAGTGGACCACTGCCCCAGTTCCCCAGACCATCATGGACCTC TTCCAGAATGGGAACTGGACAATGCAGAACCCTTCACCTGCATGCCAGTGTAGCAGCGACAAAATCAAGAAGATGCTGCCTGTG TGTCCCCCAGGGGCAGGGGGGCTGCCTCCTCCACAAAGAAAACAAAACACTGCAGATATCCTTCAGGACCTGACAGGAAGAAAC ATTTCGGATTATCTGGTGAAGACGTATGTGCAGATCATAGCCAAAAGCTTAAAGAACAAGATCTGGGTGAATGAGTTTAGGTAT GGCGGCTTTTCCCTGGGTGTCAGTAATACTCAAGCACTTCCTCCGAGTCAAGAAGTTAATGATGCCACCAAACAAATGAAGAAA CACCTAAAGCTGGCCAAGGACAGTTCTGCAGATCGATTTCTCAACAGCTTGGGAAGATTTATGACAGGACTGGACACCAGAAAT AATGTCAAGGTGTGGTTCAATAACAAGGGCTGGCATGCAATCAGCTCTTTCCTGAATGTCATCAACAATGCCATTCTCCGGGCC AACCTGCAAAAGGGAGAGAACCCTAGCCATTATGGAATTACTGCTTTCAATCATCCCCTGAATCTCACCAAGCAGCAGCTCTCA GAGGTGGCTCCGATGACCACATCAGTGGATGTCCTTGTGTCCATCTGTGTCATCTTTGCAATGTCCTTCGTCCCAGCCAGCTTT GTCGTATTCCTGATCCAGGAGCGGGTCAGCAAAGCAAAACACCTGCAGTTCATCAGTGGAGTGAAGCCTGTCATCTACTGGCTC TCTAATTTTGTCTGGGATATGTGCAATTACGTTGTCCCTGCCACACTGGTCATTATCATCTTCATCTGCTTCCAGCAGAAGTCC TATGTGTCCTCCACCAATCTGCCTGTGCTAGCCCTTCTACTTTTGCTGTATGGGTGGTCAATCACACCTCTCATGTACCCAGCC TCCTTTGTGTTCAAGATCCCCAGCACAGCCTATGTGGTGCTCACCAGCGTGAACCTCTTCATTGGCATTAATGGCAGCGTGGCC ACCTTTGTGCTGGAGCTGTTCACCGACAATAAGCTGAATAATATCAATGATATCCTGAAGTCCGTGTTCTTGATCTTCCCACAT TTTTGCCTGGGACGAGGGCTCATCGACATGGTGAAAAACCAGGCAATGGCTGATGCCCTGGAAAGGTTTGGGGAGAATCGCTTT GTGTCACCATTATCTTGGGACTTGGTGGGACGAAACCTCTTCGCCATGGCCGTGGAAGGGGTGGTGTTCTTCCTCATTACTGTT CTGATCCAGTACAGATTCTTCATCAGGCCCAGACCTGTAAATGCAAAGCTATCTCCTCTGAATGATGAAGATGAAGATGTGAGG CGGGAAAGACAGAGAATTCTTGATGGTGGAGGCCAGAATGACATCTTAGAAATCAAGGAGTTGACGAAGATATATAGAAGGAAG CGGAAGCCTGCTGTTGACAGGATTTGCGTGGGCATTCCTCCTGGTGAGTGCTTTGGGCTCCTGGGAGTTAATGGGGCTGGAAAA TCATCAACTTTCAAGATGTTAACAGGAGATACCACTGTTACCAGAGGAGATGCTTTCCTTAACAGAAATAGTATCTTATCAAAC ATCCATGAAGTACATCAGAACATGGGCTACTGCCCTCAGTTTGATGCCATCACAGAGCTGTTGACTGGGAGAGAACACGTGGAG TTCTTTGCCCTTTTGAGAGGAGTCCCAGAGAAAGAAGTTGGCAAGGTTGGTGAGTGGGCGATTCGGAAACTGGGCCTCGTGAAG TATGGAGAAAAATATGCTGGTAACTATAGTGGAGGCAACAAACGCAAGCTCTCTACAGCCATGGCTTTGATCGGCGGGCCTCCT GTGGTGTTTCTGGATGAACCCACCACAGGCATGGATCCCAAAGCCCGGCGGTTCTTGTGGAATTGTGCCCTAAGTGTTGTCAAG GAGGGGAGATCAGTAGTGCTTACATCTCATAGTATGGAAGAATGTGAAGCTCTTTGCACTAGGATGGCAATCATGGTCAATGGA AGGTTCAGGTGCCTTGGCAGTGTCCAGCATCTAAAAAATAGGTTTGGAGATGGTTATACAATAGTTGTACGAATAGCAGGGTCC AACCCGGACCTGAAGCCTGTCCAGGATTTCTTTGGACTTGCATTTCCTGGAAGTGTTCCAAAAGAGAAACACCGGAACATGCTA CAATACCAGCTTCCATCTTCATTATCTTCTCTGGCCAGGATATTCAGCATCCTCTCCCAGAGCAAAAAGCGACTCCACATAGAA GACTACTCTGTTTCTCAGACAACACTTGACCAAGTATTTGTGAACTTTGCCAAGGACCAAAGTGATGATGACCACTTAAAAGAC CTCTCATTACACAAAAACCAGACAGTAGTGGACGTTGCAGTTCTCACATCTTTTCTACAGGATGAGAAAGTGAAAGAAAGCTAT GTATGAAGAATGCTGTTCATACGGGGTGGCTGAAAGTAAAGAGGNACTAGACTTTCCTTTGCACCATGTGAAGTGTTGTGGAGA AAAGAGCCAGAAGTTGATGTGGGAAGAAGTAAACTGGATACTGTACTGATACTATT.CAATGCAATGCAATTCAATGCAATGAAA ACAAAATTCCATTACAGGGGCAGTGCCTTTGTAGCCTATGTCTTGTATGGCTCTCAAGTGAAAGACTTGAATTTAGTTTTTTAC CTATACCTATGTGAAACTCTATTATGGAACCCAATGGACATATGGGTTTGAACTCACACTTTTTTTTTTTTTTTGTTCCTGTGT ATTCTCATTGGGGTTGCAACAATAATTCATCAAGTAATCATGGCCAGCGATTATTGATCAAAATCAAAAGGTAATGCACATCCT CATTCACTAAGCCATGCCATGCCCAGGAGACTGGTTTCCCGGTGACACATCCATTGCTGGCAATGAGTGTGCCAGAGTTATTAG TGCCAAGTTTTTCAGAAAGTTTGAAGCACCATGGTGTGTCATGCTCACTTTTGTGAAAGCTGCTCTGCTCAGAGTCTATCAACA •TTGAATATCAGTTGACAGAATGGTGCCATGCGTGGCTAACATCCTGCTTTGATTCCCTCTGATAAGCTGTTCTGGTGGCAGTAA CATGCAACAAAAATGTGGGTGTCTCTAGGCACGGGAAACTTGGTTCCATTGTTATATTGTCCTATGCTTCGAGCCATGGGTCTA CAGGGTCATCCTTATGAGACTCTTAAATATACTTAGATCCTGGTAAGAGGCAAAGAATCAACAGCCAAACTGCTGGGGC GCAA
• • •GCTGCTGAAGCCAGGGCATGGGATTAAAGAGATTGTGCGTTCAAACCTAGGGAAGCCTGTGCCCATTTGTCCTGACTGTCTGCT
AACATGGTACACTGCATCTCAAGATGTTTATCTGACACAAGTGTATTATTTCTGGCTTTTTGAATTAATCTAGAAAATGAAAAG
ATGGAGTTGTATTTTGACAAAAATGTTTGTACTTTTTAATGTTATTTGGAATTTTAAGTTCTATCAGTGACTTCTGAATCCTTA
GAATGGCCTCTTTGTAGAACCCTGTGGTATAGAGGAGTATGGCCACTGCCCCACTATTTTTATTTTCTTATGTAAGTTTGCATA TCAGTCATGACTAGTGCCTAGAAAGCAATGTGATGGTCAGGATCTCATGACATTATATTTGAGTTTCTTTCAGATCATTTAGGA TACTCTTAATCTCACTTCATCAATCAAATATTTTTTGAGTGTATGCTGTAGCTGAAAGAGTATGTACGTACGTATAAGACTAGA GAGATATTAAGTCTCAGTACACTTCCTGTGCCATGTTATTCAGCTCACTGGTTTACAAATATAGGTTGTCTTGTGGTTGTAGGA GCCCACTGTAACAATACTGGGCAGCCTTTTTTTTTTTTTTTAATTGCAACAATGCAAAAGCCAAGAAAGTATAAGGGTCACAAG TCTAAACAATGAATTCTTCAACAGGGAAAACAGCTAGCTTGAAAACTTGCTGAAAAACACAACTTGTGTTTATGGCATTTAGTA CCTTCAAATAATTGGCTTTGCAGATATTGGATACCCCATTAAATCTGACAGTCTCAAATTTTTCATCTCTTCAATCACTAGTCA AGAAAAATATAAAAACAACAAATACTTCCATATGGAGCATTTTTCAGAGTTTTCTAACCCAGTCTTATTTTTCTAGTCAGTAAA CATTTGTAAAAATACTGTTTCACTAATACTTACTGTTAACTGTCTTGAGAGAAAAGAAAAATATGAGAGAACTATTGTTTGGGG AAGTTCAAGTGATCTTTCAATATCATTACTAACTTCTTCCACTTTTTCCAAAATTTGAATATTAACGCTAAAGGTGTAAGACTT CAGATTTCAAATTAATCTTTCTATATTTTTTAAATTTACAGAATATTATATAACCCACTGCTGAAAAAGAAAAAAATGATTGTT TTAGAAGTTAAAGTCAATATTGATTTTAAATATAAGTAATGAAGGCATATTTCCAATAACTAGTGATATGGCATCGTTGCATTT TACAGTATCTTCAAAAATACAGAATTTATAGAATAATTTCTCCTCATTTAATATTTTTCAAAATCAAAGTTATGGTTTCCTCAT TTTACTAAAATCGTATTCTAATTCTTCATTATAGTAAATCTATGAGCAACTCCTTACTTCGGTTCCTCTGATTTCAAGGCCATA TTTTAAAAAATCAAAAGGCACTGTGAACTATTTTGAAGAAAACACAACATTTTAATACAGATTGAAAGGACCTCTTCTGAAGCT AGAAACAATCTATAGTTATACATCTTCATTAATACTGTGTTACCTTTTAAAATAGTAATTTTTTACATTTTCCTGTGTAAACCT AATTGTGGTAGAAATTTTTACCAACTCTATACTCAATCAAGCAAAATTTCTGTATATTCCCTGTGGAATGTACCTATGTGAGTT TCAGAAATTCTCAAAATACGTGTTCAAAAATTTCTGCTTTTGCATCTTTGGGACACCTCAGAAAACTTATTAACAACTGTGAAT ATGAGAAATACAGAAGAAAATAATAAGCCCTCTATACATAAATGCCCAGCACAATTCATTGTTAAAAAACAACCAAACCTCACA CTACTGTATTTCATTATCTGTACTGAAAGCAAATGCTTTGTGACTATTAAATGTTGCACATCATTCATTCAAAAAAAAAAAAAA AAAAA 295.
PPGPERSRLGLGVSLHQRSCPKCIAVFTRVSEPRIQFPASRILPSSNTS DFDPVSGQSNYGGSQGSGQT NRPPVASNPVTPS LHSGPAPRMP PASQNPATTPMPSSSFLPEA1.LPPPLN QYNYPSTASQTNHCPRASSQPTVSGNTSLTTNHQYVSSGYPS QN SFIKSGPSVPPLV PPLPTTFQPGAPHGPPPAGGPPPVRALTPLTSSYRDVPQPLFNSAV QEGITSNTNNGSMWHSSYDEIE GGGLLATPQ TNK PKMSRSVGYSYPSLPPGYQNTTPPGATGVPPSSL YPSGPQAFTQTP GA HLTTSMSGLSLQPEGLRW N LQERNMLPSTPLKPPVPN HEDIQK NCNPELFRCT TSIPQTQALLNKAK PLGL LHPFKDLVQLPVVTSSTIVRCRSCR TYINPFVSFLDQRRWKCN CYRWDVPEEFLYNPLTRVYGEPHRRPEVQNATIEFMAPSEYMLRPPQPPVY FVFDVSHNAVET GYNSVCQS LDN DL PGNTRTKIGFITFDSTIHFYGLQESLSQPQM IVSDIEDVFIP PENLLV LNES ELVQDLLKTLP QMFTKTLETQSA GPALQAAFKLMSPTGGR SVFQTQLPTLGVGAKPREEPNHRSSAKDIHMTPSTDFYKKLALDCSGQQVAV DLFLLSGQYSDLASLGCISRYSAGSVYYYPSYHHQHNPVQVQKL KE QRYLTRKIGFEAVMRIRCTKGLSIHTFHGNFFVRST DLLSLP VNPDAGYAVQMSVEESLTDTQLVSFQSALLYTSSKGERRIRVHTLCLPWSTLNDVFLGADVQAISGLLAMAVDRS TAS SDARDALWAVIDS SAYRSSV SNQQPGLMVPFS RLFPLFVLAL Q SFQTGTNARLDERIFAMCQVKNQPLVYLM LTTHPSLYRVDNLSDEGALNISDRTIPQPPI Q SVEKLSRDGAFLMDAGSVLMWVGKNCTQNFLSQVLGVQNYASIPQPMTD LPE DTPESARIIAFIS LREQRPFFPILYVIRDESPMKANFLQNMIEDRTESALSYYEFLLHIQQQVNK .
•296
CCTCCAGGCCCAGAACGGAGCCGCCTTGGCCTCGGGGTCTCCCTACACCAACGGTCCTGTCCAAAATGCATTGCTGTCTTCACA AGAGTCAGTGAGCCAAGGATACAATTTCCAGCTTCCAGGATCCTACCCTCATCCAATACCAGCAAAGACTTTGATCCAGTCTCT GGCCAGTCTAACTATGGTGGTTCTCAGGGATCTGGGCAGACTCTTAATAGACCACCTGTGGCCTCTAATCCAGTGACACCTTCG CTTCATAGTGGTCCTGCTCCCCGAATGCCATTACCTGCTTCTCAGAACCCAGCTACTACACCAATGCCTTCTAGTAGCTTTCTT CCTGAAGCCAACCTGCCACCACCTTTGAATTGGCAATATAACTATCCATCCACAGCCTCACAAACAAACCATTGTCCTCGTGCA TCATCCCAACCAACTGTATCTGGAAATACAAGTTTAACCACAAATCATCAATATGTTTCTTCTGGATATCCTTCACTTCAAAAT AGCTTCATAAAGTCAGGTCCTTCTGTACCTCCCTTAGTGAATCCACCTCTGCCTACAACTTTTCAACCAGGAGCTCCTCATGGG CCCCCTCCAGCTGGAGGCCCACCCCCAGTGAGGGCCCTCACGCCCCTGACATCATCATATAGAGATGTACCCCAGCCCTTATTT AATTCAGCTGTCAACCAAGAAGGTATTACATCAAATACCAATAACGGATCTATGGTGGTCCACAGTAGTTACGACGAGATTGAA GGAGGTGGCTTATTGGCAACACCACAGCTTACTAACAAGAATCCCAAAATGAGCCGAAGTGTTGGATATTCATATCCCTCCTTA CCACCTGGTTATCAGAACACAACACCACCTGGTGCAACTGGAGTACCACCCTCTTCCTTGAATTACCCAAGTGGGCCACAAGCC TTTACTCAGACTCCCTTAGGTGCTAATCATTTAACCACAAGCATGAGTGGATTAAGTCTACAACCAGAGGGTCTAAGAGTTGTC •AATCTTCTTCAAGAAAGAAACATGCTTCCGTCAACACCTTTGAAGCCTCCAGTTCCAAATTTGCATGAAGACATCCAGAAACTC AACTGTAACCCAGAGTTATTTCGATGCACGCTGACTAGCATTCCTCAGACGCAGGCCTTATTGAATAAAGCCAAACTTCCTTTG GGGCTGCTGCTTCATCCTTTCAAAGACTTAGTGCAATTGCCTGTGGTTACCTCCAGTACAATTGTGAGATGCCGTTCATGCAGG ACGTACATCAATCCTTTCGTCAGCTTTCTTGATCAAAGGAGATGGAAGTGTAACTTATGTTATCGAGTCAATGATGTTCCTGAA GAATTCTTGTACAACCCTTTGACCAGAGTTTATGGAGAACCTCACAGAAGACCAGAAGTTCAAAATGCTACTATTGAGTTTATG GCTCCTTCAGAATACATGTTACGACCACCTCAGCCTCCAGTGTATCTCTTTGTATTTGATGTGTCTCACAATGCAGTCGAAACT GGATACTTGAATTCAGTTTGCCAGAGTTTGTTAGACAATCTGGATTTGCTTCCTGGCAACACTAGAACAAAAATTGGCTTCATA ACATTTGACAGTACAATCCATTTCTACGGTCTTCAGGAAAGTCTCTCTCAACCTCAGATGCTAATAGTTTCAGATATTGAAGAT GTTTTTATACCTATGCCAGAGAACTTATTAGTAAACTTAAATGAAAGTAAAGAGCTCGTGCAAGATTTACTGAAAACTTTGCCA CAAATGTTTACCAAGACTCTGGAGACCCAGAGTGCCTTGGGTCCTGCACTGCAGGCTGCCTTTAAGCTGATGTCTCCAACTGGT GGTCGAATGTCTGTCTTTCAAACACAACTCCCAACTCTTGGAGTGGGAGCCCTGAAACCACGAGAGGAACCAAACCACAGGTCA TCTGCTAAGGATATACACATGACACCATCCACTGACTTCTATAAGAAATTAGCCTTGGACTGTTCTGGTCAGCAAGTTGCTGTT GACTTATTCCTTCTCAGTGGACAGTATTCTGATTTGGCTTCTCTGGGTTGTATTTCTCGGTATTCAGCAGGTAGTGTCTATTAC TATCCCTCTTACCATCATCAGCACAACCCAGTCCAAGTACAGAAATTACAGAAGGAACTACAGAGATACCTTACTCGGAAGATT GGCTTTGAGGCAGTCATGAGGATTCGGTGCACCAAAGGTCTTTCCATTCATACTTTCCATGGAAACTTCTTTGTTAGGTCAACC GACTTACTGTCTTTGCCTAACGTCAACCCAGACGCTGGGTATGCAGTACAGATGTCAGTGGAAGAGAGTCTTACTGACACTCAG TTGGTTTCTTTTCAGTCAGCACTCTTGTATACATCCAGCAAAGGCGAAAGAAGAATTCGTGTTCATACTTTGTGTTTGCCAGTA GTTTCGACTCTGAATGATGTCTTTCTTGGAGCTGATGTTCAAGCAATTTCAGGGTTATTGGCCAATATGGCTGTTGACAGATCT ATGACTGCCAGTCTGAGTGACGCTCGGGATGCTCTAGTGAATGCAGTCATTGACTCCCTTTCAGCTTACCGTTCTTCAGTCTTA AGTAACCAGCAGCCTGGACTCATGGTTCCTTTT.TCTTTGCGGCTTTTCCCACTTTTTGTGTTGGCTCTCCTTAAACAGAAATCA TTCCAGACTGGGACAAATGCACGTCTAGATGAACGCATTTTTGCTATGTGTCAAGTGAAAAACCAGCCCTTGGTTTACCTTATG CTCACAACTCATCCCAGTTTGTATAGAGTTGACAATCTCTCAGATGAGGGAGCACTCAACATCAGTGATAGAACGATACCTCAG CCCCCCATTCTTCAGCTTTCAGTGGAGAAGCTGAGCAGAGATGGAGCTTTCCTCATGGATGCAGGCTCTGTACTGATGCTTTGG GTTGGAAAAAATTGTACACAGAATTTTCTCAGCCAAGTTCTAGGAGTTCAAAACTATGCATCAATTCCACAGCCTATGACAGAC CTTCCAGAACTTGATACACCAGAATCTGCCAGAATAATAGCTTTCATCTCTTGGCTTAGAGAGCAGAGACCATTTTTCCCAATA CTTTATGTAATAAGGGATGAGAGTCCAATGAAAGCAAACTTCCTTCAAAACATGATAGAAGACAGAACAGAATCTGCATTATCA TATTATGAATTCCTGTTGCATATACAGCAACAAGTGAATAAATGAATGAATGAAGAAATTTGACTTATTTTTAAGGAATGTCAC AATAGTGCAGAATACCTGGAAATGTGTAATACCTTCTTTTTCTATTATGTTTGTGGACTAATGTGATGATTGAGATGTTCTCAC TGTGATTTCAACAACCTATAAGCAAATAAAAGACCACAGCAGAGAATCAAACATGCAACTCTGAAATACTGTATTTTTCAAATC AGAATATAGCTACGTATGATTGGATACTTTTTTCTTGCCAATTATGTTTGAGTTGTTATGGATTAAAATAAGAATATTGCAGAG GCAAAGTACATTTTGTAAAATAAAGATTTCTGTGTTCTACATGTATATTTCTCATTTTTAATTTTTCTGAATCTTTGGCTGCTA CATTTAAAACCTCACAAACCTAAGTGTTGCAGGGAAGTTACAAATTGATTGGTAGTGATGTTTTTAAAATAAAAACAATGGAAA GTAAATATAATGTAGGAAAACTAGAATTCATTCCCCACACGTGTCTTTTTTTTTTCTTTGTTAAGGGAAAGGATCATGTTGACT AAAACTAAACTAATTCTAGTATAGCTTGAGAAAAATATGAAGAAACACATTCAAGCTTTAAAATCTGTCAGTATTCTTTATGCT TGAAGAACAAAGTCACTTTGATTTGAAGTGAGAACTATCATTAGGTGGTTTTCTGATTTCCTGATGAAGAGTTGGACATACTGT CTTAATCTATAGTGAAAAGAATTTGAGCTGTCTTCATAAACACTGGGACTAGCAATGATAATAGGGAGATAAGAAACTTTAATT ATCTTGATCCTTTAAGTGGATTTTATTTGGTGCATTTCTGCTCTGGGTATATAATAAAAGTGGGGGTTTTTGGTGAAATGAGTG- AAGAAATGAAAGGTTTCTAAAGTGCTATCCAAATACATCAGTAACATTTTTCTAAGGAGTTTAATTGTTAAATTGGAAGTCATT CATAAGAAATATTTATGCTTGAATATGAAAATCTATGAAAGCATAAATGCTGCTGTTTGATTTGGTGGATATTAAGATTATACA CATCCAACATATTAAAGTTATGAAAGAAACTTGACTTCTGAAAATCCTTAAGAGACTGCTTTCTTGATTCAGCTAGAGAAATAT TATAGTCAAAACTATTGAGTGAATTTTGTTTACAAATAGGTAAATTATACATTTGTATATTTAAAGTGCTGTGACATAGTATCT TTAAGAGTTTGGCTCAGTTTTCACAGATTCATTTTGTCTTAAGAATTTCTTAAATATGTTCATGTATAATACTTGATCAAAATA TTTTTGGGTTTTTTGTTTTGTTTTAATGGGTTAGAAAATGTTTACAATCTTGGTCTTATATGATCACCAATGGAATAGTAACTT CCAGGTTTATATCAATATGAGCTGACTTTAACTGAGTTGTTTGGGATAGGGAAGAAGCAGTCCCTCTACAGTATACAACTACTG CTTGCCAGCTGGATCAAAATAATCATGTTTTATGAAAATATCTCCCTTAAGCAGTGTTAAGGTTGGTTTGCAGTGTGTAAGTGG CACATTGAACTGGAAGTTTTCTTGAAAGCTGCTTCATCTATTAAGAAGCAATTTTCAAATTGTAGCGAATTATATTATCCCCTC TTTTAAAGAAACAGTCGTTATATGCTGATGTTTCTTAAAATAACTAAAATGTTCCTCTTAATGTGATTTTAAATGGAGTTATTT' GTAGGTCCTTTCTTAGTAGTAAAGAATCTTCTAGAGGGAAACATTTGTGCTTTTAGGGATAATCTTCCTTGTGCCTCACTAGAT CCCTAAGTGGGTATGACTCTTGTTATTACCACATGCTTTTTTAGTATATTTCACAAATTTACTTTTAAATATTATTTTAGATAC GGTGTAACATGTGCAATTCAGAATAATTTTATAACAGGTCATGAAAAACATAACTTTAGT'TAGGATTCACAATATTTGTTCTCC ACATAATGAGAGATGAATGAGCCTTTGGAGATACTGATATAAGGCAATTATTTTTTGCAATGTTGAATGTGTTTTTTAGTTTGA TTCTTTTTTTTTCCCCCAATAGGGCACTACCTGCCATATCATCTTGTATTACTTTTTGATGTAAAGCGACTAATATTTACACTA TGCCATATTTTTTTTAATTATAGTTGTAAATTATGAAAGATCCTTGAATTTTCTACAGATCTACAACTACTAATGTAACAGACA AGGGCAATCTTGGTATTTAAATCTGAGCATGGCAGTTCTACCATAAAAAGTACTCTATTTTTCTAATTTCTAGGATTTTTAAAA TAACATTTCTGTAAGTCTGACATACTAATAGTCACTCAAGCAGTACCATTTATTTTAGTTTGCATATATTTTCACTGTTTTTAA TTTAATGTATTGAGTCTAATAGACTGTTTTGCAATAATTAGAATAAAGATTTATTTCTTCTAATCAAAGATGCATAACAGCTAT TATCTAGGGGACCACCTAAATGTGATTTCAAAATTTTGTTAACTATTACAAATGTAATCCTTATATAGAAATTTTAATTTTGTA AAGTAGTGTATAATATTGTAATATTAAATTCTTGTTCTTAAATTCAAATATGTATTGATCTTCAATGTGCTGTGTTAAATCTTG CTTCTCTGAAAAGTTGGAGACAAGATTTGTCTTCCTTTTTACAGTTTGTAATTTTCACTGTTTTATTCCTGTTAAAAAAAAAAA AAA 297
M HLPLFLLASVTLPSICSHFNPLS EELGSNTGIQVFNQIVKSRPHDNIVISPHGIASVLGMLQLGADGRTKKQLAMVMRYG WGVGKILKKINKAIVSKKNKDIVTV AVFVKNASEIEVPFVTRI>JKD¥FQCEVRNV FEDPASACDSINAW¥KNETRDMIDNL LSPDLIDG¥LTRL¥LVNAVYFKGLWKSRFQPENTKKRTFVAADGKSYQ¥PMLAQ SVFRCGSTSAPNDL YNFIELPYHGESIS MLIALPTESSTPLSAIIPHISTKTIDSWMSIMVPKRVQVILPKFTAVAQTDLKEP KVLGITDMFDSSKA FAKITRSENLHVS HI QKAKIEVSEDGTKASAATTAILIARSSPPWFIVDRPFLFFIRHNPTGAVLFMGQINKP
298
ATGAACTGGCATCTCCCCCTCTTCCTCTTGGCCTCTGTGACGCTGCCTTCCATCTGCTCCCACTTCAATCCTCTGTCTCTCGAG GAACTAGGCTCCAACACGGGGATCCAGGTTTTCAATCAGATTGTGAAGTCGAGGCCTCATGACAACATCGTGATCTCTCCCCAT GGGATTGCGTCGGTCCTGGGGATGCTTCAGCTGGGGGCGGACGGCAGGACCAAGAAGCAGCTCGCCATGGTGATGAGATACGGC GTAAATGGAGTTGGTAAAATATTAAAGAAGATCAACAAGGeCATCGTCTCCAAGAAGAATAAAGACATTGTGACAGTGGCTAAC GCCGTGTTTGTTAAGAATGCCTCTGAAATTGAAGTGCCTTTTGTTACAAGGAACAAAGATGTGTTCCAGTGTGAGGTCCGGAAT GTGAACTTTGAGGATCCAGCCTCTGCCTGTGATTCCATCAATGCATGGGTTAAAAACGAAACCAGGGATATGATTGACAATCTG CTGTCCCCAGATCTTATTGATGGTGTGCTCACCAGACTGGTCCTCGTCAACGCAGTGTATTTCAAGGGTCTGTGGAAATCACGG TTCCAACCCGAGAACACAAAGAAACGCACTTTCGTGGCAGCCGACGGGAAATCCTATCAAGTGCCAATGCTGGCCCAGCTCTCC GTGTTCCGGTGTGGGTCGACAAGTGCCCCCAATGATTTATGGTACAACTTCATTGAACTGCCCTACCACGGGGAAAGCATCAGC ATGCTGATTGCACTGCCGACTGAGAGCTCCACTCCGCTGTCTGCCATCATCCCACACATCAGCACCAAGACCATAGACAGCTGG ATGAGCATCATGGTCCCCAAGAGGGTGCAGGTGATCCTGCCCAAGTTCACAGCTGTAGCACAAACAGATTTGAAGGAGCCGCTG AAAGTTCTTGGCATTACTGACATGTTTGATTCATCAAAGGCAAATTTTGCAAAAATAACAAGGTCAGAAAACCTCCATGTTTCT CATATCTTGCAAAAAGCAAAAATTGAAGTCAGTGAAGATGGAACCAAAGCTTCAGCAGCAACAACTGCAATTCTCATTGCAAGA TCATCGCCTCCCTGGTTTATAGTAGACAGACCTTTTCTGTTTTTCATCCGACATAATCCTACAGGTGCTGTGTTATTCATGGGG CAGATAAACAAACCC
299
MSQRPRAPRSALWLLAPPLLRWAPPLLTVLHSDLFQALLDILDYYEASLSESQKYRYQDEDTPPLEHSPAHLPNQA SPPVIV TDTLEAPGYELQVNGTEGE EYEEITLERGNSGLGFSIAGGTDNPHIGDDPSIFITKIIPGGAAAQDGRLRV-.DSILFWEVDV REVTHSAAVEALKEAGSIVRLYV RRKPPAEKVMEIKLIKGPKGLGFSIAGGVGNQHIPGDNSIYVTKIIEGGAAHKDGR QIG DKILAVNSVGLEDVMHEDAVAA K TYDWYLKVAKPSNAYLSDSYAPPDITTSYSQH DNEISHSSYLGTDYPTAMTPTSPRR YSPVAKDLLGEEDIPREPRRIVIHRGSTGLGFNIVGGEDGEGIFISFILAGGPADLSGE RKGDQILSVNGVDLRNASHEQAAI ALKNAGQTVTIIAQYKPEEYSRFEAKIHD REQ M SSLGSGTAS RSNPKRGFYIRALFDYDKTKDCGFLSQALSFRFGDVLH VIDASDEEWWQARRVHSDSETDDIGFIPSKRRVERREWSR KAKDWGSSSGSQGREDSVLSYETVTQMEVHYARPIIILGPTKD RA DDLLSEFPDKFGSCVPHTTRPKREYEIDGRDYHFVSSREK EKDIQAHKFIEAGQYNSHLYGTSVQSVREVAEQGKHCILD VSAAVRRLQAAHLHPIAIFIRPRSLE VLEI1.KRITEEQARKAFDRATKLEQEFTECFSA1VEGDSFEEIYHKVKRVIEDLSG PYIWPARER
300
GGATCCGCGGGACAGATGAGGAAGGGGCTTAAGTCACTGCAGCCAGAGGGATGGAGGTGGACTGATGGGAGGGCTTCTCCGGTG GGGTTAGAAGGGAAAAGTAGGGAAAGAGAAGTGTAAGGTAGATGGCAGAGGCAGAGACATGGAAAGACAGACTCTAGGGTTCCT GATGATATCTATCTCGGCCAACACAAAAGGGAGGGTACAGTGGTGGGGGCACCCAAGCTAGGGTGTGAGTACCCTAAGTGTATT CTTCTGAGATGTAGGCCATTCACTAACTCTTGGAACAGCTACAGTTTCACAGTAGGAAGACCCCCCCAGATTCACTGCCCCTCC CTTAGTAAAGCCTCTGAGACCTTCCTGAACATTCCCTTCTGTCTTTGCCCTCTGTTCCTTCCAGAGACTATGTGCCCAGGCAGA TGGATTCCTCCCGGGCCTGAGAGGAACTGCAGGAATTCTCCTGCCTCTTACCCGTAAAACCCCAACTTCTCTAGCCCTAGGGCA GGAAGTCCCAAACAATTTCTACCCCTTTTTCTGCAATTCTCATTGGGGTGAGAGGAGGCCCAGGAGGAGAGAGAGCTGGGCTCA GCTTCTTTTTGAGCTGCTGGAGCCCTCTGTGAGGAGGCCCTCTTTGCTGGCTTCTCAGGAGAGTGTGGCTAGGTTCTGCCTGCC TATGGGAAGAGGGGGCCAGGGTGTGTGGAGCAAGATGGTGCGGTGCTGGTGCCTTGGGACCTGGGGGAATGGGACAGCTGGTCG GCTCAGAGACGGCCTACTTTACTCACAGCTGGAATTTAGTGGGGAGAAGCAGCTCAACTCCAATCCTGGAGGATTAGGGAGATT AAAGTGAGAGAAGAGAGAGATGTCCCAGAGACCAAGAGCTCCCAGGTCAGCCCTCTGGCTCCTGGCACCCCCACTGCTGCGGTG GGCACCCCCACTCCTCACAGTGCTGCATAGCGACCTCTTCCAGGCCTTGCTGGACATCCTGGACTATTATGAGGCTTCCCTCTC AGAGAGTCAGAAATACCGCTACCAAGATGAAGACACGCCCCCTCTGGAGCACAGCCCGGCCCACCTCCCCAACCAGGCCAATTC TCCCCCAGTGATTGTCAACACAGATACCCTAGAAGCCCCAGGATATGAGTTGCAGGTGAACGGGACCGAGGGGGAGATGGAATA CGAGGAAATCACATTGGAAAGGGGTAACTCAGGTCTGGGCTTCAGCATCGCAGGTGGCACTGACAACCCACACATCGGTGACGA CCCATCCATTTTCATCACCAAGATCATTCCTGGTGGGGCTGCGGCCCAGGATGGCCGCCTCAGGGTCAACGACAGCATCCTGTT TGTAAATGAAGTGGACGTGCGCGAGGTGACCCACTCAGCGGCGGTGGAAGCCCTCAAAGAGGCAGGCTCCATCGTTCGCCTCTA TGTCATGCGCCGGAAGCCCCCGGCTGAGAAGGTCATGGAGATCAAGCTCATCAAGGGGCCTAAAGGTCTTGGCTTCAGCATCGC AGGGGGCGTAGGGAACCAGCACATCCCAGGAGATAATAGCATCTATGTAACAAAGATCATCGAAGGGGGTGCTGCCCACAAGGA TGGGAGGTTGCAGATTGGAGACAAGATCCTGGCGGTCAACAGTGTGGGGCTAGAGGACGTCATGCATGAAGATGCTGTGGCAGC CCTGAAGAACACGTATGATGTTGTCTACCTAAAGGTGGCCAAGCCCAGCAATGCCTACCTGAGTGACAGCTATGCTCCCCCAGA CATCACAACCTCTTATTCCCAGCACCTGGACAATGAGATCAGTCACAGCAGCTACCTGGGCACCGACTACCCCACAGCCATGAC CCCCACTTCCCCTCGGCGCTACTCTCCAGTGGCCAAGGACCTGCTCGGGGAGGAAGACATTCCCCGAGAACCGAGGCGAATTGT GATCCACCGGGGCTCCACGGGCCTGGGCTTCAACATCGTGGGTGGCGAGGACGGTGAAGGCATCTTCATCTCCTTTATCCTGGC CGGGGGCCCTGCAGACCTCAGTGGGGAGCTGCGGAAGGGGGACCAGATCCTGTCGGTCAACGGTGTGGACCTCCGAAATGCCAG CCATGAGCAGGCTGCCATTGCCCTGAAGAATGCGGGTCAGACGGTCACGATCATCGCTCAGTATAAACCAGAAGAGTACAGCCG ATTCGAGGCCAAGATCCACGACCTTCGGGAACAGCTCATGAACAGCAGCCTGGGCTCAGGGACTGCGTCCTTGCGGAGCAACCC CAAAAGGGGTTTCTACATCAGGGCCCTGTTTGATTACGACAAGACCAAGGACTGCGGCTTCCTGAGCCAGGCCCTGAGCTTCCG CTTTGGGGATGTGCTGCATGTCATCGATGCTAGTGATGAGGAGTGGTGGCAGGCACGGCGGGTCCACTCTGACAGTGAGACCGA CGACATTGGGTTCATCCCCAGCAAACGGCGGGTTGAGCGACGAGAGTGGTCAAGGTTAAAGGCCAAGGACTGGGGCTCCAGCTC TGGATCGCAGGGTCGAGAAGACTCGGTTCTGAGCTACGAGACAGTGACGCAGATGGAAGTGCACTATGCTCGCCCCATCATCAT CCTTGGGCCCACCAAGGACCGCGCCAACGATGATCTTCTCTCCGAGTTCCCCGACAAGTTTGGATCCTGTGTTCCCCATACGAC ACGGCCCAAGCGGGAGTATGAGATAGATGGCCGGGATTACCACTTTGTGTCGTCCCGGGAGAAAATGGAGAAGGACATTCAGGC GCACAAGTTCATTGAGGCCGGCCAGTACAACAGCCACCTCTATGGGACCAGCGTCCAGTCCGTGCGAGAGGTGGCAGAGCAGGG GAAGCACTGCATCCTCGATGTCTCGGCCAATGCCGTGCGGCGGCTGCAGGCGGCCCACCTGCACCCCATCGCCATCTTCATCCG CCCCCGCTCCCTGGAGAATGTGCTAGAGATTAACAAGCGGATCACAGAGGAGCAAGCCCGCAAAGCCTTCGACAGAGCCACCAA GCTGGAGCAGGAGTTCACAGAGTGCTTCTCAGCCATCGTGGAGGGTGACAGCTTTGAGGAGATCTACCACAAGGTGAAGCGTGT CATCGAGGACCTCTCAGGCCCCTACATCTGGGTTCCAGCCCGAGAGAGACTCTGATTCCTGCCCTGGCTTGGCCTGGACTCGCC CTGCCTCCATCACCTGGGCCCTTGGTCTGGACTGAATTGCCCAAGCCCTTGGCTCCCCCCGGCCTCCCTCCCACCCCTTCTTAT TTATTTCCTTTCTAACTGGATCCAGCCTGTTGGAGGGGGGACACTCCTCTGCATGTATCCCCGCACCCCAGAACTGGGCTCCTG AACGCCAGGAACCTGGGGTCTGGGGGGGAGCTGGGCTCCTTGTTCCGAGCCCTTGCTCCTTAGGATCCCCGCCCCCACCTGCCC CCAATGCACACACAGACCCACCGGGGGCCACCTGCCCTCCCCCATCCTCTCCCACACACATTCCAGAAGTCAGGGCCCCCTCGA GGAGCACCCGCTGCAGGGATGCAGGGCCACAGGCCTCCGCTCTCTCCTAAGGCAGGGTCTGGGGTCACCCCTGCCTCATCGTAA TTCCCCATGTTACCTTGATTTCTCATTTATTTTTTCCACTTTTTTTCTTCTCAAAGGTGGTTTTTTGGGGGGAGAAGCAGGGGA CTCCGCAGCGGGCCCCTGCCTTCCACATGCCCCCACCATTTTTCTTTGCCGGTTTGCATGAGTGGAAGGTCTAAATGTGGCTTT TTTTTTTTTTTTCCTGGGAATTTTTTTGGGGAAAAGGGAGGGATGGGTCTAGGGAGTGGGAAATGCGGGAGGGAGGGTGGGGCA GGGGTCGGGGGTCGGGTGTCCGGGAGCCAGGGAAGACTGGAAATGCTGCCGCCTTCTGCAATTTATTTATTTTTTTCTTTTGAG AGAGTGAAAGGAAGAGACAGATACTTGAAAAAAAAAAAAAAAAAAAA
301 MDRGEQGLLRTDPVPEEGEDVAATISATET SEEEQEE RRELAKVEEEIQTLSQVLAAKEKHLAEIKRKLGINSLQELKQNIA KG QDVTATSAY KTSETLSQAGQKASAAFSSVGSVITKKLEDVKNSPTFKSFEEKVENLKSKVGGTKPAGGDFGEVLNSAAA SATTTEP PEKTQESL
302
GAGGAGCTCTGCGCGGCGCGGCGGGCGATCCGAGCCGGGACGGGCTGCAGGCGGGGGTGCTGCAGAGGACACGAGGCGGCGGGC TGGAGACATGGACCGCGGCGAGCAAGGTCTGCTGAGAACAGACCCAGTCCCTGAGGAAGGAGAAGATGTTGCTGCCACGATCAG TGCCACAGAGACCCTCTCGGAAGAGGAGCAGGAAGAGCTAAGAAGAGAACTTGCAAAGGTAGAAGAAGAAATCCAGACTCTGTC TCAAGTGTTAGCAGCAAAAGAGAAGCATCTAGCAGAGATCAAGCGGAAACTTGGAATCAATTCTCTACAGGAACTAAAACAGAA CATTGCCAAAGGGTGGCAAGACGTGACAGCAACATCTGCTTACAAGAAGACATCTGAAACCTTATCCCAGGCTGGACAGAAGGC CTCAGCTGCTTTTTCGTCTGTTGGCTCAGTCATCACCAAAAAGCTGGAAGATGTAAAAAACTCCCCAACTTTTAAATCATTTGA AGAAAAGGTCGAAAACTTAAAGTCTAAAGTAGGGGGAACCAAGCCTGCTGGTGGTGATTTTGGAGAAGTCTTGAATTCGGCTGC AAATGCTAGTGCCACCACCACGGAGCCTCTTCCAGAAAAGACACAGGAGAGCCTGTGAGATTCCTACCTTTGTTCTGCTACCCA CTGCCAGATGCTGCAAGCGAGGTCCAAGCACATCTTGTCAACATGCATTGCCATGAATTTCTACCAGATGTGCTTTTATTTAGC TTTACATATTCCTTTGACCAAATAGTTTGTGGGTTAAACAAAATGAAAATATCTTCACCTCTATTCTTGGGAAACACCCTTTAG TGTACATTTATGTTCCTTTATTTAGGAAACACCATTATAAAAACACTTATAGTAAATGGGGACATTCACTATAATGATCTAAGA AGCTACAGATTGTCATAGTTGTTTTCCTGCTTTACAAAATTGCTCCAGATCTGGAATGCCAGTTTGACCTTTGTCTTCTATAAT ATTTCCTTTTTTTCCCCTCTTTGAATCTCTGTATATTTGATTCTTAACTAAAATTGTTCTCTTAAATATTCTGAATCCTGGTAA TTAAAAGTTTGGGTGTATTTTCTTTACCTCCAAGGAAAGAACTACTAGCTACAAAAAATATTTTGGAATAAGCATTGTTTTGGT ATAAGGTACATATTTTGGTTGAAGACACCAGACTGAAGTAAACAGCTGTGCATCCAATTTATTATAGTTTTGTAAGTAACAATA TGTAATCAAACTTCTAGGTGACTTGAGAGTGGAACCTCCTATATCATTATTTAGCACCGTTTGTGACAGTAACCATTTCAGTGT ATTGTTTATTATACCACTTATATCAACTTATTTTTCACCAGGTTAAAATTTTAATTTCTACAAAATAACATTCTGAATCAAGCA CACTGTATGTTCAGTAGGTTGAACTATGAACACTGTCATCAATGTTCAGTTCAAAAGCCTGAAAGTTTAGATCTAGAAGCTGGT AAAAATGACAATATCAATCACATTAGGGGAACCATTGTTGTCTTCACTTAATCCATTTAGCACTATTTAAAATAAGCACACCAA GTTATATGACTAATATAACTTGAAAATTTTTTATACTGAGGGGTTGGTGATAACTCTTGAGGATGTAATGCATTAATAAAAATC AACTCATCATTTTCTACTTGTTTTCAATGTGTTGGAAACTGTAAAATGATACTGTAGAACCTGTCTCCTACTTTGAAAACTGAA TGTCAGGGCTGAGTGAATCAAAGTGTCTAGACATATTTGCATAGAGGCCAAGGTATTCTATTCTAATAACTGCTTACTCAACAC TACCACCTTTTCCTTATACTGTATATGATTATGGCCTACAATGTTGTATTTGTTATTTATTAAATTGTGATTGTTTTATTATTG TTTATGCCAAATGTTAACTGCCAAGCTTGGAGTGACCTAAAGCATTTTTTAAAAGCATGGCTAGATTTACTTCAGTATAAATTA TCTTATGAAAACCAAATTTTAAAAGCCACAGGTGTTGATTGTTATAAAATAACATGCTGCCATTCTTGATTGCTAGAGTTTTTG TTAGTACTTTGGATGCAATTAAAACTATGTGCTATCACATGTGAAAAGCTTAATAAATTCCATCTATCAGTAGTATAGGTCTCA ATATTTATTATGAGACCAGTGGTCTGGAAACAGCTTGTTGTACCGAATCAACTGGAGTCTATGCTTAAAAAAAAAAATTTTTTT TTAACCATCCTTAAATTATTGCTTAATGGTATCATATTAACATATTCTAAATAAGGGCTTTAAGGCACAGGCTGTTGAAGCATT TTCTCAGAGGAGTGGATCTGTAGAAGTCTGTCTTTCTATAGAAATATTGTGCTTACTCAAGTGTTAAATTATTTTTTCTATGAA CTAGTCTACTTCTTAAAATTCAAACATATTCTTTTGATCACATTGTTTCTTGAGCATCCTGCCCTGCTACTAACTTTTCAACAA GGCAAAATGGAGTAAAGTGGCAATTTCTTTAGATGAGTGAAATACCCTCAAGTCTCTTTTCTGCCCAAAAAGGGAAAAGTGATA GAAATGGGGGTGGCAAGTGGGGTGAGTGGATGAAGGTGGGTATTGGGGGTGGCTGTGAAAGAAAATAATGGAGAATCACTTTTC TAGACATCTACCTATACTTAATCTAAGAAACAAAGTAATCTACTGTAAAGTACTCTGCCCCTTGAAAGAAGTATTAAAAAGAGT GAGGATGGATTTAGAAAAAAACATGAATTTAGAAATATTCAAAATGGTTTTTGTGGCAGATTCAATATTATGAATTCACAGATA TTTAAAGAATGAGAAACATAGTAATTAGTAGAAATGCCAGAAACAGTTCCTGGTTCCTCTTGTGTTTGACACTAAGAAAAAGC AAGAGTGTGAAATCTCAGATACTTATGAAATCTCACAGATGTAAGGACTCAAGTGTAGAAGAAAATATCCCCTTCTTACAAAAA 5 GAAATGTCAATTTATGGAGTTTGTGGGAAATAGGGCAAGAATTCTTATGCTTATGAGAGCCAAGTAGTCAGTGGAAGAGAGTAG AGCTCAAAACTGGATTATCACCTTAGCAACTTAGAATAGTTTGAAATAGAAAAAAAGTATTTAATTTGGATCTGGATCTGTTAA' GATATGCACAGTCTATTTTTTGTATAGTATTGGAAAATAAAAATGCTATAATTTG
• 303
MSWRVSNGSPSLERMDARQAEHP PSACRNLFGPVDHEE TRDLEKHCRDMEEASQRKMFDFQNHKPLEGKYEWQEVEKGSL 0 PEFYYRPPRPPKGACKVPAQESQDVSGSRPAAPLIGAPANSEDTHL¥DPKTDPSDSQTGLAEQCAGIRKRPATDDSSTQNKRA RTEE VSDGSPNAGSVEQTPKKPGLRRRQT
304
ATGTCAAACGTGCGAGTGTCTAACGGGAGCCCTAGCCTGGAGCGGATGGACGCCAGGCAGGCGGAGCACCCCAAGCCCTCGGCC TGCAGGAACCTCTTCGGCCCGGTGGACCACGAAGAGTTAACCCGGGACTTGGAGAAGCACTGCAGAGACATGGAAGAGGCGAGC 5 CAGCGCAAGTGGAATTTCGATTTTCAGAATCACAAACCCCTAGAGGGCAAGTACGAGTGGCAAGAGGTGGAGAAGGGCAGCTTG CCCGAGTTCTACTACAGACCCCCGCGGCCCCCCAAAGGTGCCTGCAAGGTGCCGGCGCAGGAGAGCCAGGATGTCAGCGGGAGC CGCCCGGCGGCGCCTTTAATTGGGGCTCCGGCTAACTCTGAGGACACGCATTTGGTGGACCCAAAGACTGATCCGTCGGACAGC CAGACGGGGTTAGCGGAGCAATGCGCAGGAATAAGGAAGCGACCTGCAACCGACGATTCTTCTACTCAAAACAAAAGAGCCAAC AGAACAGAAGAAAATGTTTCAGACGGTTCCCCAAATGCCGGTTCTGTGGAGCAGACGCCCAAGAAGCCTGGCCTCAGAAGACGT 0 CAAACGTAA
305 CFSFIMPP-y -ADILDIWAVDSQIASDGSIPVDFLLPTGIYIQ E¥PREATISYIKQMLWKQVHNYPMFNLL DIDSYMFACVN
: . •QTAVYEELEDETRRLCD¥RPFLPVLKLVTRSCDPGEK DSKIG¥LIGKGLHEFDS--KDPEVNEFRRKMRKFSEEKILSLVGLS
MDWLKQTYPPEHEPSIPENLEDK YGGK IVAVHFENCQDVFSFQVSPNMNPIKVNELAIQKRLTIHGKEDEVSPYDYVLQVSG 5 RVEYVFGDHPLIQFQYIrøCVMMLPHFILVECC IKKMYEQEMIAIE IN SSN PLP PPKKTRIISHWE MPFQIV
LVKGNKLNTEETVKVHVRAGLFHGTE LCKTIVSSEVSGK DHIW EPLEFDINICDLPRMARLCFA¥YAVLDKVKTKKSTKTI
NPSKYQTIRKAGKVHYPVAWVNT VFDFKGQLRTGDII HSWSSFPDELEEMLNPMGTVQTNPYTENATALHVKFPENKKQPYY
YPPFDKIIEKAAEIASSDSA VSSRGGKKFLPVLKEILDRDPLSQLCENEMD I TLRQDCREIFPQSLPKLL SIK K EDV
AQLQA LQIWPKLPPREA EL DFNYPDQYVREYAVGCLRQ SDEELSQY LQLVQV KYEPFLDCALSRF LERALGNRRIGQ 0 FLF HLRSEVHIPAVSVQFGVILEAYCRGSVGHMKVLSKQVEALNKLKTLNSLIKLNAVKLNRAKGKEAMHTCLKQSAYREALS
DLQSPLNPCVI SELYVEKCKYMDSKMKPLWLVYrøKVFGEDSVGVIFKNGDD RQDM TLQMLRLMDLLWKEAGLDLRMLPYG
C ATGDRSGLIEWSTSETIADIQ NSSNVAAAAAFNKDALLN KEYNSGDDLDRAIEEFT SCAGYCVASYVLGIGDRHSDN
IMVKKTGQLFHIDFGHI GNFKSKFGIKRERVPFII-TYDFIHVIQQGKTGNTEKFGRFRQCCEDAYLILRRHGNLFITLFALML
TAG PELTSVKDIQYLKDSLALGKSEEEALKQFKQKFDEA RES TTKVWWMAHTVRKDYRS 5 306
ATGTGCT CAGTTTCATAATGCCTCCTGCTATGGCAGACATCCTTGACATCTGGGCGGTGGATTCACAGATAGCATCTGATGGC TCCATACCTGTGGATTTCCTTTTGCCCACTGGGATTTATATCCAGTTGGAGGTACCTCGGGAAGCTACCATTTCTTATATTAAG CAGATGTTATGGAAGCAAGTTCACAATTACCCAATGTTCAACCTCCTTATGGATATTGACTCCTATATGTTTGGATGTGTGAAT CAGACTGCTGTATATGAGGAGCTTGAAGATGAAACACGAAGACTCTGTGATGTCAGACCTTTTCTT.CCAGTTCTCAAATTAGTG 0 ACAAGAAGTTGTGACCCAGGGGAAAAATTAGACTCAAAAATTGGAGTCCTTATAGGAAAAGGTCTGCATGAATTTGATTCCTTG AAGGATCCTGAAGTAAATGAATTTCGAAGAAAAATGCGCAAATTCAGCGAGGAAAAAATCCTGTCACTTGTGGGATTGTCTTGG ATGGACTGGCTAAAACAAACATATCCACCAGAGCATGAACCATCCATCCCTGAAAACTTAGAAGATAAACTTTATGGGGGAAAG CTCATCGTAGCTGTTCATTTTGAAAACTGCCAGGACGTGTTTAGCTTTCAAGTGTCTCCTAATATGAATCCTATCAAAGTAAAT GAATTGGCAATCCAAAAACGTTTGACTATTCATGGGAAGGAAGATGAAGTTAGCCCCTATGAT'ΓATGTGTTGCAAGTCAGCGGG 5 AGAGTAGAATATGTTTTTGGTGATCATCCACTAATTCAGTTCCAGTATATCCGGAACTGTGTGATGAACAGAGCCCTGCCCCAT TTTATACTTGTGGAATGCTGCAAGATCAAGAAAATGTATGAACAAGAAATGATTGCCATAGAGGCTGCCATAAATCGAAATTCA TCTAATCTTCCTCTTCCATTACCACCAAAGAAAACACGAATTATTTCTCATGTTTGGGAAAATAACAACCCTTTCCAAATTGTC TTGGTTAAGGGAAATAAACTTAACACAGAGGAAACTGTAAAAGTTCATGTCAGGGCTGGTCTTTTTCATGGTACTGAGCTCCTG TGTAAAACCATCGTAAGCTCAGAGGTATCAGGGAAAAATGATCATATTTGGAATGAACCACTGGAATTTGATATTAATATTTGT GACTTACCAAGAATGGCTCGATTATGTTTTGCTGTTTATGCAGTTTTGGATAAAGTAAAAACGAAGAAATCAACGAAAACTATT AATCCCTCTAAATATCAGACCATCAGGAAAGCTGGAAAAGTGCATTATCCTGTAGCGTGGGTAAATACGATGGTTTTTGACTTT AAAGGACAATTGAGAACTGGAGACATAATATTACACAGCTGGTCTTCATTTCCTGATGAACTCGAAGAAATGTTGAATCCAATG GGAACTGTTCAAACAAATCCATATACTGAAAATGCAACAGCTTTGCATGTTAAATTTCCAGAGAATAAAAAACAACCTTATTAT TACCCTCCCTTCGATAAGATTATTGAAAAGGCAGCTGAGATTGCAAGCAGTGATAGTGCTAATGTGTCAAGTCGAGGTGGAAAA AAGTTTCTTCCTGTATTGAAAGAAATCTTGGACAGGGATCCCTTGTCTCAACTGTGTGAAAATGAAATGGATCTTATTTGGACT TTGCGACAAGACTGCCGAGAGATTTTCCCACAATCACTGCCAAAATTACTGCTGTCAATCAAGTGGAATAAACTTGAGGATGTT GCTCAGGTTCAGGCGCTGCTTCAGATTTGGCCTAAACTGCCCCCCCGGGAGGCCCTAGAGCTTCTGGATTTCAACTATCCAGAC CAGTACGTTCGAGAATATGCTGTAGGCTGCCTGCGACAGATGAGTGATGAAGAACTTTCTCAATATCTTTTACAACTGGTGCAA GTGTTAAAATATGAGCCTTTTCTTGATTGTGCCCTCTCTAGATTCCTATTAGAAAGAGCACTTGGTAATCGGAGGATAGGGCAG TTTCTATTTTGGCATCTTAGGTCAGAAGTGCACATTCCTGCTGTCTCAGTACAATTTGGTGTCATCCTTGAAGCATACTGCCGG GGAAGTGTGGGGCACATGAAAGTGCTTTCTAAGCAGGTTGAAGCACTCAATAAGTTAAAAACTTTAAATAGTTTAATCAAACTG AATGCCGTGAAGTTAAACAGAGCCAAAGGGAAGGAGGCCATGCATACCTGTTTAAAACAGAGTGCTTACCGGGAAGCCCTCTCT GACCTGCAGTCACCCCTGAACCCATGTGTTATCCTCTCAGAACTCTATGTTGAAAAGTGCAAATACATGGATTCCAAAATGAAG CCTTTGTGGCTGGTATACAATAACAAGGTATTTGGTGAGGATTCAGTTGGAGTGATTTTTAAAAATGGTGATGATTTACGACAG GATATGTTGACACTCCAAATGTTGCGCTTGATGGATTTACTCTGGAAAGAAGCTGGTTTGGATCTTCGGATGTTGCCTTATGGC TGTTTAGCAACAGGAGATCGCTCTGGCCTCATTGAAGTTGTGAGCACCTCTGAAACAATTGCTGACATTCAGCTGAACAGTAGC AATGTGGCTGCTGCAGCAGCCTTCAACAAAGATGCCCTTCTGAACTGGCTTAAAGAATACAACTCTGGGGATGACCTGGACCGA GCCATTGAGGAATTTACACTGTCCTGTGCTGGCTACTGTGTAGCTTCTTATGTCCTTGGGATTGGTGACAGACATAGTGACAAC ATCATGGTCAAAAAAACTGGCCAGCTCTTCCACATTGACTTTGGACATATTCTTGGAAATTTCAAATCTAAGTTTGGCATTAAA AGGGAGCGAGTGCCTTTTATTCTTACCTATGATTTCATCCATGTCATTCAACAAGGAAAAACAGGAAATACAGAAAAGTTTGGC CGGTTCCGCCAGTGTTGTGAGGATGCATATCTGATTTTACGACGGCATGGGAATCTCTTCATCACTCTCTTTGCGCTGATGTTG ACTGCAGGGCTTCCTGAACTCACATCAGTCAAAGATATACAGTATCTTAAGGACTCTCTTGCATTAGGGAAGAGTGAAGAAGAA GCACTCAAACAGTTTAAGCAAAAATTTGATGAGGCGCTCAGGGAAAGCTGGACTACTAAAGTGAACTGGATGGCCCACACAGTT CGGAAAGACTACAGATCTTAA
307
MMVLDTADIAIVA YFILVMCIGFFAMKSNRSTVSGYF AGRSMT VTIGAS FVSNIGSEHFIGLAGSGAASGFAVGAWEF • NALLL QLLG VFIPIYIRSGVYTMPEYLSKRFGGHRIQ¥YFAALSLILYIFTK SVDLYSGALFIQESLGNLYVSVI IGM TALLTVTGGVAVIYTDTLQALLMIIGALTLMIISIMEIGGFEE¥KRRYMLASPDVTSILLTYN SNTNSC VSPKKEA KMLR NPTDEDVPWPGFILGQTPASVWYWCADQVIVQRVL KNIAHAKGST MAGFLKL PMFIIVVPGMISRILFTDDIACINPEHC MLVCGSI^GCSNIAYPRLWKVPVGLRGLMMAVMIAAMSDLDSIFNSASTIFT DVYKLIRKSASSRELMIVGRIFVAFMVV ISIAWVPIIVE QGGQMYLYIQEVADYLTPPVAALFLLAIF KRCNEQGAFYGGMAGFVGAVRLILAFAYRAPECDQPDNRPG FIKDIHYMYVATGLFWVTGLITVIVSLLTPPPTKEQIRTTTF SKKNLWKENCSPKEEPYQMQEKSILRCSENETIHHIIPN GKSEDSIKGLQPEDV1.LLVTCREEGNP¥ASLGHSEAETP¥DAYSNGQAALMGEKERKKETDDGGRY KFID FCGFKSKSLSKR S RDL EEEAVCLQMLEETRQVK¥I NIGLFAVCS GIFMFVYFS
308
GCGGCCGCCCGCGGGCGGAGAGGGGGCGGCGCGGCGGeAAGGCGCGCGGGCGGGGCGGGGCGCGCCGAGGGGGCGTGGCGCGGC GTCTGCGCAGCTGCCAGCGCCTTTAAGCCCGGGCTCGCGCTCTCGGACCGTGCTTTCGCCGCCTGGGAGCCGTCCGGCGCAGCA GTTTCTAGGTCCCCACTGTCCCCGCCGTCCCGCCCCTTCGCGTCCCGGGAACCGGTTGGCTTCCGAGCCGCACTCGCCGATCCT CCAGGCATGCCCCGCTACGAGCTGGCTTTAATCCTGAAAGCCATGCAGCGGGTAAGTGACCTTCCCTCAGAGCCGGTTTTCCCG CGCGGGCGCCCCCTGTGCTTGTCATGACCCCTATATTGAGGTTGGCAAATAGATGTATGTTTATGTGTTGAATAAAATAATTAA TAAAATAATTAAGGTACGTATATATAGTTTTATGACTGGATATGGCTTTGGGTATGAAGGCTTCTGCTTTATAGAAAAATGCTG ATTTTTTTGTTTTCTATTATAAATGAGTAGAAAAACCTTGTAAGATCTGAAATGAAGATACTGGATGTGTTACCATAGAATAAA CAAAGACTGGCATTGGGAGACTAGAAGGAGCTTTAGAGGCAGATGGGACTGGGTTTTGGATTGTAGCACCTACTTCCTAAGGAC TTTAACCTTCTGGATCCTCAGTTCCTTCTTTGTAAGCCGGAAGTAATTCATTTGGGAGGGTATTTGAAGATAAAGTGGTTATGT GACCTTGGAGGTAGTTAAGTGTAGTTCTGTCATTAAAGTAGCTTTGTGGTCTTAGGCAAGTCGCTGTGAACTTCATTGCCTAGT TTTTCATTATTCCCAGTTTATTAATGAAGAAACTCTAAAAGATAAAACTTATTATATCTAAGTTTATTTCATCAGAATCCCAAA .CTAGATCAAAGCTGAAATACAGTTGCTTGTTAAGTAAATGTTTGAATTAGTGGTGTTGGTGCTTACTACTCTGCTCCCATCTAT TATTGCCATGAGGGGTGTGGGCCTGGTTTTGCCAGCTTTTTTTTTCTCTCTTCCTCCTACCAGCCAGAAATCCAGATTTTATAG GAAATCTGGTTTTTTTTTTTTGATGTTGCCAACTAATTGAATACTTAGGTACCATGGATCAAATGTAATGTATCTGTGGGTTAG GTTGGCTCTCAT.TTTGTAATCTAGATATTCAGATAATTAGCTGTAGGTTGTCTGTAAATCTCTTAGCATTTATGTTGACAAAGC CCACCTTGTTAATTGGTCACTGGTTTGCAGTAGGACTGATTTCAGCAATGGCAGGCATATTCAATTCTTGAAAGTATCTATAGT TTCGGATTGTTGGGTTGTATATGTGCATTTAGGCTAAAATATACATGTAGGCTTCAGAGCTGCACCGTGTAAACTGTGAGGGAG TGACATTCACAGTCCACTTTTTCTTTCAATGTCTGAGTGATATCTTGTTTTAGGCATGTATTAGTACTATTTGGTTTGTACCCA TTGTATTAACCTCTTAGGTGTTTGAAATACTACTGGCATGCAAAGATTGCTTTGCCTAGAAAATATTTTTTTTTGCTCAGAGTG TATCTGTGGAATTAAAAATAGTTTACCCATGATCCCTGGAAAATAGTATTACCATGAAAAAAATTCAGGTGCTCTCTTGGTAAA GATTATAGAGGAGGGAGGTGATGACATTTTTATTTTTGACCAGGCTTTGTGTTTCCATAAAATAGAAGCCAAGTTATTACCTTG ACTAACCTTCCTTTTTTGTCTTTTTTTTCACTCCCACTCCAGATAGATAACATCAAATTGCAAATAAAACGAACTCAGATCCCA GGTTGTTCTTACGTACGTTTTGGCCCAAGGTGTAATTGACTTGTTTTGCTTCCCCTTGCAATCATTTTTACTATGATTACAGTC CCAGGTAAGGTAATTTCTGTCCACTTTGGGCATACCTCAGTAGAGGTTGGTGTAGATGAAAGCTTAAAAATGAAATTGCAAGTG AAAGCACAGACTTAGCAAAACTTCTTTATTGGAGCCCTCAATCCTCATAAACTGGCATTTTTCTGCTTCTGCCCCAGAATCGAG AATTCCTGGTTTTGTCTTTGTTTTGACTTGAGTTTTTAAAAGTTTCTCTGTAACACCTACCCTGGAGTGGTTAAGTGCTTTAAT TTTGTCAGGTGAAGAAACCAAGTGCAGTTATGGTAGCCGGGTTGCTGTGGATATAATCCAGTTTGAGAAAATTCTCATTGTGGT GATCAGAAGTGCAGTGTTGTGGTTGCATTTCAGCTGCTGGGAAGATGCTCTTGCAAATCCATGTGTCGTCTTTGCTTCCGTTAG AAAGGTGCAGAATCAGTGTAAGTTCCAGATATCTGCTCCCTTTTCATTTTGTGCTCAGATGCCCCGTGTATGAATTCCGAATAT AAAACATCTGTTCAGTCTGGTTTTGATTCAGATTTAAGGTGAATTTCTGTTGCTCAGTTGAAAAGCTAAATTTGAGTGTAGGCT CTGTCAGGCATGTTGTAGGAAAGGTGTATGGTACTGAAGTGTGTGGTTTTGTTTTTTAACTGCTTGACACTGTTAAGTAAGCAA ATGACCCAGTCATGGGTTGTTTTGATTGCCATTCTTCTGTTGGTGTACTGCTTGCCTTCTGTTTTGTTAATAGTCATATGAGAA AACAGTTGTATGAAGTATAGTATCTTGAAGCTTTAAGACACCAAGTTTCCATTAGGCAGCCTAAGTCTCGCAGACTTTGGTAGC ACTGTTGGTCTCATGGGAATGCCATTCTCATGTGTGGACTAAGTAAGGGCCAGGAGATTTTGCAAATTTTGTGTGTGTAAGAAG ATCGAAGAAAACATTTTTCCTAATGTCACTGTCTTGAGTATTTTATCTGATTAGGATGGACTCATTGGAAACTATTGATAATTT CAAGATTTCTTGTCATCTGGCATACAAAGAAAACAGTCGTGACCCTATTTCCCTGGATTTTTCTATCCCTCTACTTGTCCTGTG TTTGCAATGCAAGAGGAAAATCGAGCTGCCTTTATAATCTAGAATACCATGTTTCTGTTTTTATTTCTTAGGTTTAATTCAGGG CGTAATTTCTACCAGTCCCTCCAAATACTGTTAAAGTTACTCTTTTTGTGGTCTTACTTCTTACTTCTTGAGTGTTATATTCTC CAAACCTTGGAGAAAATTAGAAGGTTTTAAAGTTTTCCAACTGAAAAGTATCTTTCAGAGGAAATACCCTAATTTCTGAATCTT CTATTTATAACTTGGCCTGGAGAATTATAATCTGGTCTACCAGGAAGGTGCTTGTGCTTAGGTTTTCTGCCTTAGTCACATGGA AAGATGAGCAGAAGCGATTCCTTCTAGAAACAGTTTTTTTCTAGAAACATAAAATTGGAACCAAGTAGACTGAGAACAGAAAAA AAACACAAAGTTGACCTGGTAGGATGTTTTACCTCTATAAACCTCATAGTTGCTAGCCTTTGAGGGAGGCTAGATGAGTTGATA ATAATGCCTAACCTTAGCAATGGATTGAAGTAGGGGTGCAGGGGTTATGTAGGTGTGTATATGTATTTAGGATATATATACACA CCTACATATTATACACACACACATATGTACAATTCTCTTGAATCCTCAGCCATCTAAGGTTAGGTAGAGCTATTTCCGTGTTGG GAATGGAAAAACTGAAGAATTAAAACACAGACTTGGTCATACGTAATGGTAAATACAGTAGTTTAATGAAATTTTGTATTGTAC CTATCACTCAGCTTCAACTGTTAATTTCCAGTCTGCTCACCTCTGTTTTCTTTATCTTAAAATTTTTTTCATTAATTTCCCTTG GCTAACATGACTAAAAAAAT.TTCAGACTTAAAGAGCAGTTCATTTAACACTTGTATGATTTTTGCCTAGATCACTAATTGTTAG AATATGCCTTATTTTATCTTTT.TTTAATCTGCGTTATTTCGAGAGTTGCAGACATCTTGACATACCTTTCTTAGGAATAAGGGC CTTCCTCCTAACCACAACATAGTCATCACATTCAAAACGGACATTGATACGATACTACCACCAAATATTCAATTCATATAGAAA TTTACGCTGTTCTTCCAGTAATAGTTTTTAGTGTTTTAATTCAGTATTCAATCAAGGATCATATATTTACTTGTTTAGTCTCCT TGAACAGTTCCAAAGCCTTTGTCATTAATAACAGTGGCACTTTGAGGAGTTTTGGAGTCCAGGCCTACTGTTTTGCAGAAACCC TCACTTTGGAGTTGACTGTAGTTGCGTTTTCATGATTAGAGTTAGATTAGCCATTGTTGACAGGAATGAGTATTTCATAGGGAT GTCAATGCATCACACCGGGAGGCATACCACTTTGTTAAGCAGTCATTTGGTTAGGTGGCATTCACCAGAATGGGCCATTGTAAA TGTACCCTATTTCCCTTTTGTATTAAGTGATCTATGGAATAACAAACTTGAGACTGAATATTTTGTTTTCCAACAATCTGCATT
GGTTTTAGCATCTGTTGGTGACTGAATCAGTTATTGCAGGAGTACTTTAAAGCAAACTTAGATATATCATTTCACCTGTAAGTA
ATTAGTGTATAAGAAATAAGGACTTTTTTTTTTTTTTTTTTGAGACTGAGTCTTGCTCTTTCGCCCAAGCTGGAGTGCCAGTGG
CGTGATCTCGGCTCACTGCAAGCTCTGCCTACCGGGTTTCACGCCATTCTCCTGCCTCAGCCCCAGCTGGGACTGGGACTACAG GCGCCCGCCACCGCACCCAGCTAATTTTTTGTAGTTTTAGTAGAGACGGGGTTTCACCGTGTTAGCTAGGGTGGTCTTGATGTC
CTGACCTCGTGATTCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACTGCGCCCGGCCAGAAATAAGGAC TTTTAAACAACCGTAGTGCCTTTACACCTAACTACAATTCCTTAACACCTCATGTTCATGTTCAAATTCCCTGAATTGTCAAAA GTGTCTGTCTACAGTTTTGGTTGACTCTGAATCTAAACAAGGTCCACAAATTATGTTTGCTTAATGACCTTAAGTCTCTTACTC TGTAATAGCTTCTTACCCCACTCTTTACCTTTCCGGATTTGGCTGGTCACTTATGCTGTTTATATATATTCTTCTATTCCAGGT AATTTCTGTAGACCCATAGGTTCTAGAAATTTGATTAGATTCAGGTTTTGTTTTGTTTTGTTTTGTAAGAGCACTTAAGTGGTC TTGGGAGGGATAGATCACATCAAGAGGGACACATGTCTGCATTTTAGAGAAAAATTAATCTTGGTGTGGGTACAGATGTTAGCA GCTGCATGCGTCCATTTTGAATCCCCCAGCAGCCTTTCTCCTGAAAATTGTAGCATCCCTGTACTCATAGCCTGGGTGCATTAC TTCAGGGCTTACCGGTGGTGATTTTCCTCATTACATTAGTCCTTTTGCATCAGTTAGCTGGATTTTATCTGACTTGTGTTTATT CCTAGTTTGTGTTTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTATCTCCCTGAAAGGTGTTGTAAAAGGATGCGTTCTCCATC TTTATTTCAAAAAGGATGTTCATGAACTCCCTTAGTGATCCTCTCAAATGTCCTCAGTTTTCTCATTTGTAAATTGGGGATCAT TATCATGTCTGCCTCTTGGGGTTTTTGTTAGGATTAAATGAGCTCAAACATGTAGTGTAAAAATAGTGGTTGGCACATGGTGTT TGGTAAATGCTAGTTACTAAGGTAACTTCTTTAGTTTTGTGGGAACTCTGAACTCAAGTTGTAATGGAGAGGTGGAAGAGGATT CTTCATGAGTTGACATCAGGGTGCTTGGGTTTCTGTTGGGTGAGCTGAAGGGAATTGTTGCTTGCCGGCACTGACCTGCTCTTT CAGCTGTGTGGGAACAGTTGCCAGACAGACACGCACAGGGAAGGTCTGCACATATCACTGCACAGTAAGAGGTGGATGTCGACA GTTGCAGCAGTAAAACTTGAAACACGTTCCGCAGTGGAGTTAGCACAGTGAAGGGAAGTGGGCCAGACTGGTGGTAGGTGGTAG GTTGAGGGAGATGGTGGCTCCAGATACAGGTTTTTACTATGTCATGGGCCACTGAGATTTTTATCTGAATGAACATATTTGTCT AGTCCAGTTTGCCTTGTCATTACACATACCCTCAACTGGAGCTATTTGAGATTGCAGATCACTGGTGGAGGAGGGAGGAGGCTC TTTTTCCCTTTAGCCTCTTTAATCTGCATCTCTTGTTGCTTAAAAAACCACTGTTGATGGTAATATAGGATATTGGAAGTTTAG CAGTCTTGATGGCGAAGAACTTAGTTGTTAATATTTGATTTTTTTATTTAACAAACATTTGAGCACCTGTAATATGTAAGATGG TGTTCTGGACACTAGGACACATCAGGGAACAACACAGAAAATTCTACCCTCATGGAGTTTACATACATGGTAGTGAGGAGACAG AAGAAACGTTTAAGTTTTATAGCGTGTTAGGTGTTGAGTACTATGGATAAATACAAAGTTGGAAGGGAGGCATTGAGATGGTCA GGGAAGTTACTTTTGTGCAAAGACGTAAAAGGAGAGGAGACAGGTCTTGTGGAAACCTGGGGTTACAAAGTGTTGCCTGCATAG GAAATAGCCAGTCCCAGAGGCTAGTTTGGTCCATTGTGATGAAAGGGTTGACTGCTTGCTGTGCTAGTGCCCTGTAGTGGGCCA
AGGGCAGAAGCATGGAGACAAGAGGCTGGGACAGTGATCTGGATGAGATGGAATGGTGATTTGAACTAAGGTGCTAGTAGTTGT
CTTTGATTCTGGATATATTTTAAGTATCGCCAACAGGCTTTGCTGATGGATTGATTGCATGTGGGTTGAGGGAGAAAGTGAGCA
GTCAAGGATGACTAAAATTTTTGGACTGAGCAATAGTGAGGATGAAGTTGCTGTTCTGAGATGGGGAGGATTGAGAGTAGAACA CATTTTTTGGGCAAGAGCAAATTATTCATACCCCGGAACAACAGGCAACTACAACACTTCATCCATTAAGAGCAGTTGTCCATA AATTTTACTGTGAGAACCCTTGCATTTGTAGATTGTACAGCTAATTCCTTTAACTTAATGTTTTAAAGTTGTGGGAGTTGATAA AGATTGGCTTAGATAGAATCTATAGCTGTGATGACTGGGTCAAGTATAGAATACACTTAAGACTTACTATTTTTCCCCTTCTGG TGGAATGACTAATTAACACTGATAAAAAGAATGAAGGCAGAAAGCGTTGAACTTGGATGGTGAGAACATAGATACGTCTGGTCT TACAGCTGACCCATCAGGGCTTTGCTGTATGTGAAGCCTATGCCTGGGACTTCTTTTTACTTTTAATCTCTGCATTTTATCCAT ACACATCCATTCACATGATCACACAAAGATTTCAACTGGTTTTTATCTTACGTGCTGTTTGCAGTCTTACTTTGTTAACAGTTG TTACATATCCATCTTGTGTATTTTCAAGCACAACTTTTTAAACACGCATGATCTTTTATCAATATCGTTAATGTTTCTTCCTGT* CAGTAATGTCCTTTTCACTGAAGGTAGTATTGCATAGTGATTAAGGGCAAAAGCTGTTTAGACATATAGATGTGAGGCAACATC CTGGCTGTAACACAGACAGCTGTGGCCTGGGGTGAGTTATACTACCTCATGGCTTCAGTTTTCTCATCTGTAAAATGGTCATAA TAATTGTACTTATCTCATGATTGTTATAAGGATTAAAGTAATGCACATAAAACTAGACACAGTACCTAGATGGTGTTAGGACTT AGGTTAGTGTAAGATTTTTTTTTTTTTTTAAATTTCCATTATTTATAACTCACTTATCTTTGATAAACAGTCTTTTACAAGCAG ATAGTGTTGAGCCTCTTGAATTCTTATTGAGTTACACAAATGTTTGGTTAAGATTACATAGTAATAGGCATTGCTGCTCTGTTA TTTCATATTTCCTTTTCTTTTTGAGACAGTCTCGCTCTGTTGCCCAGGCTGGAGTGCAGAGGTGTGATCTCGGCTCACTGCAAC CTCCACCTCTCTGGGTTCAAGCGATCCTCTTGCCACAGCCTCCTGAGTAGCTGGGATTACAGGCGTGTGCTACCACACCTGGCT GATTTTTGTGTTTTTTTAGAGATGAGGTTTGGCCAGGCAGGTCTCGAACTCCTGGCCTCAAGTGATCCACCCGCCTTGGCCTCC CAAAGTGCTGGGATTACAGGTGTGAGTCACCACGCCCAGCCTGTTATTTCATGTTTTCATTTATCTTTAACAAAATGGGTTGTT GGGAGTTTGCTCCTATATGTGATCTAGTATCATTCACATAAAAGTTAAAACCAGTAGTAGTTTCATAGTTGTTCTTCCCTCCCT GACTGCCATATCTACAAGGTCTTATTTCTCTGAGATTTCTATAAAAAAATTCATGATGAGCCAAACTTATTGGTAGAATCAGGT TAAAATGAATATATCTTGGGCGGAGTGTATATGGATGAAGTAAATCTGGTGGTTTATGAACTTTTCTAGGTGAATAAGATTTTA TTTGAGGAAATGGTTTACTTTGGAAATTATCCATTCTTAACCCCTCCCCACTCCTGTCCCGGGAGAAACTGATAAAAGTAGAGC TGTTCTGGTGGTAGAGGGTTGGAAGGAGGGCCGCAGTCCCTCCCTACTCTGCCTCAACTTCACCCATCAGAATACAGCTTCAGC ACCATTTGAGTCCAATCAGGGTTTTGTATAATTAATAACTTTTAAAAAGTTGAGGGTGCAAGTTTAATAGAAATGTTTTGTCAA AAAGATTTAAGGGCAAATTCTTTATATTTTAGGGATGGTTAAAACATTACGGTACAGGTTGAATATCCCGTATCTTAAATGCTT GGGACCAGAAGTGTTTTGGATTGTGGGATATTGCATATTACTTGGTGGCTGAGCATCCCATATCTGAACATCCCAAACCCAAAA TGCTCCAGTGAGCATTTCCTTTGAGCATCATGTCAGTTCTCAAAAAGTTTTGGATTTGGGAGGAGCATTTCAGATTTTGTATTT TTGCATTAGGGATACTTAATCTGTAGTGTTGTCTTTAGCTCCACTTACAATTTAAAACTGGCTGGAGTTCAGGCCAGTTATATT AGGAAAACCTGTTTTGCTCTTTGTGTTACTGATGAACCGCTACAGTATCCTTGCTCCACATTTTTAAAGTAAGCAGGGGTTGAG GACAGTCCTATGTGAGTACACATACACTCTGCATCAAGCGTTAGTAGTCTATTCCACCACAGGAATTTGCTTTCCTAGAACTTG AGTCAAGGTGACAAAAGTGAAAGCATGTATGTAAAGTCTTAAGAATTTTATATACATTTTTTCTTTTTGTATTTTACTTGAAGT GATTTAAGTAGGAGCTAATAGTTGATGAGACAGTTGGGAGTCTAAAATGTTTGAGAGAGCTGCATCTTTAATGCATTATTTTAT CTAATCTTTCTATATATAAATAACTTGGGAAAATCCTAATATGCCTTGCACATAGTTGACAGTTTAATTTGAAAGGAACTAATA TCACTTCTAGTATATTCAGGTTGTAGGGAGTAAACTGACATTTACTGAGCCACCTCCCCATTGCACTGGGCAATACTAGCTTTC TCTGTTACTTATTCCTTATAAATCATAAGGAGCAAGTTGGTTTCATTTTAAAAGCCAGACAGTTGAGACTTGTTGAGGCTCATA GAGATGAAGTTGTTGCCTGAGATCCTACAGTTAGGAAGTGACGGAGCATGGAACCCAGCCCTTAAAAACTGTGCTGTTTTCTTC TGTACCGTGCCACCTACATAGATGTGGTACCTACACCCACCTCCCTTCTTACAGAATCATGAAATCTGTCTGTTGGGGTGGGGA GAAAACAAGCTTGGGTATGCCCATGTTTTTTGTTTTTGGTAGGTTACACAAAAGTGATTGTAATTCAGGTAATTAGTTTTCAGA GGTGTCTGTGTGTTCTATAACCCTTCAATTATTAGCTGGCTAAGTGAATATTTTTCATTTGGATCAGAGGATGAGCAGGGCTCA TCAAGCTTACCATTGACAGAGTGCTGGACTAGGCGTCTCAGATTGTACCTTGAGTGTGTGGTTTGTAAATTGACTCCAAAGCTA AAAGAGGTGGTTGTTTGGTCACGTTTAAGATTATTGCGTACTACTCTTTGCAGGCCCCGCCCTGTGTCATTGAACTTATGACTT GAAGCCCTGAGTATAGGAGATAATTTTTCTTGTTCCTTGTTTGGTTTTAGTGGCAGGTGGTTTTTTATTTTATTATTTTTTTGA TAGAGTGCCCATATATCCTGCTGTTTACATATAGTTCCAGAATAAGTTTCTGGTTTGGAAGATAAATTATATGGTCACCCAGAC AGTACTAGAGAGATCTGGTCATGATAACTAATTACATTTTGGTTAACATGGTTATATCACCTGAAGGAGTGCTTATTTAAATTT GGTCTTACCTTTTTTTCTCTTTCTATTTGGTCAAATGCAGCAAATATTTATATTTACACTTCTCTATTTGGATTAATTCTTCAG TTGCAATTTAATTTATCCAGATGCGTGGAATAGAACCAAAACTGCATTCTAATTCTGTGCAAAACAATAAAATACTACTTTCTG AGAAGGATGCCTTCTCTTTTGGGAAGAAGGGGAATCTGCTCTGTTTCAAAGCACCTTTGTGTTCAAGGTTTGGCTAAATCTGCT CATCACCACTAGGGGACTGTTTCTTTTTGCATTCTACAAGTATTACTCCCATTACAGAAGCTTTTTAAGAAAAAAATGGACTAC CAAGGAACCCACCTACATGCTTTTCATAACTATACCTATTTTATTGTCTTATAATTTGACTTGAGAGGTTTGCGTGAATGATGA ACTGTGACAAAAAGCATATATAAATATAAAAATACAAGTTAAAAAGCCTCATGTTAGCTGAAGATTTTCCATGTGTATTCTTAT AAAAATAAGGGAACCCTGGACAGTGCTCATTGTATTTTGTTGAAGAAATGTTAACTTCTTTAAAAGGGAGGAAAACATATATAT ATATATATAACATACTGTATATTCAGAACCATTTTTAAGGGATGTAGTTTATCTCTTGAMGACTGAAATTCAAGGCTGTGACT ATGACTAGAGTGTAAAATATAGCTGCATTGCATTATAGTATTTTATATATTTGTACAAACCAAATTGACCTGTTTTTGGTTTTG TTTTTCCTTTTCCAGTCTTTACCAGGTGCTGGTCTCTGCATGTGTTTTGTTGGAAGTTGGAAAATGTAGACACGACCCACAGAG TGGTATGGTATCCAGTGAGAAGGGAACTGTCCGCAGTGGCTTTGAAGGATATGAGGAAGCCTAGGCGGAGAGTTGAGAATTCAG CCTTGAGCTAGTGTTAGGGTACTATTTGGTACCTCTCCTGTGGGCAGAGCGACTTTACTAGAGAAGTTAGGAGTTAGGGCTAGC ATGAGAACTTCATGCAGTTTGAGCATTCATCAGGCAGCAGAATATAGCTTCTATATTTACCTTGCATAAATCAGATTTGACAAT GAAGAACAATGTTACTGATAGTAACAGTGCTTCCCAGTGATTGAGGAAGTGCTTGTTTTCTTTTTCAGCACTTTGTTCTATGAA CAAATAAGGTGCAGCAGCTAGTATGACACATAACCCACCGTATTTCCCCCCCAACGGCCAGATGAAACCAGAAATACCCACTGT GTTTTTCTCTCCCTTCTTTGGAAAGCACGTGGTTGGTACTGCCATTGGGAAGAGTGATACCTGATTAGCCAGGTAGCCTTCTGA AAATTGAAACAAGTGGCCTGAGGATGACTTGGATGGCTGTTGGGTAGCAGAGAGCCCTGGAGGCAGGGTTTCATAACTGCGAAC AGCAGTTTTCATTGTAATTGACACAGCAGATTTCATTGTAATTGACAAGCTTCCCTTATGCAGAAACATTTAACGATACCTTTT TAAATAATGTTTACTAGTCATCTGATTAGATTTTATTAAAAATTTAGATGATTCGTCCTACATAATGTCAAAGCATTTGTTTAA AAACTTGGAAGCTTTTGGGGGTGGGGAAGGTGGTCATAGAAATATGATCATCTTCAGGATTTGGCAGGTATGAAGTGATACAAA CCTCAACTTTTAAGATTTTTTTTTTTTTTTTTGCTTTTCTCTGGCAATCAATCTTATTTATGCCAGCCGTTGACACTTAGAAAG GATTTAAATCACTTTTCATAGCATAATTATTGTATTGCTTAATGCTTTAAAAAGGCACGCAGATGGGATTGAGACATTTCTATC CAGGCAGTTTTTTCTGCATTAGACCTAAGAACCTAATTTTGTAGGGCAGTAGTCTCTAGGCATTATGTTTAGCTCCTTTTGTCA GTGAGAAGTGTGTTGTAAAGTTTCTAATACTGTGGTCTGTTTTGAACGGTTTTGAGAAGAGGTAGCTTTAGTATAATTTATAGG ACTTAAAAGGAAAATGCCTAGAATCATCAGAAAAAGCATGGAAAAACATTCTTCTCTGAGGTTGCCTTATTGGAAAAGGAGAAA .TCATTTAGAAGTTAATGTGTGGAAGGCATTAGGTTGAATAAAATTGTTGTTCGTATTGATCTGTCAGCTGCAATTACAATTAAC TGAAAATTTAGTATTTGTCTCTTTTTCAGGAGAGAAGCCGTCAAATTTTAATACATTTAATTTTAGGTATATTTAAATGTCTGT TTTGCAGAGTGATTATCTTAATCCAGAACTGAAAAATTCCTGATGGTCCTACTGAAGATTTATCTAATGGTCCACAAATGTCTG TTTTGTTGAGGTTTGGCGGACATAATAATAAATCATTTTTTAGTCTTCTGAAAACTTTTCTCCTCCTCCCTCTTTTCTCTGCTT CTTATACCCTTCAACAAAAAGCATTAAAAGGAAAACATAAAATCACGCCTTTAGTCAGTGCCGTTATCCTCTCAGAGGTTGTTT TGGAAATACTGCCTGATGAAAAGGAAGAGAAGGAAATTGCTTCTTTTAAAGTTTGCTTTTTATCTTCTTGCAGCATCTTCTAAC TGGCAGAAATAATACAATTTTTGAGTTGTTTTGTAAGTTGGATATTTTTAGTTTTGTGTGGAATGTCGTGTTTCCCATTAGGGC AGGGGGCGTCTCACAAGATCTAGGTTACTGTATGACAACTATATCCATTTACTGGAGTTTAAGAAGCTTTATAACAATACATTT CCAGAGACTAGGCAGTACTTGGTTTTCTGTATTTAAATTTTCTGAGGGTAGATGATAACATCTAGTAAACACCACCTGCCTGTT CCATCCAGGACCCTAACTGGCCATAAAGTTACCCCCAAACTCTCCTAGGATTCATAGTATTTTAAGATTTCATTTTTGTGCCCT TATTACGAATATAATTAGTGTTTTCTCCCCTTTAGGGTGCTTTAAGATCTTAGTGCCTGTCCTAATCTGAGCATACCACAGTAA GACAAGAAAGGGCAATGCTGTGGTAGGCAGTTAGCTGCTGAAGTTAGGCCACTTAGTTATGAGGTAGATGAATTTCTGTCCTCA GCTCAAAATGATAATATTCTCACTGACAAAAGTATCAGCTGTGATCATATAGATTGCTCTTTCCTGTGGAACTGAAGTGTATTA AAAAAATTTTTTTTCTTCCAATAAAGAATGTCTCGTTGCGCCGGGTTTGCTAGACTGAAAGTTTCCTCATCACGTGGCGAGACC TCCTCTACTTCAATCTTTGTCTTTTGTCTCTGCTGCCTTGCAGGGTTGGTACAGTAGGCTTCACTAGACTTAGCTGCAACTCAG AATTTCTCCTCCAGCACCTGAGTAAATGCTGATGGTCTTGTGGAGAGTGGATTAAGAGTACGAGCTAAGTTCTCAATCCCAATT AAGAAGCGGAAAATTTAAACTGTCTTCTTCAAAGTTTATCACAACCACCACCATCAAGACAGCAAACCAAAGGACAAAGACTTT GACCCTGCTGTGTTGCTCTGTGTAGTCCAGTTCACGTATGGTTTACAGACTTGGCTGGGGTTACTAAAAATAAATAAAAAGTTG GACACTTCTGTCATTGGAGCGCTATTATTCACAAGTTACCAGAATGAGAGCTGTACTGGACACAGCAGACATTGCCATAGTGGC CCTGTATTTTATCCTGGTCATGTGCATTGGTTTTTTTGCCATGTGGAAATCTAATAGAAGCACCGTGAGTGGATACTTCCTGGC GGGGCGCTCTATGACCTGGGTAACAATTGGTGCCTCTCTGTTTGTGAGCAATATTGGGAGTGAGCACTTCATTGGGCTGGCAGG ATCTGGAGCTGCAAGTGGATTTGCAGTGGGCGCATGGGAATTCAATGCCTTACTGCTTTTACAACTTCTGGGATGGGTTTTCAT CCCAATTTACATCCGGTCAGGGGTATATACCATGCCTGAATACTTGTCCAAGCGATTTGGTGGCCATAGGATTCAGGTCTATTT TGCAGCCTTGTCTCTGATTCTCTATATTTTCACCAAGCTCTCGGTGGATCTGTATTCGGGTGCCCTTTTTATCCAGGAGTCTTT GGGTTGGAATCTTTATGTGTCTGTCATCCTGCTCATTGGCATGACTGCTTTGCTGACTGTCACCGGAGGCCTTGTTGCAGTGAT CTACACAGACACTCTGCAGGCTCTGCTCATGATCATTGGGGCACTTACACTTATGATTATTAGCATAATGGAGATTGGCGGGTT TGAGGAAGTTAAGAGAAGGTACATGTTGGCCTCACCCGATGTCACTTCCATCTTATTGACATACAACCTTTCCAACACAAATTC TTGTAATGTCTCCCCTAAGAAAGAAGCCCTGAAAATGCTGCGGAATCCAACAGATGAAGATGTTCCTTGGCCTGGATTCATTCT TGGGCAGACCCCAGCTTCAGTATGGTACTGGTGTGCTGACCAAGTCATCGTGCAGAGGGTCCTTGCAGCCAAAAACATTGCTCA TGCCAAAGGCTCTACTCTTATGGCTGGCTTCTTAAAGCTCCTGCCAATGTTTATCATAGTTGTCCCAGGAATGATTTCCAGGAT ACTGTTTACTGATGATATAGCTTGCATCAACCCAGAGCACTGCATGCTGGTGTGTGGAAGCAGAGCTGGTTGCTCCAATATTGC TTACCCACGCCTGGTGATGAAGCTGGTTCCTGTGGGCCTTCGGGGTTTAATGATGGCAGTGATGATTGCAGCTCTGATGAGTGA CTTAGACTCTATCTTTAACAGTGCCAGTACCATATTCACCCTCGATGTGTACAAACTTATCCGCAAGAGCGCAAGCTCCCGGGA GTTAATGATTGTGGGGAGGATATTTGTGGCATTTATGGTGGTGATCAGCATAGCATGGGTGCCAATCATCGTGGAGATGCAAGG AGGCCAGATGTACCTTTACATTCAGGAGGTAGCAGATTACCTGACACCCCCAGTGGCAGCCTTGTTCCTGCTGGCAATTTTCTG GAAGCGCTGCAATGAACAAGGGGCTTTCTATGGTGGAATGGCTGGCTTTGTTCTTGGAGCAGTCCGTTTGATACTGGCCTTTGC CTACCGTGCCCCAGAATGTGACCAACCTGATAATAGGCCGGGCTTCATCAAAGACATCCATTATATGTATGTGGCCACAGGATT GTTTTGGGTCACGGGACTCATTACTGTAATTGTGAGCCTTCTCACACCACCTCCCACAAAGGAACAGATTCGAACCACCACCTT TTGGTCTAAGAAGAACCTGGTGGTGAAGGAGAACTGCTCCCCAAAAGAGGAACCATACCAAATGCAAGAAAAGAGCATTCTGAG ATGCAGTGAGAATAATGAGACCATCAACCACATCATTCCCAACGGGAAATCTGAAGACAGCATTAAGGGCCTTCAGCCTGAAGA TGTTAATCTGTTGGTAACCTGCAGAGAGGAGGGCAACCCAGTGGCATCCTTAGGTCATTCAGAGGCAGAAACACCAGTTGACGC TTACTCCAATGGGCAAGCAGCTCTCATGGGTGAGAAAGAGAGAAAGAAAGAAACGGATGATGGAGGTCGGTACTGGAAGTTCAT AGACTGGTTTTGTGGCTTTAAAAGTAAGAGCCTCAGCAAGAGGAGTCTCAGAGACCTGATGGAAGAGGAGGCTGTTTGTTTACA GATGCTAGAAGAGACTCGGCAAGTTAAAGTAATACTAAATATTGGACTTTTTGCTGTGTGTTCACTTGGAATTTTCATGTTTGT TTATTTCTCCTTATGAACTTAAGGATATGGTGAGACACTAACTTAAGACAATACTGACTGGTCTTTGGGGAAAAAAGTTATGTA ACTGTGCATCTCTCAGGCATTGTTTACGCTGTAGGTTTTAGCCAAATTTTACTTAGCAGAAAATCATCTAATTACAAGACTTTA TTTTCCCAGAGATGGATTAAAGTAAATCTTCAACTTAAGTGAAGCCAAACGTAACAGACTGAATTGTGCAAATGTGGTTTTAAA TTTTGCATACCAAAGTAAGAAGAGACCAATTATTCTCACAGAGCACTTAGAGCAGAATATATGTTAAGTTACCATGAATTAAGG TATACTGTCTGCACTGCCAAGTCTTGGCAGACCTTACCCTGAAGTAGAAGATTTGCTCATTTCTAAAGTTTTTTTTCTGTCTCT GTAATCCCTCCTACCATTAAGAAAAACTTATTTCTTAGACATTGTACAATCAGTTATGTACTGAAAATCGAATGTGCTTGTGTG ATACTTGTTTCAGGACAAGTTCATTTGCCAGGTTCATTTTGTTAGCATGAGCCTACGGATTCTGATTTCCCAAAGAAAGAATGT TTTCCTGTAGGTATTTTTGTACCACCAGTATATGGAATGTTAGGGAAAAACTTTGTTCCAGTTCCTTTT'ΓTTTTTTCTTTCTAC TTTCAAGTTTAAGTGAACCATACTGAAATGACCAACAAGTCTGCCTGTAAAGTTACATGTCATGATTGTGTTGTTAAATGATTA TGGGGGAGAAAATGAAGTAAATGTTGCTGATGATCCCCATATTTATTGATCATATTAAGGTTGTTTATATAGTTTGGAAATGAC CAGCCCCCTAAGCAGTGTTTGATTAACTTATGCTAATCAGATGATTACTCATATATTCTGCTAATTTTCTAGCTTTATTCTTGT TATTTGGAAAAATTATTAGCCAAATGCCTTCCTAGGTGGATCCAGTTGGAAGATATGTCCAGAAACCTGAAGAAAAATTGACGC TGCCTTTGTGTGCTGGATTGCTCTACTTGATTAGATCATGATATATCAAGGTTGAATTTTTAGAGGGAAAATTTAATTCTGATA TCTTATTGCATCCTTGATAAGTTTTTCCCTGATTTTTTTTTCCTCCAAAGACTTTCCATCTGGACACAGCCTCCACATTTTTGT TGTAGTGACTTAGAGCATAAGGATGTTTCAGTGCCAATTCCGGCCGTCGGTAACAGAAAACTCAGTGCATACTTTGCTGTTGTT AGGTTGTCAATATAGTCTTTCTGTAGGATGGATAGCATGTTTGAGAGGTGCCAAACAAGAACTTTTGGGGTTAGTAGTGTGTCT TGTGGAGGGTATTACAGGACTGTGTAATTATAGGACTCTAACTTGACATGGCTTGGCACCCACTTGCAGCTAGTGGGTACAGGG TACAAMGATGTTAGAGAAAAGCTCTACAGATTACGTACTTCTGTGTCTTCGTATGCTCAACACTGTCCTTTGTCCTCCATGAA AGATGAAGGAAGCAAATTATGTATGTACTTTCTTTGACCTTCTTTAATCTCTGATACTTTTTAGATTGCATGATTTTACTAGGC TTGTATTTAGGGAAATTACTTTCATAAATACTTTTGTAGATTTTGAATCAAAACTCAGTCTTTTTAATTTTTTTGTAGTETATA AACTAGTTTCATTATGATGGACTTGATTAGTCCAAAGTTAATTTTAGAAATTGTCAGGTAGCATAGTGTCTTCCCATGATCAGG AGGCTTTCTGAAGGACTGAGTCTGTAAATGAAAAAATAATTTATGTATGAATAGCATGTATTTCTGAAGAGCTTAGAGTGCCTC GTAGAATTTTTCTCAATTTTATTCTTGAGGTTTATAATTTGGGGGCCAAATAGATAGAGCTCATCATTTTCTTGTTTGGAAGTT GAGGCTGCGACATGTCCAAGGTTATGAAGTCTCTTTTGGGAAGAACAGAAACCAGGTCTCCAAATCTGGACTCATGGTTTGTTC AGATGTGTCTGGACAAATGGTTGTCAATGTTTTGTCCTGTTTTTTCAAAGGAACTGTTCTTCCTTTGGGACAACCTTTTGGTGT TTGGGAAAGTAATAAGATCTTGGATTTTTCAAATTAACATTAAGTTGTAAGAACTAAAATTTTCTTTGAACCACACTACTGTGT AATTCACTGATAATTGACATATTGGCTGGGCAGCCTATCTCTTCCATATCCAGCGTAAATGAATAGGAGGTGTCTGTGATTTTT TTTTTCTCCCTTTATTTAACATTGAGTCCTAGTAGTTTGGAGAATTAGGGTCCCTCTACCTTCTTTCTGCTCTTGTCTTAGTAA GATACATAAGGTACATCATCTTGTGTCTGTGTGTATATAGCAGTAGGTCAAGTTTAGAGTACTAAAGTCTGTAAATAAGGAATG ACTATTAGCATATTCATTAGAATTGTTTATTCTTGCCAGTATAAACATCATTTTATTTAGACTAAAGTCCCTGAAGCTTGTCTT TCTTATTGCTTTCCAGTAAATAGATAATGTGCTCGAGTAAGTTTGTGAATTGCTGATTGCAACTTAATTCAGGGACCAGTCTTC AATCTATATTTCATTAGAATGATTGTCCCTGGAATGATCATACATGGACTGTCTTAAGCTAGCAAAATGTTCATACTTTACACT GACTAAATGGGTCCTAAATGATGACATTGGTCTTTAGACATTAACATGTGTATATTTTTATATTAGCTCAAGCTAAGGTTCAGA ATTGAAGCTTGATATTGACTAGAATAGCTAAAAGTCAAAATGAGGTGAGGACACTGGTCTTGGAAGGTAGAGAAAAATAAATGT CTTACCAGGTGTTAATGGTATCCCCAGTTCTTAGACTTTTGTCTTCTCAGGCAATTTTCATCTCAAGATCTGATGAGAAGGGCA TATTACATTGGTATGCAGGATGATTATTGCATATTTTGTGGGACCTCTAATTTCCCTGGTCATCTTTCAGAATATTCTGTTCTG CCACCCCCAGAGAGTAAACACTTGAGCCGATTTCTTCTTCCCCAGCTATTCTTTCCTGGGGGTAATTATGCTTTGTCTTTAGAT TAGAGAAGCATCAAGCAATAGCAATGGTGCTGTGTCCTTCGGCCTAAATTCAATAGATCTCATCTCCTAGGGCTTCCTTTTCAC TTGGCTCAAAGGATCCATTGTATTTTGGCACAAAGAGCCTGGCCAGGGTCATGTAGCCATAGCTCTTAGGGATGATACCTCAAG AAATTAGCTGGGACCCATCACTCTGTGAAACTTCACATTTTAAGAACTGAGTTGAGGGGGTTGTTATGCACTTCTGTAACTTGA GGCTAAGCAAGGGGTTAACTCTTGTGAGAGCCAATAGAGTGTGTCTGTATTCGCAGTCCATGGCTCATTTTCTTTATAGTAGGC ATATGGATCTTCCCCTCTGACTTTGAATATCATTTGGTGTGGCCTGTGGGTTATTTTCATTCTTTACCACCAAATAAAGCGGCT TATTAGCTACTCAGTTACTTGCTACTCAAAGGTTAGGTCTTCCCTGTTCCTGCTTGGCAGTGTTAAAGCTTACAGGGTTAACTT ATGATGATTCTCCTGGCTCATTTTCATCAGAGGCATGATGACTGGAAAGGGATCACATGGGTCGTTGGTGGTGACACCTCACTG TTTCCTAGGTTTGGATAGAGAGATGTATACAAGACCTTTCCTGTTAAATTACGTGACTACAGAGACTTGCCAGGACAAAATTTC CTAAGAAATCAGAAAAATGATTAAGTGAGATAAGTACCTGGGTGACACAGATATTAGCCCGTTGGTAAAAGACAACAAATATTA GCTTAAAATCTGCATATGTAGAATCATTTTCATTAGATTTAGAGCTTGAAGCACCTTGGCTCTCAGCTACTTTAAACTCCTCCC CATATAAATCAGGGCACCAATAAATAAGTTTCAGCTTTTTAAACCCTGGTTTGATGTTAAGCATTATAAAGTACGAAGTTTGTT ACCACAGTAGAGATAATTTAGTAGAAAAATGCTTTGAGGCTTCAGTATTTGTAAGATTTTGCATTAGCCAGATGCTAGGTTGTT GAAGGCATTTCAGTGTTGATAATAGCCTGAGCAGACTTCTTTACAAATGGGATCTGTTTCTATATGTGTATATGCCCACTTACC ATTCAGAGAGACTGGTCTTTCTCTTTGTCTCCCTTCACATTGCTGTGTCAGTCCTACACCTAGTCTTTTCAGCACTTAGCAAAT TCAAATTTGGATTTTTTGGTCAGCTTAGTTCACTTTAAGGCATATTGGCATGGTGTGTGAAAGTGATGTTTGGCCCCAGTATTG AGGACTTTTAGATCCAAATAATGACTCATTAAATATAATTATGTTTTAAGTATACTGAATTTCTGTTAGCTTAAAATGTTAATC CTCAGGAATGATTTCCTCACACTTTGTGTTGGCTAATAATAAAAGCACTGTTTTATCCTCAAAACTCCTTTTTCAAAAATTAGG GAGAGAGCAGTAGTGATCATTTATGTGAGCCCCTTTGAAATGATGGTGTCAGAGTGCAGAGAAACAATGGAGTTTTGATGCCAA AAAGGTTTTTTTGCAGTAAAAGTAAAAATTTGGAATTAGTTGGCATATAAAGGAACCCTTTTGTACTGGAACGTATGAGGCTGG ATTGTGAAAAGGTAATCTTTCGATTGCTAGACTTGGTTAACTTAGGGCTGCAAATCTTTTTCTTCTATCAAGGTCACTTAATAT GGAATGTTTTTGTCAGACTGTCCTTTGTTGGAATACTTTAGCTGTTCAGCTACTTTGACTCCTAGGAGAGAATTTAGTTAAGGT TCAAAGTAATTAACTGGCTTTGCCAGTGGTGAGTCCCACACCATTATTCACTTAGTAGTCATATAAATGTTTTTATTTACTCTC TTCAATGCTGAGAATAAGGCTTTAAATTACTGATTCACCTTTAAAGGAATGTTGTGAGAATTGATGTAATTTCTGTTTCTGTTT CCATCTAAACTTCTTTATAAAAAGAGGGATTAGTTTTTTTGTTTTGGGGTAAGCACCTAATTTATCCAGTAACCAACAACCCTA ACCATTGGCATATATAGTCTTTCACTCAGAAATAAACAAAAACTGTTTGGTATATCTGTATCATTGCTAATCTTGTGCACTTTA CTTTTTGGGCAGTACCATACATAGTCTGAGGCTATTGACTTAAACCAATAACTGTACTTTATGTAATGACTCTTAAATTTGGTT ACCTGGGTTCACAGCTTGCTTGAAGAGAAAGGATGCTAGAATAAAGTAAGCAGCTGAAGAGCGAGCAAATCAAGACAAAACACA GTGGTCTCAGATTTTTCGTAGTGTGGGAACAGTGGTTTTGCTCTATACCACTGAAAAGCACTATAACATAATTGTTGTCCATGA TACTGAAGCTTTTCCCCTCACTTCTAGGTTGTTTACATTCAGAGCTCTATCAATAAGAGGAATACATATTACAGTGAATTCGAC AACCGCACAAGTTGGCAGTAGGTATCCCCAACCTAATTTATCTTGGTAAATTCACCCTGTTTCCTAGTGCTGCTGGATAAAAGA GTGTTTACTTTTTATTGCTCTTAGACAGAGTAGTCTAGATAAGTTTTCAATTTATCAACATAGCCTAGACTTCTGTAAGTGGAA TGTTCATTAGTAACTCATCTTTTTGTTGTTATAATTGGAAACAGAAACGAGGCTTATTGCTATTGCAGAAATCCCAAACTGGCA AAGGCCAGTATATATGGTATTCCATAATATAACCAGCTTTTGAAATTTATGTGTTTGGATTAGTGCCTTCTGGTTACCAGTATT GACTCTGCTAGTTTGCACCTTTCCGTTCTTAACAGAAAATTTGTATTTGTTATTCCTCTTAAATTTTGTCGTAACTAGTGAAGG AAGTAAAAAAAAAAAAAAAAACATGCATTACATTGACATACTTTATGTGCAGCCTTTATTTAGGTTCAGTGAAACCAGGTAGTT CTGTATTTGTGTTGTAGCCTAAATGTTGTTTCTTTTATATCCATTAAAAACTTAAAGTTACTTATGTTCTGTGATCTTAATTTT GTTGTGTTTCCATTGTAGGTTGATAGGTATATCGAGAACAGGTACGTGACAACAGTTTATATTCCATGATAGAAAGCTAAAGTC CATAGAAAGCACAAAATCGTGTTCACACATTAGTGTACCCACACATAGAAAGCACAAGACTAATAGTATTCTCTGTATCCCACA AGTGCCAGTCATAAAGGCCACCAGGTATTTGTCTCAGAGTTGCTATGAGCACTACAGTATTGATAAGCCCAAGACAATGCGGTA TCTAAACTGGTCCTAATGGTAAGGGACCCAAAGGAATAATCTCAATAAGTTTGTACCACATTGATGGAGGGAGAGAATACAAAT GTCAAGAATGCCAAAATTATATTTGGGGGTTACTAGCTAAAATGGGGTTTGAGGGCTTTTTACTGCAACTTGAAACTGGAGAAA TAGGGACAGATGTCTAGGTTTTTGGTGGGTGGAACAGGTGACATATTTCTGTTTTAAGCTGTAGTGTGATTGGGGTTTTTTGTA AAAAATCTTAAATCTTTTAGGAAATATTACCTCTTAACAGTGCCCCCCCAAACATGCAGAAAGTCATACTTTAACAGGGCAAAT ACTACTTGTCTTTGATTTTTTTTGTGTACGTTTGTATGTGAGAGATGAAGTTACCTTTATTTTTTTCCTATACTTGACTGTGCT TCATTTTAATAAAGGATAATTTGATCTGA 309
MSLQRLLQHSSNGNLADFCAGPAYSSYSTLTGSLTMNDNRRIQMADTVATLPRGRKQ ALTRSSSLSDFS SQRKVTVEKQD NETFGFEIQSYRPQNQNACSSEMFTLICKIQEDSPAHCAGLQAGDVLANINGVSTEGFTYKQ DLIRSSGNLLTIETLNGTMI KRTELEAKLQVLKQTLKQKWVEYRSLQLQEHR LHGDAACPSLE MDLDE SLFGPLPGPGPALVDR RLSSESSCKSWLSS MTMDSEDGYQTCVSEDSSRGAFSRQTSTDDECFIPKEGDDFLRRSSSRRRSISNTSSGSMSPLWEGNLSSMFGTLPRKSRKGS VRKQLLKFIPG HRAVEEEESRF
310
GCACGAGGCGAGCTGGAGTGATCTTTATTCACAATGTCTTTACAAAGGCTCCTGCAACACAGCAGCAATGGCAATTTGGCGGAC TTCTGCGCTGGGCCAGCGTATAGCTCTTACTCCACACTCACCGGCAGCCTTACGATGAACGATAATAGAAGGATTCAAATGCTA GCAGACACGGTGGCTACTCTGCCTCGGGGACGAAAGCAGCTTGCTTTGACCAGATCAAGTTCTTTAAGTGACTTTTCGTGGTCT CAAAGAAAGCTTGTTACTGTGGAGAAGCAGGATAATGAAACATTTGGATTTGAAATTCAGTCTTACAGGCCCCAGAATCAGAAT GCCTGCTCCTCGGAAATGTTCACTTTGATATGCAAAATACAGGAGGACAGCCCAGCTCACTGTGCTGGCCTGCAAGCTGGTGAT GTCCTTGCAAATATCAATGGTGTGAGCACAGAAGGTTTTACCTACAAACAAGTCGTTGACCTGATCAGATGGTCCGGAAACCTG CTAACGATAGAGACTCTTAATGGAACAATGATTCTGAAAAGAACGGAGCTTGAAGCAAAGCTGCAGGTTTTAAAGCAAACTTTG AAACAAAAATGGGTGGAGTACAGATCTCTGCAGTTACAGGAACATCGTCTGCTTCATGGTGATGCAGCTAATTGCCCCAGTTTG GAAAACATGGACTTGGATGAATTGTCTTTGTTTGGACCCCTGCCTGGGCCAGGCCCAGCCCTTGTGGACCGGAATCGATTATCC AGTGAGAGCAGCTGTAAGAGCTGGCTGAGCTCCATGACGATGGACAGTGAAGATGGCTACCAGACGTGTGTGTCTGAGGACTCC AGCAGGGGTGCCTTCAGTCGGCAGACGAGTACAGAT.GATGAGTGCTTTATCCCCAAGGAGGGGGATGATTTTCTGAGGAGGTCA TCTTCAAGGAGGAACCGGAGCATCAGTAACACCAGCAGCGGATCCATGTCTCCCTTGTGGGAGGGCAACTTATCAAGCATGTTT GGGACCCTGCCCCGGAAGAGCAGAAAGGGAAGTGTCCGAAAGCAACTCTTGAAATTTATCCCTGGCCTTCATCGTGCTGTGGAA GAGGAAGAAAGTCGCTTTTGACGGATTGTGGTGTCCTTTCAAATTAGCTTATTTCACAAATATCTCTAGACTCACCCAGATCCC AGCTTGGTGGGAAAGTGCAGAAGAATTGCAAAACTGACATCCCATTTCACAGCAATAGTGACCTTTATTTAAATTGTTGTGTTA TAGTTTATGCTTCTTAAATCATTTTTCAACCTAAACAGCCAATTTGTAAGCAGACAGGAAAACTAAATAATAAGTTAATTAATA TAACAAAGATGCAGGTTCCTGCTCATTCCAGTAATGTCTTTGAAAGCAAAACTAATATTTATTTTCTAGATTATCCCTGTGAAT AATTGAGAACTTTTTGGAGTCAAGTATGAATAAAGGTGTGGCAGAATATAATAATCTGGACTATTTTCTATAGGATAATTGCTG GGTTATAAAATCTTAGGTTTGCTTATGCCCAGTAGCTCCTGCGGAGGCTTAATAATAGGCAATTTTGAATTTGTTCAAACCTGT AATGGCTTGTAAACAAAGATGACCATCAGCTGTTTCTCACATCTATAGTGACAATAAAGCGGGAAGTATAAGATTTAATAGGAG GGGTTAAGGTTCATGAGAACCATGGAAAGATGTGGTCTGAGATGGGTGCTGCAAAGATCATAATAAAGTCATTTTTATAGACAG TCTAAACAAAAAAAAAAAAAAAAAAAAAAA
311 MEQQDQSMKEGRLTLVLALATLIAAFGSSFQYGY VAAVNSPALLMQQFYNETYYGRTGEFMEDFP TLWSVTVSMFPFGGFI
GS LVGPLVNKFGRKGA FN IFSIVPAILMGCSRVATSFELIIISR VGICAGVSS VVPMYLGELAPK LRGALGWPQL FITVGILVAQIFGLR LLANVDGWPI GLTGVPAALQLLLLPFFPESPRYLLIQKKDEAAAKKALQTLRGWDSVDREVAEIRQ
EDEAEKAAGFISVLKLFR RSLRWQLLSIIVLMGGQQLSGVAIYYYADQIYLSAGyPEEH¥QYVTAGTGAVNVV TFCAVFW
ELLGRRLLLLLGFSICLIACCVLTAALALQDTVS MPYISIVC¥ISYVIGHALGPSPIPALLITEIFLQSSRPSAFMVGGSVHW LSNFTVGLIFPFIQEGLGPYSFIVFAVICL TTIYIFLIVPETKAKTFIEINQIFTKMNKVSEVYPEKEELKELPPVTSEQ
312
CTTCTCTCTCCATTCAGTGCACGCGTTACTTTGGCTAAAAGGAGGTGAGCGGCACTCTGCCCTTCCAGAGCAAGCATGGAGCAA CAGGATCAGAGCATGAAGGAAGGGAGGCTGACGCTTGTGCTTGCCCTGGCAACCCTGATAGCTGCCTTTGGGTCATCCTTCCAG TATGGGTACAACGTGGCTGCTGTCAACTCCCCAGCACTGCTCATGCAACAATTTTACAATGAGACTTACTATGGTAGGACCGGT GAATTCATGGAAGACTTCCCCTTGACGTTGCTGTGGTCTGTAACCGTGTCCATGTTTCCATTTGGAGGGTTTATCGGATCCCTC CTGGTCGGCCCCTTGGTGAATAAATTTGGCAGAAAAGGGGCCTTGCTGTTCAACAACATATTTTCTATCGTGCCTGCGATCTTA ATGGGATGCAGCAGAGTCGCCACATCATTTGAGCTTATCATTATTTCCAGACTTTTGGTGGGAATATGTGCAGGTGTATCTTCC AACGTGGTCCCCATGTACTTAGGGGAGCTGGCCCCTAAAAACCTGCGGGGGGCTCTCGGGGTGGTGCCCCAGCTCTTCATCACT GTTGGCATCCTTGTGGCCCAGATCTTTGGTCTTCGGAATCTCCTTGCAAACGTAGATGGCTGGCCGATCCTGCTGGGGCTGACC GGGGTCCCCGCGGCGCTGCAGCTCCTTCTGCTGCCCTTCTTCCCCGAGAGCCCCAGGTACCTGCTGATTCAGAAGAAAGACGAA GCGGCCGCCAAGAAAGCCCTACAGACGCTGCGCGGCTGGGACTCTGTGGACAGGGAGGTGGCCGAGATCCGGCAGGAGGATGAG GCAGAGAAGGCCGCGGGCTTCATCTCCGTGCTGAAGCTGTTCCGGATGCGCTCGCTGCGCTGGCAGCTGCTGTCCATCATCGTC CTCATGGGCGGCCAGCAGCTGTCGGGCGTCAACGCTATCTACTACTACGCGGACCAGATCTACCTGAGCGCCGGCGTGCCGGAG GAGCACGTGCAGTACGTGACGGCCGGCACCGGGGCCGTGAACGTGGTCATGACCTTCTGCGCCGTGTTCGTGGTGGAGCTCCTG GGTCGGAGGCTGCTGCTGCTGCTGGGCTTCTCCATCTGCCTCATAGCCTGCTGCGTGCTCACTGCAGCTCTGGCACTGCAGGAC ACAGTGTCCTGGATGCCATACATCAGCATCGTCTGTGTCATCTCCTACGTCATAGGACATGCCCTCGGGCCCAGTCCCATACCC GCGCTGCTCATCACTGAGATCTTCCTGCAGTCCTCTCGGCCATCTGCCTTCATGGTGGGGGGCAGTGTGCACTGGCTCTCCAAC TTCACCGTGGGCTTGATCTTCCCGTTCATCCAGGAGGGCCTCGGCCCGTACAGCTTCATTGTCTTCGCCGTGATCTGCCTCCTC ACCACCATCTACATCTTCTTGATTGTCCCGGAGACCAAGGCCAAGACGTTCATAGAGATCAACCAGATTTTCACCAAGATGAAT AAGGTGTCTGAAGTGTACCCGGAAAAGGAGGAACTGAAAGAGCTTCCACCTGTCACTTCGGAACAGTGACTCTGGAGAGGAAGC CAGTGGAGCTGGTCTGCCAGGGGCTTCCCACTTTGGCTTATTTTTCTGACTTCTAGCTGTCTGTGAATATCCAGAAATAAAACA ACTCTGATGTGGAATGCAGTCCTCATCTCCAGCCTCCCCACCCCAGTGGGAACTGTGCAAAGGGCTGCCTTGCTGTTCTTGAAG CTGGGCTGTCTCTCTCCATGTTGGCCTGTCACCAGACCCGAGTCAATTAAACAGCTGGTCCTCCACTTTGCTGGTTCAGCCTTC GTGTGGCTCCTGGTAACGTGGCTCCACCTTGATGGGTCAACCTTTGTGTGGCTCCTGGTAACATAACAACAACAGTTACTATAG TGGTGAGATGGAAGGAATCAAATTTTGCCAGAGAAACTAACTCGGTGGCCCCAACAGGTCTTCCGGGGCCATGGGCATTTGTTT AGAGCCAAATTCATCCTCTTACCAGATCCTTTTCCAGAAATACCTGTCTAGGAAGGTGTGATGTCAGAAACAATGACATCCAGA AAGCTGAGGAACAGGTTCCTGTGGAGACACTGAGTCAGAATTCTTCATCCAAATTATTTTGTTAGTGGAAAATGGAATTGCTTC TGTGTAGTCAATAAAATGAACCTGATCACTTTTC
313
MSVAVDPQPSWTRVWLPLVSSTYD MSSAYLSTKDQYPYLKSVCEMAENGVKTITSVAMTSALPIIQK EPQIAVANTYAC KGLDRIEERLPI NQPSTQIVANAKGAVTGAKDAVTTTVTGAKDSVASTITGVMDKTKGAVTGSVEKTKSVVSGSINTVLGSRM MQ VSSGVENALTKSELLVEQYLPLTEEELEKEAKKVEGFD VQKPSYY LGSLST HSRAYQQALSRVKEAKQKSQQTISQ LHSTVHLIEFARK1 YSA1IQKIQDAQDK YLSWE KRSIGYDDTDESHCAEQFESRT AIARNLTQQLQTTCHT LSNIQGVP QNIQDQAKHMGV GDIYSVFR SFKEVSDS LTSSKGQ QKMKESLDDVMDYLVMTP N LVGPFYPQLTESQNAQDQGA EMDKSSQETQRSEHKTH
313 SVAVDPQPSWTRVV PLVSSTYDLMSSAYLSTKDQYPYLKSVCEMAENGVKTITSVAMTSALPIIQKLEPQIAVA TYAC KGLDRIEERLPILNQPSTQIVANAKGAVTGAKDAVTTTVTGAKDSVASTITGVMDKTKGAVTGSVEKTKSWSGSINTV GSRM MQ VSSGVENALTKSEL VEQYLPLTEEELEKEAKKVEGFDLVQKPSYYVR GS STKLHSRAYQQALSRVKEAKQKSQQTISQ LHSTVHLIEFARKNVYSANQKIQDAQDKLYLSWVE KRSIGYDDTDESHCAEQFESRTLAIAR LTQQLQTTCHTL SNIQGVP QNIQDQAKHMGV GDIYSVFRNMSFKEVSDSLLTSSKGQLQKMKESLDDVMDYLVMTP MLVGPFYPQLTESQNAQDQGA EMDKSSQETQRSEHKTH 314
ATGGCATCCGTTGCAGTTGATCCACAACCGAGTGTGGTGACTCGGGTGGTCAACCTGCCCTTGGTGAGCTCCACGTATGACCTC ATGTCCTCAGCCTATCTCAGTACAAAGGACCAGTATCCCTACCTGAAGTCTGTGTGTGAGATGGCAGAGAACGGTGTGAAGACC' ATCACCTCCGTGGCCATGACCAGTGCTCTGCCCATCATCCAGAAGCTAGAGCCGCAAATTGCAGTTGCCAATACCTATGCCTGT AAGGGGCTAGACAGGATTGAGGAGAGACTGCCTATTCTGAATCAGCCATCAACTCAGATTGTTGCCAATGCCAAAGGCGCTGTG ACTGGGGCAAAAGATGCTGTGACGACTACTGTGACTGGGGCCAAGGATTCTGTGGCCAGCACGATCACAGGGGTGATGGACAAG ACCAAAGGGGCAGTGACTGGCAGTGTGGAGAAGACCAAGTCTGTGGTCAGTGGCAGCATTAACACAGTCTTGGGGAGTCGGATG ATGCAGCTCGTGAGCAGTGGCGTAGAAAATGCACTCACCAAATCAGAGCTGTTGGTAGAACAGTACCTCCCTCTCACTGAGGAA GAACTAGAAAAAGAAGCAAAAAAAGTTGAAGGATTTGATCTGGTTCAGAAGCCAAGTTATTATGTTAGACTGGGATCCCTGTCT ACCAAGCTTCACTCCCGTGCCTACCAGCAGGCTCTCAGCAGGGTTAAAGAAGCTAAGCAAAAAAGCCAACAGACCATTTCTCAG CTCCATTCTACTGTTCACCTGATTGAATTTGCCAGGAAGAATGTGTATAGTGCCAATCAGAAAATTCAGGATGCTCAGGATAAG CTCTACCTCTCATGGGTAGAGTGGAAAAGGAGCATTGGATATGATGATACTGATGAGTCCCACTGTGCTGAGCAAT'TTGAGTCA CGTACTCTTGCAATTGCCCGCAACCTGACTCAGCAGCTCCAGACCACGTGCCACACCCTCCTGTCCAACATCCAAGGTGTACCA CAGAACATCCAAGATCAAGCCAAGCACATGGGGGTGATGGCAGGCGACATCTACTCAGTGTTCCGCAATGCTGCCTCCTTTAAA GAAGTGTCTGACAGCCTCCTCACTTCTAGCAAGGGGCAGCTGCAGAAAATGAAGGAATCTTTAGATGACGTGATGGATTATCTT GTTAACAACACGCCCCTCAACTGGCTGGTAGGTCCCTTTTATCCTCAGCTGACTGAGTCTCAGAATGCTCAGGACCAAGGTGCA GAGATGGACAAGAGCAGCCAGGAGACCCAGCGATCTGAGCATAAAACTCATTAA
315
MCLRGGCSPRAPAAAPQPRPPPALPPRPRAPVPASRPGRPLLTPARPCGRMRRGSPGPRLGGSRGERRRPAGRDPARVGPGQGL RRPARPGPAA TETGQGIVHALTDLSIPGMTSGNGNSASSIAGTAPQNGENKPPQAI¥KPQILTHVIEGF¥IQEGADVSRWDAR LLVGNLKKKYAQGFLPEKLPQQDHTTTTDSEMEEPYLQESKEEGAPLKLKCELCGRVDFAYKFKRSKRFCSMACAKRYNVGCTK RVGLFHSDRSKLQKAGAATHNRRRPAKPVCHH PRIPRSSQQA CPFRL LLCVTHSQEDSSRCSDNSSYEEPLSPISASSSTS AGDKASGTWSSPTCICGTWWAWDTTSCQVSHQVNVEDVYEFIRSLPGCQEIAEEFRAQEIDGQALLL KEDHLMSVMNIKLGPA LKIYARISMLKDS 316
GGCGCCGCATGTGTCTCCGCGGCGGCTGCAGCCCTCGAGCGCCCGCCGCCGCGCCCCAACCCCGGCCGCCGCCCGCCCTCCCGC CCCGGCCTCGCGCCCCCGTCCCGGCCTCGCGCCCCGGCCGCCCTTTGTTGACGCCGGCCAGGCCGTGCGGTCGGATGCGCCGCG GCAGCCCCGGGCCCCGGCTCGGAGGCTCCCGGGGCGAGAGGAGGCGGCCCGCCGGCCGGGACCCCGCGCGAGTCGGCCCCGGCC AGGGGCTGCGTAGGCCCGCCCGGCCAGGCCCAGCCGCCTGGACAGAGACAGGGCAGGGCATTGTTCATGCACTGACCGACCTCA GCATCCCCGGCATGACCTCAGGGAACGGAAACTCTGCCTCCAGCATCGCCGGCACTGCCCCCCAGAATGGTGAGAATAAACCAC CACAGGCCATTGTGAAACCCCAAATCCTGACGCATGTTATCGAAGGGTTTGTGATCCAGGAGGGGGCGGACGTTTCCCGGTGGG ACGCTCGTCTGCTGGTGGGGAATCTCAAGAAGAAGTATGCACAGGGGTTCCTGCCTGAGAAACTTCCACAGCAGGATCACACCA CCACCACTGACTCGGAGATGGAGGAGCCCTATCTGCAAGAATCCAAAGAGGAGGGTGCTCCCCTCAAACTCAAGTGTGAGCTCT GTGGCCGGGTGGACTTTGCCTATAAGTTCAAGCGTTCCAAGCGCTTCTGTTCCATGGCTTGTGCAAAGAGGTACAACGTGGGAT GCACCAAACGGGTGGGACTTTTCCACTCAGACCGGAGCAAGCTGCAGAAGGCAGGAGCTGCGACCCACAACCGCCGTCGGCCAG CAAAGCCAGTCTGCCACCACTTACCAAGGATACCAAGAAGCAGCCAACAGGCACTGTGCCCCTTTCGGTTACTGCTGCTTTGCG TAACACACAGCCAGGAAGACTCCAGCCGTTGCTCAGATAACTCAAGCTATGAGGAACCCTTGTCACCCATCTCAGCCAGCTCAT CTACTTCCGCCGGCGACAAGGCCAGCGGGACCTGGAGCTCCCCGACATGCATATGCGGGACCTGGTGGGCATGGGACACCACTT CCTGCCAAGTGAGCCACCAAGTGAATGTAGAAGACGTCTACGAATTCATCCGCTCTCTGCCAGGCTGCCAGGAGATAGCAGAGG AATTCCGTGCCCAGGAAATCGACGGGCAAGCCCTGCTGCTGCTCAAGGAGGACCACCTGATGAGCGTTATGAACATCAAGCTGG GGCCCGCCCTGAAGATCTACGCCCGCATCAGCATGCTCAAGGACTCCTAGGGCTGGTGGCACCAGGATTCTGGCCCAGGGCGCC TCCTCCCGACTGAGCAGAGCCAGACAGACATTCCTGAGGGGCCCAGAAATGGCGGCGTTGGAGGGCAGGGGCTCTCCCTAGGGG CATAGCTGGTGAGGAGGTCTGGGCACCTCCTCCATGGCTCTCAGGGGCCTTTCATTTCTGTGGGAGGGGCAGAGAGGTAGGTGG CACAGAAGATGGGGCTTTATGCTTGTAAATATTGATAGCACTGGCTTCCTCCAAAGTCCCAATACTCTAGCCCCGCTCTCTTCC CCTCTTTCTGTCCCCCATTTTCCAGGGGGTATATGGTCAGGGCTCCCCAACCTGAGTTGGTTACTTCAAGGGCAGCCAGCAGGC CTGGATGGAGGCCTAGAAAGCCCTTGCCTTCCTTCCTCCCACTTCTTTCTCCAGGCCTGGTTAACTCTTCCGTTGTCAGCTTCT CCCCCTTCAGCCTGTTTCTGCAGCAGCCAGGGTTCTCCCCCCTACACCCTCTGCAGGTGGAGAGAGAGAAGCTGGGCCCAGCCG CGGTGCCTGCTGGCCAAGACGCCTTAACGCTGTGTGTATGACTGTGTGACTGTGTGGGAGCCTGGACTGACAGATAGGCCAAGG GCTACTCTCTGGCATCTCCAGGTGTTTTGTAGCAAACAGCCACTTAGTGCTTTGTCCTGGACTCCACTCAGCCTCAGGATGGGG AATAGCCAAGAATGGCAGCCTCAGCGCAGAGGCAAGGTCAGAAAGAGACGGCGCTTCAGAGTTTCCTTTCCAGACACCCCTCCC CGCACTGTGAAGTTCCCCTGACCGCCCTCCTGGTTCACAAAGAGCATTAAGAAAGCTGCGGTGGTCTGAGCAACATAGCCCAGA CGTGGAGCCTCCTGGCCTGCCTGCCCGCCCACCCTGGGAGTCCAGTGGTGAGGCTCAGAGAACTTCTAAGGGGAAAGAACAGCT GGAGTTTCTGTTGATGTGAAGAAGGCAGCTCTTGGCCTCCCACTCCCACACTTCTTTGCCTATAAATCTTCCTAGCAGCAATTT GAGCTACCTGAGGAGGAGGCAGGGCAGAAGGGCAAGGGCCTGCCTCTGACCTGCCGTGTCCTTTGCAGGAAGGAGGTAGGCACC TTTCTGAGCTTATTCTATTCCCCACCCACACCCCCAGGCAGGGTTGGAAATGAAGGACTTTTTTAACCTTTGTTTTGTTTTTTA AAAATAAATCTGTAAAATCTGAAAAAAAAAAAAAA
317
MHPFYTRAATMIGEIAAAVSFISKFLRTKGLTSERQLQTFSQSLQEL AEHYKHHWFPEKPCKGSGYRCIRINHKMDPLIGQAA QRIGLSSQELFRLLPSELT W¥DPYEVSYRIGEDGSIC¥ YEASPAGGSTQNSTWQMVDSRISCKEE LGRTSPSK YNMMT VSG
318 CCTCTCGGAGCTGGAAATGCAGCTATTGAGATCTTCGAATGCTGCGGAGCTGGAGGCGGAGGCAGCTGGGGAGGTCCGAGCGAT GTGACCAGGCCGCCATCGCTCGTCTCTTCCTCTCTCCTGCCGCCTCCTGTGTCGAAAATAACTTTTTTAGTCTAAAGAAAGAAA GACAAAAGTAGTCGTCCGCCCCTCACGCCCTCTCTTCCTCTCAGCCTTCCGCCCGGTGAGGAAGCCCGGGGTGGCTGCTCCGCC GTCGGGGCCGCGCCGCCGAGCCCCAGCGCCCCGGGCCGCCCCCGCACGCCGCCCCCATGCATCCCTTCTACACCCGGGCCGCCA CCATGATAGGCGAGATCGCCGCCGCCGTGTCCTTCATCTCCAAGTTTCTCCGCACCAAGGGGCTGACGAGCGAGCGACAGCTGC AGACCTTCAGCCAGAGCCTGCAGGAGCTGCTGGCAGAACATTATAAACATCACTGGTTCCCAGAAAAGCCATGCAAGGGATCGG GTTACCGTTGTATTCGCATCAACCATAAAATGGATCCTCTGATTGGACAGGCAGCACAGCGGATTGGACTGAGCAGTCAGGAGC TGTTCAGGCTTCTCCCAAGTGAACTCACACTCTGGGTTGACCCCTATGAAGTGTCCTACAGAATTGGAGAGGATGGCTCCATCT GTGTGCTGTATGAAGCCTCACCAGCAGGAGGTAGCACTCAAAACAGCACCAACGTGCAAATGGTAGACAGCCGAATCAGCTGTA AGGAGGAACTTCTCTTGGGCAGAACGAGCCCTTCCAAAAACTACAATATGATGACTGTATCAGGTTAAGATATAGTCTGTGGAT GGATCATCTGATGATGATCCATAAATTTGATTTTTGCTTTGGGTGGGCTCCTCTTGGGGATGGATTATGGAATTTAAACCATGT CACAGCTGTGAAGATCTGGCACAAGATAGAATGGTAAAAAAAAAAAAAAATTTTAAGTGACAGTGCCATAGTTTGGACAGTACC TTTCAATGATTAATTTTAATAGCCTGTGAGTCCAAGTAAATGATCACTTTATTTGCTAGGGAGGGAAGTCCTAGGGTGGTTTCA GTTTCTCCCAGACATACCTAAATTTTTACATCAATCCTTTTAAAGAAAATCTGTATTTCAAAGAATCTTTCTCTGCAGTAAATC TCGCAGGGGAATTTGCACTATTACACTTGAAAGTTGTTATTGTTAACCTTTTCGGCAGCTTTTAATAGGAAAGTTAAACGTTTT AAACATGGTAGTACTGGAAATTTTACAAGACTTTTACCTAGCACTTAAATATGTATAAATGTACATAAAGACAAACTAGTAAGC ATGACCTGGGGAAATGGTCAGACCTTGTATTGTGTTTTTGGCCTTGAAAGTAGCAAGTGACCAGAATCTGCCATGGCAACAGGC TTTAAAAAAGACCCTTAAAAAGACACTGTCTCAACTGTGGTGTTAGCACCAGCCAGCTCTCTGTACATTTGCTAGCTTGTAGTT TTCTAAGACTGAGTAAACTTCTTATTTTTAGAAAGTGGAGGTCTGGTTTGTAACTTTCCTTGTACTTAATTGGGTAAAAGTCTT TTCCACAAACCACCATCTATTTTGTGAACTTTGTTAGTCATCTTTTATTTGGTAAATTATGAACTGGTGTAAATTTGTACAGTT CATGTATATTGATTGTGGCAAAGTTGTACAGATTTCTATATTTTGGATGAGAAATTTTTCTTCTCTCTATAATAAATCGTTTCT TATCTTGGCATTTTTAACC
319 TKARVMYDFAAEPG E TVNEGEIITITNPDVGGGWLEGRNIKGERGLVPTDYVEILPSDGKDQFSCGNSVADQAFLDSLS ASTAQASSSMS HQVGSGNDPWSAWSASKSGN ESSEGWGAQPEGAGAQRNTNTPN WDTAFGHPQAYQGPATGDDDDWDED WDGPKSSSYFKDSESADAGGAQRGNSRASSSSMKIPLNKFPGFAKBGTEQY LAKQLAKPKEKIPIIVGDYGPMWVYPTSTFDC WADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYER LVKFGSAIPIPSLPDKQVTGRFEEEFIKMRMERLQA MT RMCRHPVISESEVFQQF NFRDEKEWKTGKRKAERDELAGVMIFSTMEPEAPDLD VEIEQKCEAVGKFTKAMDDGVKELLTVG QEH KRCTGP PKEYQKIGKA QSLAT¥FSSSGYQGETDLNDAITEAGKTYEEIASLVAEQPKKD HFLMECNHEYKGF GCFP DIIGTHKGAIEKVKESDK VATSKITLQDKQNMVKRVSIMSYALQAEM HFHSNRIYDYNSVIRLY EQQ¥QFYETIAEKLRQA J.SRFPVM
320
CGGGAGACGAGCCGGCCGTCCCGGGCCGGGGGACCCGCCCGCCATGGCCACCAAGGCTCGGGTTATGTATGATTTTGCTGCTGA ACCTGGAAATAATGAACTGACGGTTAATGAAGGAGAAATCATCACAATCACAAATCCGGATGTAGGTGGAGGATGGCTGGAAGG AAGAAACATCAAAGGAGAACGAGGGCTGGTTCCCACAGACTACGTTGAAATTTTACCCAGTGATGGAAAAGATCAATTTTCTTG TGGAAATTCAGTGGCTGACCAAGCCTTCCTTGATTCTCTCTCAGCCAGCACAGCTCAGGCCAGTTCGTCGGCTGCCAGCAACAA TCACCAGGTTGGCAGTGGCAATGACCCCTGGTCAGCCTGGAGTGCCTCCAAATCTGGGAACTGGGAAAGCTCAGAAGGCTGGGG GGCCCAGCCAGAGGGGGCTGGAGCCCAAAGAAACACAAACACTCCCAACAACTGGGACACTGCCTTCGGCCACCCCCAGGCCTA CCAAGGACCAGCAACTGGTGATGATGATGACTGGGATGAAGACTGGGATGGGCCCAAATCCTCTTCCTACTTTAAGGATTCAGA GTCAGCTGATGCAGGCGGCGCTCAGCGAGGAAACAGTCGTGCTAGTTCCTCATCCATGAAAATTCCCCTTAACAAATTTCCTGG ATTTGCGAAACCTGGCACGGAACAGTATTTGTTGGCCAAACAACTAGCAAAACCCAAAGAGAAAATTCCCATCATTGTTGGAGA TTATGGCCCAATGTGGGTTTATCCTACCTCTACTTTTGACTGTGTGGTAGCAGATCCCAGAAAAGGCTCCAAAATGTATGGTCT AAAGAGCTACATCGAATATCAGCTAACACCTACTAACACTAATCGATCTGTAAACCACAGGTATAAGCACTTTGACTGGTTATA TGAGCGTCTCCTGGTTAAGTTTGGGTCAGCCATTCCAATCCCTTCTCTTCCAGACAAACAAGTCACAGGCCGCTTTGAAGAGGA ATTTATCAAAATGCGCATGGAGAGACTTCAGGCCTGGATGACCAGGATGTGTCGCCATCCAGTAATCTCAGAAAGTGAAGTTTT CCAGCAGTTCCTAAATTTCCGAGATGAGAAGGAATGGAAAACTGGAAAGAGGAAGGCCGAGAGAGATGAGCTGGCGGGAGTCAT GATATTTTCCACCATGGAACCAGAGGCACCTGACTTGGACTTAGTAGAAATAGAGCAGAAGTGCGAGGCTGTGGGGAAGTTCAC CAAGGCCATGGATGACGGCGTGAAGGAGCTGCTGACGGTGGGGCAGGAGCACTGGAAGCGCTGCACGGGCCCATTACCCAAGGA ATATCAGAAGATAGGAAAGGCCTTGCAGAGTTTGGCCACAGTGTTCAGTTCCAGTGGCTATCAAGGTGAAACAGATCTCAATGA TGCAATAACAGAAGCAGGAAAGACTTATGAAGAAATTGCCAGTCTCGTGGCAGAACAGCCAAAGAAAGATCTCCATTTCCTGAT GGAATGTAATCACGAGTATAAAGGTTTTCTTGGCTGCTTCCCTGACATCATTGGCACTCACAAGGGAGCAATAGAAAAAGTGAA AGAAAGTGACAAACTAGTTGCAACAAGTAAAATCACCCTACAAGACAAACAGAACATGGTGAAGAGAGTCAGCATCATGTCTTA CGCGTTGCAAGCTGAGATGAATCACTTTCACAGTAACCGGATCTATGATTACAACAGTGTCATCCGCCTGTACCTGGAGCAGCA AGTGCAATTTTACGAAACGATTGCAGAAAAGCTGAGGCAGGCCCTCAGCCGCTTTCCAGTGATGTAGGACAGAACGGGCCTTGA AGAGAATGCCGCGTGCTTTCTCCTGACTTGGGGCAATGCAATTCAAAACTTTTTTTCCCCTATTATTCAGAAAAAAAAGGAAAC AAAACCAAAAAGAAAGAGTTGCAAAAAACTGCATTTATTTTATTAGCCACCCTAAATGCGTCAGTTATTTAGGGATGGTCTTTT GTTCATTTCCGCATCCATTATTTAAACCAGTGGAAATTGTCTCTATTTTTGGAAAGTACTTAAAAGTTACCAGAATTTTCAATG GAAAATGAGGGGTTTCTCCCCACTGATATTTTACATAGAGTCATAATTTATATGTCTTATAAATTATAAGTCTTATATAATTTA TAAGTCTCCCACAATCTTCCAGTTCTTACCCAGTGTCAGATAATTAATTACTAATTACTTTCTTAAAAACATGAACTATGCCAG AATAAAAAATATCTATGTTTGTATAAAAAAAAAAAAAAAAAA
321
MKDLGAEHAGHEGVQ G LVYLEQEERFQPREKGLS IEATPENDNTLCPG RNAKVEDLRSLANFFGSCTETFVLAVNIL DRF ALMK¥KPKHLSCIGVCSFLLAARIVEEDCNIPSTHDVIRISQCKCTASDIKRMEKIISEKLHYE EATTA NF HLYHTΪ I CHTSERKEILSLDKLEAQLKACNCRLIFSKAKPSVLALCLLNLEVETLKSVELLEILLLVKKHSKINDTEFFYWRE VSKCL AEYSSPECCKPDLKKLWIVSRRTAQN HNSYYSVPELPTIPEGGCFDESESEDSCEDMSCGEESI-SSSPPSDQECTFFFNFKV AQTLCFPS
322
CCGGTCGGATGCCGGACCGGGGGCACCGCTGAGGCGGTGGGTCCCCGACCTGCGAGACAGGTTTGGAAGCCCCCGCTGCGCCCA GTCCGTGCGGACCGCGAGGCCGCGGGCGGGTGGAGGCGCGTCTCCGGCACGATGAAGGATTTGGGGGCAGAGCACTTGGCAGGT CATGAAGGGGTCCAACTTCTCGGGTTGTTGAACGTCTACCTGGAACAAGAAGAGAGATTCCAACCTCGAGAAAAAGGGCTGAGT TTGATTGAGGCTACCCCGGAGAATGATAACACTTTGTGTCCAGGATTGAGAAATGCCAAAGTTGAAGATTTAAGGAGTTTAGCC AACTTTTTTGGATCTTGCACTGAAACTTTTGTCCTGGCTGTCAATATTTTGGACAGGTTCTTGGCTCTTATGAAGGTGAAACCT AAACATTTGTCTTGCATTGGAGTCTGTTCTTTTTTGCTGGCTGCTAGAATAGTTGAAGAAGACTGCAATATTCCATCCACTCAT GATGTGATCCGGATTAGTCAGTGTAAATGTACTGCTTCTGACATAAAACGGATGGAAAAAATAATTTCAGAAAAATTGCACTAT GAATTGGAAGCTACTACTGCCTTAAACTTTTTGCACTTATACCATACTATTATACTTTGTCATACTTCAGAAAGGAAAGAAATA CTGAGCCTTGATAAACTAGAAGCTCAGCTGAAAGCTTGCAACTGCCGACTCATCTTTTCAAAAGCAAAACCATCTGTATTAGCC TTGTGCCTTCTCAATTTGGAAGTGGAAACTTTGAAATCTGTTGAATTACTGGAAATTCTCTTGCTAGTTAAAAAACATTCCAAG ATTAATGACACTGAGTTCTTCTACTGGAGAGAGTTGGTTTCTAAATGCCTAGCCGAGTATTCTTCTCCTGAATGTTGCAAACCA GATCTTAAGAAGTTGGTTTGGATCGTTTCAAGGCGCACAGCCCAGAACCTCCACAACAGCTACTATAGTGTTCCTGAGCTGCCA ACGATACCTGAGGGGGGTTGTTTTGATGAAAGTGAAAGTGAGGACTCTTGTGAAGATATGAGTTGTGGAGAGGAGAGTCTCAGC AGCTCTCCTCCCAGTGATCAAGAGTGCACCTTCTTTTTCAACTTCAAAGTGGCACAAACACTGTGCTTTCCATCTTAGAAATCT GATTGTTCTGTCAGAATTTATATTTACAGGGTTTCAAAGCAATAAATGGGGGAATAGGTAGTTTCCTGGTTTAGCCCCCATCTA GTCAGGAATTAATATACTGGAATACCTACCTTCTATTTGTTATTCAGATCAGATCTGGCCTATTTTCATATTTATCCTAAGCCA TCAAATGGGGTAGTGCCTCTTAAACCATTAACAGTACTTTAGACATTGGCACTTTATTTTTCTCGTAGATCTTTAGCTACTTTG GGGAGGAGGGAAGGTGCTGATACCTTCAATTTGTTACTTTTCAAGATTTTTAAAAATAACTAGTGTAGCTTATCTTAAACATTT TATAAAACCTTCAGATGTCTTTAAGCAGATTGGAAGTATGCAAGTGCTTCCTTAGCAGGGACAGTGGATAATCCTTAATGGTTT ATCATAGATTTCACCCTCCCCCCTTCTCAGAAGAGTGAGTATGCTCTTAAATGTCAAACACATTTTTGTTGTTTTGTTTTTTAA ATGATCAGTGTCTATTTGATGTGATGCAGATCTTATAAATTTGGGAATTATAATATTGACATTTCTGTGATTTTTATATATGTA ATGTCTTAATTGAGATTTGTGTTAAGGCAGAAATAATTAGGCTAGGGCTCTTAGTTTTCATTCCTATTGCCCCAAGTATTGTCA AACTATGGTATTATTTTAATGTTACTTTAAAAATCCATAATCTGCTAGTTTTGCATGTACTTATATGAAAACAGTGCAGTAAGT. TGAAAACTCAGTATCTATGGAATTGATAAATGTTGATCTGGTGTAGTATATTTTATCCGCATTTTCTTATATTAAAAAATGTTC TGCATGATTACATTTTATTTGCCTTTGT
323 MPPHPLNKHTHTHTHTHTHTHTHKM LGTAAPSCSLRMAVQAQRRAVGKTGSWSTLSPHTSQALHCLAGILHGICHACSQGEKS SCHSAKSK PGKVYKMTLDP¥KKQ¥SPELAMQ
324 AGGCAGTGTGTGGCCCAGGGAAAGCTGCGTTTCATGGAGGCTTCCAGGAGGCTGCCCTGTAAAGCCAGGCAGGTGGCTTCAAGT GCCATTCCTGCAAGTGCCCCTGCTTCAGCTCTCAGGCCCATCCAATGCCTCGAGCCCACGGGGGTGTCCCGGCAGGTCTGCGTC ATCACGACCCAGTAACGCTGCTGGCTGTGTCCTCATGCCCTCTTCCTCTGGCTGGCCAGTCATCTTTGTCACTTCTACACCTTT GAGTGTGTACAGGCTGAATGTTGAGTGATGCCCCCCCACCCTCTCAATAAACACACACACACACACACACACACACACACACAC 5 AAAATGTTATTAGGCACAGCAGCTCCATCCTGCTCCCTGAGAATGGCAGTGCAGGCACAGAGAAGAGCAGTTGGGAAGACAGGC AGCTGGTCTACCCTGTCCCCGCACACTTCACAGGCACTCCACTGCTTGGCAGGAATTCTGCATGGCATCTGCCACGCATGCTCA CAGGGTGAAAAATCAAGCTGTCACTCTGCAAAATCTAAAAACCCTGGAAAGGTCTATAAGATGACATTAGACCCAGTTAAGAAG CAAGTGTCACCTGAGTTGGCCATGCAATGAATGAATATTATAAGCAGTATTGGAGAACTAGGCGGTTGCTTACTAAGAAGTGTC TTGGAAACATTCGAGTTCATACAGTGCATGACAAAGTAATAGAAGGCTGCAAGCACTGAAAATGCACCCGAATCTGGTACCTAG 0 GATGAGTACATGAATAGTGATGAATAGCCCTTTGTGCTGTGTGCTATATACAACCATTTGCATTCAGAAAGCAGCATTTGAGGC
TGAGTTCCATTACTGGTGATTGAAGTATTTTCAGGAGCAGATACATGTGGTGCATGTTATATGCACTTAGTTTGAAAGTATCCC
* TCACCCAAAAAGTGCAGAACCTCTGAAAGGTGAGCCGTGGTGCAGGTGCCCCCCTCGCTGTTCGGGTCAGTTCTTGGCCATGCT
TGGCCTGTCACACGCCGGGTCTCAACAACATCGTGCGAGGAGACAGTGACTGGTTTCAGCCCAAGAGTCAACTGTTGAGCATGA
CATCAGGAAGCCTGTACTGTCCTGATCCCACCAGGCTTGGGTTAATTTCCTATTGCTTCAGAGAAAGAGAGGCGCTCTTGTGCT 5 TTTGAGAGAGCTCTCATGTTAAAAAGAGGTTGTCTTTGCACTGCGCTTGGTATGATTTGTTTTCTTATAAAACAGGAAGAGAAC CTAGAATGTGCCTTTCGTGAAGGTCTGACAAATGGGGTCTCAGAGTCCTAGGACCCGCACCAAGGTCAGAGTCCACCTGTAGAG GCTGAGCATTTCTACATGCACCCAGGGTGCTGGGCTGAGGCTAAGGGTGGACGCGTAGACCCCATCACAGGCTTCCTTCCTGAG CCCAAGTCCCCCATTTGGTCACTATCCCTTCTCAGAGCAAGTGGATTCTCTTTTCCTCACTTGGAATATTCAATGTTGAAGTAG TGGCCTGGAGTGGCCTTTCCCTCAGCTGCCTGTCTGGGCTCCCTGGCTTCCCGGATCTTCATCTCATACGTGAGGCAATAGGAG 0 GAGTTTCTATTCATTGAGACAAACAGTGAGCGGGCACCAACAGGCCAGCAGCTTGGCCCTTTTCACAGAGGTGGCCTTGGAGTC TGGAGTCTGGGCAGCTGTCTGCCTCTCTACGGCTCTGCTTCCCAGCGGGCACACGGGTCCGGAGCCTCAGAATGAAGTGGTGCA GAGGCGCAGGGCACACCTAGGAGAAGCTCAATGACCACCAAAGCCCTTGAGGAGAGACGGGGTTTGCTGTGTTAGAGAAATGGC AACCCCCAGGACCATGCACGGCTCTGGCAGTGCACAGTGGCTGATTTTCACCAGTTCCTCCTACCCCTGCCTCTGTCGGAGACT AGAAAACATTCTACCCCTTCAGGTCTTCTTTTAAAAGAAAAGAGCTATGGCAAAGCGTGCCATACAAAGTTAAAAAAAGGAAGA 5 GTGGCTTTGCGTTCTTGACCATGGCCACAATTCTGGTCACTTCTAGCATCTGACCTTGAGAACGGTGTAGAGGCTCTGAGCCAC CGCTGGCCTTTGAGAGAGTCTCACTCTCCAGCTAGCTCTTTGTGTAGTGTCCAGGGCCCCGGCAGTCAGGATAGAGCGAGCAAA AGAAGATGGACAGTGGACAGGGCGCAGTGGCTCACGCCTGTAATCCCAGCGCTTTGGGAGAGCGAGGCGGGCAGATCACAAGGT CAAGAGATCAAGACCATTCTGGCCAACATGGTGAAACCCTGTTTCTACTAAAAATACAAAAATTAGCTGGGCATGGTGGTGCGT GCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCCGAGATCGT 0 GCCACTGCACTCCAGCCTGGGTGACAGAGCAAGACTCCGTCTCAAAAAAGATGGCCATGCTGGCCAAGGCTGGGCTCATAGGAA ATATCTGTAGTAGGATGAAAGGAATCTGGCCTAGGGAGCCCCGGACTCGGTTTACCTACCCCGTACTCATCCCACTCATCTGTC TACCCTAGTGTCCATCATGCCCTGGATGAATCATAGGTGGGAGGGACAGAAGCCGAGAACACCAGGCACACGGGGTGGGGGGAA TGGGGGGAGCCSAGGTGATCCCCTTTGGAAAGTGGATTGATCCTCTCCCCTGTGGAATGACAGCTTAACCTGATTAACCCACTG GGGCTTGCTATTTTATGAGCATTTTTAAACAGAAAGGAAAGATGATATCCCAGTGCAGGTAGACTTTATTTTTGAAAGCATCGT 5 GGCCCCTCGCCTCTCCCTCTCCCCCAGAACCTTGGCCAGAATTGAGTCTTCGCGTTGGGGAGGCCACGCTGGAACCATTGCTCT AGGGCTGAAGGTGGAAGTAGGGCCACTGCCGCAGCTTCAGCCAGAGCCCTCGCTGCTTCGCAGAATTTAACAAGCACACGACTG GGATTCCTTTGGATATGAGAAAGGAAGGCAAGTGCGGGCAAAGGGAAGCTCCTCCCGTTTTTCATAAACAGAAGTAAGATGTCC TCTTTCCCAGGTTTGCACAATCACTTCTGGCAAATTAATTGAAGGTCCTTGAATTCAGCCAGTGCACGAAACCTTTGCATGTTC TTCTGAAACTGTACTTCTTCCCTATTCTGTCTACCCACACTCTGCGAACTTTGCCTTTTCCTTAAACACATTCCAGACCAAACA 0 CTGTTCAGTTTGTTAAAAAAAAAAAAAAAAAAA * * *
325 . . . . .. .
MGTSLSPNDP PLNPLSIQQTT LL LSV ATVHVGQRL RQRRRQLRSAPPGPFA PLIGNAAAVGQAAH SFAR ARRYGDV FQIRLGSCPIWLNGERAIHQALVQQGSAFADRPAFASFRVVSGGRSMAFGHYSEHWKVQRRAAHSfflRNFFTRQPRSRQVLEG HV SEARE ¥ALLVRGSADGAFLDPRPLTWAVANV--SA¥CFGCRYSHDDPEFRELLSHNEEFGRTVGAGSLVDVMPW QYFPN 5 PVRTVFREFEQLNRNFSNFILDKFLRHCESLRPGAAPRDMMDAFILSAEKKAAGDSHGGGAR DLENVPATITDIFGASQDT S TALQWLLLLFTRYPDVQTRVQAELDQWGRDR PCMGDQPN PYV AFLYEAMRFSSFVPVTIPHATTANTSV GYHIPKDTVV FWQ SWHDPVKWPNPENFDPARFLDKDGLINKDLTSRVMIFSVGKRRCIGEELSKTMQLFLFISI AHQCDFR PNEPAKMN FSYG TIKPKSFKVNVTLRESMELLDSAVQN QAKETCQ
326 ACTCTGGAGTGGGAGTGGGAGCGAGCGCTTCTGCGACTCCAGTTGTGAGAGCCGCAAGGGCATGGGAATTGACGCCACTCACCG ACCCCCAGTCTCAATCTCAACGCTGTGAGGAAACCTCGACTTTGCCAGGTCCCCAAGGGCAGCGGGGCTCGGCGAGCGAGGCAC CCTTCTCCGTCCCCATCCCAATCCAAGCGCTCCTGGCACTGACGACGCCAAGAGACTCGAGTGGGAGTTAAAGCTTCCAGTGAG GGCAGCAGGTGTCCAGGCCGGGCCTGCGGGTTCCTGTTGACGTCTTGCCCTAGGCAAAGGTCCCAGTTCCTTCTCGGAGCCGGC TGTCCCGCGCCACTGGAAACCGCACCTCCCCGCAGCATGGGCACCAGCCTCAG'CCCGAACGACCCTTGGCCGCTAAACCCGCTG TCCATCCAGCAGACCACGCTCCTGCTACTCCTGTCGGTGCTGGCCACTGTGCATGTGGGCCAGCGGCTGCTGAGGCAACGGAGG CGGCAGCTCCGGTCCGCGCCCCCGGGCCCGTTTGCGTGGCCACTGATCGGAAACGCGGCGGCGGTGGGCCAGGCGGCTCACCTC TCGTTCGCTCGCCTGGCGCGGCGCTACGGCGACGTTTTCCAGATCCGCCTGGGCAGCTGCCCCATAGTGGTGCTGAATGGCGAG CGCGCCATCCACCAGGCCCTGGTGCAGCAGGGCTCGGCCTTCGCCGACCGGCCGGCCTTCGCCTCCTTCCGTGTGGTGTCCGGC GGCCGCAGCATGGCTTTCGGCCACTACTCGGAGCACTGGAAGGTGCAGCGGCGCGCAGCCCACAGCATGATGCGCAACTTCTTC ACGCGCCAGCCGCGCAGCCGCCAAGTCCTCGAGGGCCACGTGCTGAGCGAGGCGCGCGAGCTGGTGGCGCTGCTGGTGCGCGGC AGCGCGGACGGCGCCTTCCTCGACCCGAGGCCGCTGACCGTCGTGGCCGTGGCCAACGTCATGAGTGCCGTGTGTTTCGGCTGC CGCTACAGCCACGACGACCCCGAGTTCCGTGAGCTGCTCAGCCACAACGAAGAGTTCGGGCGCACGGTGGGCGCGGGCAGCCTG GTGGACGTGATGCCCTGGCTGCAGTACTTCCCCAACCCGGTGCGCACCGTTTTCCGCGAATTCGAGCAGCTCAACCGCAACTTC AGCAACTTCATCCTGGACAAGTTCTTGAGGCACTGCGAAAGCCTTCGGCCCGGGGCCGCCCCCCGCGACATGATGGACGCCTTT ATCCTCTCTGCGGAAAAGAAGGCGGCCGGGGACTCGCACGGTGGTGGCGCGCGGCTGGATTTGGAGAACGTACCGGCCACTATC ACTGACATCTTCGGCGCCAGCCAGGACACCCTGTCCACCGCGCTGCAGTGGCTGCTCCTCCTCTTCACCAGGTATCCTGATGTG CAGACTCGAGTGCAGGCAGAATTGGATCAGGTCGTGGGGAGGGACCGTCTGCCTTGTATGGGTGACCAGCCCAACCTGCCCTAT GTCCTGGCCTTCCTTTATGAAGC.CATGCGCTTCTCCAGCTTTGTGCCTGTCACTATTCCTCATGCCACCACTGCCAACACCTCT GTCTTGGGCTACCACATTCCCAAGGACACTGTGGTTTTTGTCAACCAGTGGTCTGTGAATCATGACCCAGTGAAGTGGCCTAAC CCGGAGAACTTTGATCCAGCTCGATTCTTGGACAAGGATGGCCTCATCAACAAGGACCTGACCAGCAGAGTGATGATTTTTTCA GTGGGCAAAAGGCGGTGCATTGGCGAAGAACTTTCTAAGATGCAGCTTTTTCTCTTCATCTCCATCCTGGCTCACCAGTGCGAT TTCAGGGCCAACCCAAATGAGCCTGCGAAAATGAATTTCAGTTATGGTCTAACCATTAAACCCAAGTCATTTAAAGTCAATGTC ACTCTCAGAGAGTCCATGGAGCTCCTTGATAGTGCTGTCCAAAATTTACAAGCCAAGGAAACT.TGCCAATAAGAAGCAAGAGGC AAGCTGAAATTTTAGAAATATTCACATCTTCGGAGATGAGGAGTAAAATTCAGTTTTTTTCCAGTTCCTCTTTTGTGCTGCTTC TCAATTAGCGTTTAAGGTGAGCATAAATCAACTGTCCATCAGGTGAGGTGTGCTCCATACCCAGCGGTTCTTCATGAGTAGTGG GCTATGCAGGAGCTTCTGGGAGATTTTTTTGAGTCAAAGACTTAAAGGGCCCAATGAATTATTATATACATACTGCATCTTGGT TATTTCTGAAGGTAGCATTCTTTGGAGTTAAAATGCACATATAGACACATACACCCAAACACTTACACCAAACTACTGAATGAA GAAGTATTTTGGTAACCAGGCCATTTTTGGTGGGAATCCAAGATTGGTCTCCCATATGCAGAAATAGACAAAAAGTATATTAAA CAAAGTTTCAGAGTATATTGTTGAAGAGACAGAGACAAGTAATTTCAGTGTAAAGTGTGTGATTGAAGGTGATAAGGGAAAAGA TAAAGACCAGAAATTCCCTTTTCACCTTTTCAGGAAAATAACTTAGACTCTAGTATTTATGGGTGGATTTATCCTTTTGCCTTC TGGTATACTTCCTTACTTTTAAGGATAAATCATAAAGTCAGTTGCTCAAAAAGAAATCAATAGTTGAATTAGTGAGTATAGTGG GGTTCCATGAGTTATCATGAATTTTAAAGTATGCATTATTAAATTGTAAAACTCCAAGGTGATGTTGTACCTCTTTTGCTTGCC AAAGTACAGAATTTGAATTATCAGCAAAGAAAAAAAAAAAAGCCAGCCAAGCTTTAAATTATGTGACCATAATGTACTGATTTC AGTAAGTCTCATAGGTTAAAAAAAAAAGTCACCAAATAGTGTGAAATATATTACTTAACTGTCCGTAAGCAGTATATTAGTATT ATCTTGTTCAGGAAAAGGTTGAATAATATATGCCTTGTGTAATATTGAAMTTGAAAAGTACAACTAACGCAACCAAGTGTGCT AAAAATGAGCTTGATTAAATCAACCACCTATTTTTGACATGGAAATGAAGCAGGGTTTCTTTTCTTCACTCAAATTTTGGCGAA TCTCAAAATTAGATCCTAAGATGTGTTCTTATTTTTATAACATCTTTATTGAAATTCTATTTATAATACAGAATCTTGTTTTGA AAATAACCTAATTAATATATTAAAATTCCAAATTCATGGCATGCTTAAATTTTAACTAAATTTTAAAGCCATTCTGATTATTGA GTTCCAGTTGAAGTTAGTGGAAATCTGAACATTCTCCTGTGGAAGGCAGAGAAATCTAAGCTGTGTCTGCCCAATGAATAATGG AAAATGCCATGAATTACCTGGATGTTCTTTTTACGAGGTGACAAGAGTTGGGGACAGAACTCCCATTACAACTGACCAAGTTTC TCTTCTAGATGATTTTTTGAAAGTTAACATTAATGCCTGCTTTTTGGAAAGTCAGAATCAGAAGATAGTCTTGGAAGCTGTTTG GAAAAGACAGTGGAGATGAGGTCAGTTGTGTTTTTTAAGATGGCAATTACTTTGGTAGCTGGGAAAGCATAAAGCTCAAATGAA ATGTATGCATTCACATTTAGAAAAGTGAATTGAAGTTTGAAGTTTTAAAGTTCATTGCAATTAAACTTCCAAAGAAAGTTCTAC AGTGTCCTAAGTGCTAAGTGCTTATTACATTTTATTAAGCTTTTTGGAATCTTTGTACCAAAATTTTAAAAAAGGGAGTTTTTG ATAGTTGTGTGTATGTGTGTGTGGGGTGGGGGGATGGTAAGAGAAAAGAGAGAAACACTGAAAAGAAGGAAAGATGGTTAAACA TTTTCCCACTCATTCTGAATTAATTAATTTGGAGCACAAAATTCAAAGCATGGACATTTAGAAGAAAGATGTTTGGCGTAGCAG AGTTAAATCTCAAATAGGCTATTAAAAAAGTCTACAACATAGCAGATCTGTTTTGTGGTTTGGAATATTAAAAAACTTCATGTA ATTTTATTTTAAAATTTCATAGCTGTACTTCTTGAATATAAAAAATCATGCCAGTATTTTTAAAGGCATTAGAGTCAACTACAC AAAGCAGGCTTGCCCAGTACATTTAAATTTTTTGGCACTTGCCATTCCAAAATATTATGCCCCACCAAGGCTGAGACAGTGAAT TTGGGCTGCTGTAGCCTATTTTTTTAGATTGAGAAATGTGTAGCTGCAAAAATAATCATGAACCAATCTGGATGCCTCATTATG TCAACCAGGTCCAGATGTGCTATAATCTGTTTTTACGTATGTAGGCCCAGTCGTCATCAGATGCTTGCGGCAAAAGAAAGCTGT GTTTATATGGAAGAAAGTAAGGTGCTTGGAGTTTACCTGGCTTATTTAATATGCTTATAACCTAGTTAAAGAAAGGAAAAGAAA ACAAAAAACGAATGAAAATAACTGAATTTGGAGGCTGGAGTAATCAGATTACTGCTTTAATCAGAAACCCTCATTGTGTTTCTA CCGGAGAGAGAATGTATTTGCTGACAACCATTAAAGTCAGAAGTTTTACTCCAGGTTATTGCAATAAAGTATAATGTTTATTAA ATGCTTCATTTGTATGTCAAAGCTTTGACTCTATAAGCAAATTGCTTTTTTCCAAAACAAAAAGATGTCTCAGGTTTGTTTTGT GAATTTTCTAAAAGCTTTCATGTCCCAGAACTTAGCCTTTACCTGTGAAGTGTTACTACAGCCTTAATATTTTCCTAGTAGATC TATATTAGATCAAATAGTTGCATAGCAGTATATGTTAATTTGTGTGTTTTTAGCTGTGACACAACTGTGTGATTAAAAGGTATA CTTTAGTAGACATTTATAACTCAAGGATACCTTCTTATTTAATCTTTTCTTATTTTTGTACTTTATCATGAATGCTTTTAGTGT GTGCATAATAGCTACAGTGCATAGTTGTAGACAAAGTACATTCTGGGGAAACAACATTTATATGTAGCCTTTACTGTTTGATAT ACCAAATTAAAAAAAAATTGTATCTCATTACTTATACTGGGACACCATTACCAAAATAATAAAAATCACTTTCATAATCTTGAA AAAA
327
MTTT VSATIFDLSEVLCKGNKM YSAPSAGGCLLDRKAVGTPAGGGFPRRHSVTLPSSKFHQNQ LSSLKGEPAPALSSRDS RFRDRSFSEGGERLLPTQKQPGGGQWSSRYKTE CRPFEENGACKYGDKCQFAHGIHELRSLTRHPKYKTELCRTFHTIGFCP YGPRCHFIHNAEERRALAGARDLSADRPRLQHSFSFAGFPSAAATAAATG LDSPTSITPPPI SADD GSPTLPDGTN PFA FSSQE ASLFAPSMG PGGGSPTTF FRPMSESPHMFDSPPSPQDSLSDQEGYLSSSSSSHSGSDSPTLDNSRRLPIFSRLSIS DD
328
CGGAGTCAGAAAGGCGAGGGGCGCCGGGAACTGGCGTGTGGGACTCCAGACAGGAGAGGCTGCGCCTTCCCCGCACCGGGACCT TCGCGACACACCAGATCCTCGCCCCTGGCTCGCGCGAACGCACAGGATGACCACCACCCTCGTGTCTGCCACCATCTTCGACTT GAGCGAAGTTTTATGCAAGGGTAACAAGATGCTCAACTATAGTGCTCCCAGTGCAGGGGGTTGCCTGCTGGACAGAAAGGCAGT GGGCACCCCTGCTGGTGGGGGCTTCCCTCGGAGGCACTCAGTCACCCTGCCCAGCTCCAAGTTCCACCAGAACCAGCTCCTCAG CAGCCTCAAGGGTGAGCCAGCCCCCGCTCTGAGCTCGCGAGACAGCCGCTTCCGAGACCGCTCCTTCTCGGAAGGGGGCGAGCG GCTGCTGCCCACCCAGAAGCAGCCCGGGGGCGGCCAGGTCAACTCCAGCCGCTACAAGACGGAGCTGTGCCGCCCCTTTGAGGA AAACGGTGCCTGTAAGTACGGGGACAAGTGCCAGTTCGCACACGGCATCCACGAGCTCCGCAGCCTGACCCGCCACCCCAAGTA CAAGACGGAGCTGTGCCGCACCTTCCACACCATCGGCTTTTGCCCCTACGGGCCCCGCTGCCACTTCATCCACAACGCTGAAGA GCGCCGTGCCCTGGCCGGGGCCCGGGACCTCTCCGCTGACCGTCCCCGCCTCCAGCATAGCTTTAGCTTTGCTGGGTTTCCCAG TGCCGCTGCCACCGCCGCTGCCACCGGGCTGCTGGACAGCCCCACGTCCATCACCCCACCCCCTATTCTGAGCGCCGATGACCT CCTGGGCTCACCTACCCTGCCCGATGGCACCAATAACCCTTTTGCCTTCTCCAGCCAGGAGCTGGCAAGCCTCTTTGCCCCTAG CATGGGGCTGCCCGGGGGTGGCTCCCCGACCACCTTCCTCTTCCGGCCCATGTCCGAGTCCCCTCACATGTTTGACTCTCCCCC CAGCCCTCAGGATTCTCTCTCGGACCAGGAGGGCTACCTGAGCAGCTCCAGCAGCAGCCACAGTGGCTCAGACTCCCCGACCTT GGACAACTCAAGACGCCTGCCCATCTTCAGCAGACTTTCCATCTCAGATGACTAAGCCAGGGTAGGGAGGGACCTCCTGCCTAC TCCAGCCCCTACCCTGCACCCACATCCCATACCCTCTTCTCCCTACCCATCCCATTCCCCACAGGCCCTACATTAACAAGGTTA AGCTCAACCCCTTTCCCCCAGCACCTCAGAATGTGCCCTCCCTCTCCCCCTCATAACCCCACCTAACATAAGGACAAGTCAATT TGTCAGTAGCTTCTTCTGGCTTGAAACCCCCTCCCTGGATTTTATAGCCCACTTACCATGCATAACAGACAAGTCCCATATTTT GTCAGTAGATGCCTTTTTTTTTCCGGCTTAAGCCTTAAGTGCCAAATCACAAGAGAAAAAGCAGTAACAGTTTACAGAAGCAAC TTAGTGCCTTGTAATCTAACTTTGTCACTGTGACTACATTACCTCTTCAGCGCCAGAGGGCACCCGTGGGCCTCCCGGAGCCTC TGCCCATGGCGGGGTGGAGACCCGGAACCAGCAGCCCCCTCCACTGGCGACACAACTGCACCTTCCCTCATTTCAGTCTCCCGC ACACTTATTCCTCCTCCCCTCTTCCCGGTGGCACCTCTCCACCTGTACCCGCCCCCCCACCCCCCCCACCCCTGCCCCTTGGAA GAGTTGTTGCCAGACCAGGGTTTTGGGGGAAACCTGTCTTGACATTCAAAACCTTTTTCTTCCCGATCTGAACCCCTGTTGACT AATCTTGCCTGGGTTTGTGTAGGTCTGCAGGAAGGAAGGCTGAAAAAGCGGACGAAGATTTTGACTTAAGTGGGACTTTGTGAT TTAATTTTTTCTTTTTTTTAAGTGGGGAGGAAGGGGAAGCTAGATGGACTAGGAGAGACTTGATTTTGGTGCTAAAGTTCCCCA GTTCATATGTGACATCTTTTTAAAAAAAATAACAACAAAAAAAAAATGAGAGAAAAGCTAAAAAAAAAAAAGTAAGGGGTGAGC AGTTAATGGTATTCATTCCACATACAATATCTGTGTAAAACGATTTCCTGTAGAAGTAGCTTTAATGGTTTTTGCTCTAGAATA CCGTAGGTCTATCCTTAGAGCACTCACGCCATGCTTTCTTCCCTGGGTTTTAAACTTCATATAACTTTCAGAAATTGGAGAGCA AAAATTTTGCTTGTCACTGCACATCAATATAAAAAAGCTTATTTAACTTATCAAAACGTATTTATTGCCAAACTATGCTTTTTT TTGTTAATTTTGTTCATATTTATCGGGATGACAAATCCATAGAATATATTCTTTTATGTTAAATTATGATCTTCATATTAATCT TAAAATTTTGTGACGTGTCTTTTTCCTTTTTTTCCACAGTTTTAATATATTATTCTTCAACGACATTTTTTGTAACTTTACACT TTTTTGGTTATTTTATTTTAAAAAAATGAAAAATTAATTTAAAAAAATGCAAAAAACTGTTGGATTATTTATTTTAGAAATTCC CCCCTTTGTGTTGGACTGCAAATTGAGTTTCTTTCTCTTTAGGCCTTTCACAACTAGGACTGAGAATGTATGTAAAAGTTCTGT GACAGTACAGAAGGAAAACAACTTTTTATGTATAGCTTCTAAAAGGGGAAAAAAAAAAAAAGAGAAACCCTTTGACTTCCACGT GCCCATCTCAAGACATTCCACTCACAGATTTGAGGTTCTGGATTCCAGGTCTGGAGTTTTCCAATGTTAATGTAAACAGAACTG GCACACACACATTAAGATGAATGTAATTATTATTCCTCTTGCTGGTCACTACCGTCGCTTTCTATTTCTCTTTCTTTGTGTGAA TTTATTTAAAAGAAAAAAAAACTTTTTGTAACGACTATTTGCAGTTTAAAAATCAATAAACCCCGTTTTTTCAAGAAACATT 329
MATFPPATSAPQQPPGPEDEDSS DESDLYSLAHSYLGGGGRKGRTKREAAATNRPSPGGHERKLVTKLQNSERKKRGARR
330
CAGCCTTATAAGCTGAGGGAGTGGAGAGGCCCGGGGCCAGGAAAGCAGAGACAGACAAAGCGTTAGGAGAAGAAGAGAGGCAGG GAAGACAAGCCAGGCACGATGGCCACCTTCCCACCAGCAACCAGCGCCCCCCAGCAGCCCCCAGGCCCGGAGGACGAGGACTCC AGCCTGGATGAATCTGACCTCTATAGCCTGGCCCATTCCTACCTCGGAGGTGGAGGCCGGAAAGGTCGCACCAAGAGAGAAGCT GCTGCCAACACCAACCGCCCCAGCCCTGGCGGGCACGAGAGGAAACTGGTGACCAAGCTGCAGAATTCAGAGAGGAAGAAGCGA GGGGCACGGCGCTGAGACAGAGCTGGAGATGAGGCCAGACCATGGACACTACACCCAGCAATAGAGACGGGACTGCGGAGGAAG GAGGACCCAGGACAGGATCCAGGCCGGCTTGCCACACCCCCCACCCCTAGGACTTATTCCCGCTGACTGAGTCTCTGAGGGGCT ACCAGGAAAGCGCCTCCAACCCTAGCAAAAGTGCAAGATGGGGAGTGAGAGGCTGGGAATGGAGGGGCAGAGCCAGGAAGATCC CCCAGAAAAGAAAGCTACAGAAGAAACTGGGGCTCCTCCAGGGTGGCAGCAACAATAAATAGACACGCACGGCAGCCACAGCTT GGGTGTGTGTTCATCCTTGTTAAAAAAAAAAAAAAAAAAAAAAAAAA
331
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENA FNKIFLPTIYSIIFLTGIVGNGLVILVMGYQKKRSMTDKYRHLSVAD FVITLPFWAVDAVANWYFGNFLCKAVHVIYT LYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKWYVGVWIPA LLT IPDFIFA1 SEADDRYICDRFYPNDLWVWFQFQHIMVG ILPGIVILSCYCIIISK SHSKGHQKRKALKTTVILILAFFACW LPYYIGISIDSFIL EIIKQGCEFENTVHK ISITEALAFFHCCLNPILYAF GAKFKTSAQHALTSVSRGSSLKI SKGKRGG HSS¥STESESSSFHSS
332
GTTTGTTGGCTGCGGCAGCAGGTAGCAAAGTGACGCCGAGGGCCTGAGTGCTCCAGTAGCCACCGCATCTGGAGAACCAGCGGT TACCATGGAGGGGATCAGTATATACACTTCAGATAACTACACCGAGGAAATGGGCTCAGGGGACTATGACTCCATGAAGGAACC CTGTTTCCGTGAAGAAAATGCTAATTTCAATAAAATCTTCCTGCCCACCATCTACTCCATCATCTTCTTAACTGGCATTGTGGG CAATGGATTGGTCATCCTGGTCATGGGTTACCAGAAGAAACTGAGAAGCATGACGGACAAGTACAGGCTGCACCTGTCAGTGGC CGACCTCCTCTTTGTCATCACGCTTCCCTTCTGGGCAGTTGATGCCGTGGCAAACTGGTACTTTGGGAACTTCCTATGCAAGGC AGTCCATGTCATCTACACAGTCAACCTCTACAGCAGTGTCCTCATCCTGGCCTTCATCAGTCTGGACCGCTACCTGGCCATCGT CCACGCCACCAACAGTCAGAGGCCAAGGAAGCTGTTGGCTGAAAAGGTGGTCTATGTTGGCGTCTGGATCCCTGCCCTCCTGCT GACTATTCCCGACTTCATCTTTGCCAACGTCAGTGAGGCAGATGACAGATATATCTGTGACCGCTTCTACCCCAATGACTTGTG GGTGGTTGTGTTCCAGTTTCAGCACATCATGGTTGGCCTTATCCTGCCTGGTATTGTCATCCTGTCCTGCTATTGCATTATCAT CTCCAAGCTGTCACACTCCAAGGGCCACCAGAAGCGCAAGGCCCTCAAGACCACAGTCATCCTCATCCTGGCTTTCTTCGCCTG TTGGCTGCCTTACTACATTGGGATCAGCATCGACTCCTTCATCCTCCTGGAAATCATCAAGCAAGGGTGTGAGTTTGAGAACAC TGTGCACAAGTGGATTTCCATCACCGAGGCCCTAGCTTTCTTCCACTGTTGTCTGAACCCCATCCTCTATGCTTTCCTTGGAGC CAAATTTAAAACCTCTGCCCAGCACGCACTCACCTCTGTGAGCAGAGGGTCCAGCCTCAAGATCCTCTCCAAAGGAAAGCGAGG TGGACATTCATCTGTTTCCACTGAGTCTGAGTCTTCAAGTTTTCACTCCAGCTAACACAGATGTAAAAGACTTTTTTTTATACG ATAAATAACTTTTTTTTAAGTTACACATTTTTCAGATATAAAAGACTGACCAATATTGTACAGTTTTTATTGCTTGTTGGATTT TTGTCTTGTGTTTCTTTAGTTTTTGTGAAGTTTAATTGACTTATTTATATAAATTTTTTTTGTTTCATATTGATGTGTGTCTAG GCAGGACCTGTGGCCAAGTTCTTAGTTGCTGTATGTCTCGTGGTAGGACTGTAGAAAAGGGAACTGAACATTCCAGAGCGTGTA GTGAATCACGTAAAGCTAGAAATGATCCCCAGCTGTTTATGCATAGATAATCTCTCCATTCCCGTGGAACGTTTTTCCTGTTCT TAAGACGTGATTTTGCTGTAGAAGATGGCACTTATAACCAAAGCCCAAAGTGGTATAGAAATGCTGGTTTTTCAGTTTTCAGGA GTGGGTTGATTTCAGCACCTACAGTGTACAGTCTTGTATTAAGTTGTTAATAAAAGTACATGTTAAACTTACTTAGTGTTATG
333 MALKERIG RYSLLFVGLLQ NIWFGALLRPIIIRGPASPKIVIQENRKEAQYM ENEKTRTSIDSIDSGVELTTSPKNVPTH TNPELEPKADLQQVLVKTSPRPSKKKAPLLDFSILKEKSFICYALFGLLATL
334 AGCAATTCATGGCTCTGAAGGAGCGCATTGGCTGGAGATACAGCCTCCTCTTCGTGGGCCTACTACAGTTAAACATTGTCGTCT TCGGAGCACTGCTCAGACCCATCATCATCAGAGGACCAGCGTCACCAAAAATAGTCATCCAGGAAAATCGGAAAGAAGCACAGT ATATGCTTGAAAATGAGAAAACACGAACCTCAATAGACTCCATTGACTCAGGAGTAGAACTAACTACCTCACCTAAAAATGTGC CTACTCACACTAACCCAGAACTGGAGCCGAAGGCAGACCTGCAGCAGGTCCTGGTGAAGACCAGCCCCAGGCCAAGCAAAAAGA AAGCCCCGCTATTAGACTTCTCCATTTTGAAAGAGAAAAGTTTTATTTGTTATGCATTATTTGGTCTCCTTGCGACACTGTGAT TCTTTGCACCTTCCTTGTACATCATTCCTCTGGGCATTAGTCTGGGCATTGACCAGGACAGCGCTGCTTTTTTATTATCTACAA TGGCCATTGCAGAAGTTTTCAGGAGGATCGGAGCTGGTTTTGTCCTCAACAGAGAGCCCATTCGTGTGATTTACATTGAGCTCA TCTGCGTCATCTTATTGACTGTGTCTCTGTTTGCCTTTACTTTTGCTAGGGAATTCTGGGGTCTAATGTCATGTAGCGTATTTT TTGGGTTTATGGTTGGAACAACAGGAGGGACCCACATTCCACTGCTTGCTGAGGATGATGTTGTGGGCATTGAGAAGATGTCTT CTGCAGCTGGGGTCTACATCTTCATTCAGAGCATAGCAGGACTGGCTGGACCACCCCTTGCGGTTTGTTGGTGGACCAAAGTAA GATCTACAGCAGGGCCTTCTACTCCTGCGCAGCTGGCATGGCCCTGGCTGCTGTGTGCCTCGCCCTGGTGAGACCGTGTAAGAT GGGACTGTGCCAGCATCATCACTCAGGTGAAACAAAGGTAGTGAGCCATCGTGGGAAGACTTTACAGGACATACCTGAAGACTT TCTGGAAATGGATCTTGCAAAAAATGAGCACAGAGTTCACGTGCAAATGGAGCCGGTATGACACACTTTCTTACAACAACAGCC ACTGTGTTGGCTGGAGAGGGATGGGGTGGGCCCAACGGAGACACAAGGAGGTAGAGGAGCTAACCCCTCTACTCCACTTTCAAA ACTACATTTTAAAGGGAATGTGTATGTGAAGAGCACTACCAACATCGCTTTTGTTTTAAGTTTTCCTTTTTGCTTGTTTTTAAA GCCAAAACAAAAAACAACCAAGCACTCTTCCATATATAAATCTGGCTGTATTCAGTAGCAATACAAMGATATGTAGAAAGACT CTTTGGTTCACATTCCAATATTAAAATAGTGACACGAACTGGCAAAGTGGTTTTAAAAGCTTTCACATGGGATAAATGATTTTC TTTCTTTCTTTTCTTTCTTCGTATGGTCTTGTCAGAATAAACTACTATCTTGAATAAAACAACATCCAACCCAGGTCATTGAAA TGAAATTGGCCAGTC 335
MTWSVPQREPLVLGGR APLGFSSRGYFGALPMVTTAPPPLPRIPDPRALPPTLFLPHFLGGDGPCLTPQPRAPAA PNRSLA VAGGTPRAAPKKRRKKKVRASPAGQLPSRFHQYQQHRPSLEGGRSPATGPSGAQE¥PGPAAALAPSPAAAAGTEGASPDLAPLR PAAPGQTPLRKEVLKSKMGKSEKIALPHGQ VHGIHLYEQPKINRQKSKYNLPLTKITSAKRNENNFWQDSVSSDRIQKQEKKP FK TENIKNSHLKKSAFLTEVSQKENYAGAKFSDPPSPSV PKPPSHWMGSTVENSNQNRE MAVH KTL KVQT 336
TGTTCCGCGATCTTCTCAGGCTCTCCTAGCAGCATCCATCGCCGCCACCCTATCTTCACTGGCTTCACCTTCTCCTTCTCTCTT CGTTGCTGAGCGACAAGCTTCCTAGCGCTATGACTGTCGTCTCCGTCCCGCAGCGGGAGCCGCTCGTCCTGGGTGGC'CGCCTTG CGCCGCTTGGCTTTTCC.TCCCGAGGTTACTTTGGGGCCCTCCCGATGGTGACCACGGCTCCGCCTCCTTTACCCCGGATCCCGG ACCCCCGGGCACTGCCCCCGACCCTCTTCCTCCCTCATTTCCTAGGGGGAGATGGCCCGTGTCTGACCCCCCAGCCTCGCGCTC CAGCAGCTCTGCCCAACCGCAGCCTCGCCGTGGCGGGAGGCACTCCTCGGGCAGCGCCGAAGAAGCGGCGAAAGAAGAAGGTGC GGGCCAGCCCCGCAGGGCAGCTGCCCAGCCGCTTCCACCAGTACCAGCAGCACCGGCCGAGTCTGGAGGGCGGCCGGAGCCCCG CGACCGGCCCGAGCGGAGCGCAGGAGGTCCCGGGCCCGGCCGCCGCCTTGGGCCCGAGTCCTGCAGCCGCAGCCGGCACGGAGG GAGCCAGCCCCGACCTTGCCCCGCTGCGGCCCGCGGCTCCCGGCCAAACCCCCCTCAGGAAAGAGGTTTTAAAATCAAAGATGG GAAAATCGGAGAAAATTGCCCTTCCCCATGGCCAGCTTGTTCATGGTATACACTTGTATGAGCAACCAAAGATAAACAGACAGA AAAGCAAATATAACTTGCCACTAACCAAGATCACCTCTGCAAAAAGAAATGAAAACAACTTTTGGCAGGATTCTGTTTCATCTG ACAGAATTCAGAAGCAGGAAAAAAAGCCTTTTAAAAATACCGAGAACATTAAAAATTCGCATTTGAAGAAATCAGCATTTCTAA CTGAAGTGAGCCAAAAGGAAAATTATGCTGGGGCAAAGTTTAGTGATCCACCTTCTCCTAGTGTTCTTCCAAAGCCTCCTAGTC ACTGGATGGGAAGCACTGTTGAAAATTCCAACCAAAACAGGGAGCTGATGGCAGTACACTTAAAAACCCTCCTCAAAGTTCAAA CTTAGATTTCAGATTTCAGTATGTGTGTAAAACATAATTTTTCCCATATCCCTGGACTCTTGAGAAAATTGGTACAGAAATGGA AATTTGCCTTGTTGCAACATACAATTGCAAAAGATGAGTTTAAAAAATTACATACAAACAGCTTGTATTATATTTTATATTTTG TAAATACTGTATACCATGTATTATGTGTATATTGTTCATACTTGAGAGGTATATTATAGTTTTGTTATGAAAGTATGTATTTTG CCCTGCCCACATTGCAGGTGTTTTGTATATATACAATGGATAAATTTTAAGTGTGTGCTAAGGCACATGGAAGACCGATTTTAT TTGCACAAGGTACTGAGATTTTTTTCAAGAAACAGCTGTCAAATCTCAAGGTGAAGATCTAAATGTGAACAGTTTACTAATGCA CTACTGAAGTTTAAATCTGTGGCACAATCAATGTAAGCATGGGGTTTGTTTCTCTAAATTGATTTGTAATCTGAAATTACTGAA CAACTCCTATTCCCATTTTTGCTAAACTCAATTTCTGGTTTTGGTATATATCCATTCCAGCTTAATGCCTCTAATTTTAATGCC AACAAAATTGGTTGTAATCAAATTTTAAAATAATAATAATTTGGCCCCCCCTTTTAAAATAGTCTTGACTCTTTGTGTGTGACT GTTTCTCATGTTTGAATGTGTGACTAGGAGATGATTTTGTGTGGTTGGATTTTTTTGACTTCTACTTTACTGGCTGAGTGTGAG CCGCCATGCCTGGCCATAATCTACATTTTCTTACCAGGAGCAGCATTGAGGTTTTTGAGCATAGTACTTGACTACTCTAGAGGC TGAGACGGGAGCATCTCTTGAGCCTGAGAAGTGGAGATTGCAATTGAGCTAGGATCAGGCCACTGCACTCCAGCCTGGGTAACA GACGCTGTCTCAAAAAAAAGGCCAAGAGAAAGTAAGGGAGACAGA
337
MAEVEDQAARDMKRLEEKDKERK VKGIRDDIEEEDDQEAYFRYMAENPTAGWQEEEEDN EYDSDGNPIAPTKKIIDPLPPI DHSEIDYPPFEKNFYNEHEEITNLTPQQLID RHKLNLR¥SGAAPPRPGSSFAHFGFDEQLMHQIRKSEYTQPTPIQCQGVPVA LSGRDMIGIAKTGSGKT FI PMLIHIMDQKE EPGDGPIAVIVCPTRE CQQIHAECKRFGKAYNLRSVAVYGGGSM EQAK ALQEGAEIVVCTPGRLIDHVKKKATNLQRVSYLVFDEADRMFDMGFEYQVRSIASHVRPDRQT LFSATFRKKIEK ARDILID PIRWQGDIGE EDVTQIVEILHSGPSKra^ TRRLVEFTSSGSV LFVTKKT NAEELAN LKQEGHNLGL HGDMDQSER K VISDFKKKDIPVLVATDVAARGLDIPSIKTVINYDVARDIDTHTHRIGRTGRAGEKGVAYTL TPKDSNFAGDLVR LEGA QH ¥SKELLDLMQNAWFRKSRFKGGKGKKLNIGGGGLGYRERPGLGSE DRGNMWMSNYEAYKPSTGAMGDRLTAMKAAFQSQY KSHFVAAS SNQKAGSSAAGASG TSAGSLNSVPTNSAQQGHNSPDSPVTSAAKGIPGFGNTGNISGAPVTYPSAGAQGVNNTA SGN SREGTGGSNGKRERYTENRGSSRHSHGETGNRHSDSPRHGDGGRHGDGYRHPESSSRHTDGHRHGENRHGGSAGRHGENR GA DGRNGESRKEAFNRESKMEPKMEPKVDSSKMDKVDSKTDKTADGFAVPEPPKRKKSRWDS
338 GTCCATCTTGCTGCTGTCCACTTTGGGTTCCATCTTGGGCTGCATCTTGCTCTCACGATTAAAAGCTTCTTTCCTGCTTTCCCC ATTCCGACCATCATTTGCACCCCGGTTCTCCCCATGCCGGCCTGCGCTTCCTCCATGTCTGTTCTCCCCGTGCCGATGGCCATC AGTATGACGGCTGCTGCTTTCTGGATGGCGGTATCCATCTCCATGGCGACCACCATCTCCGTGACGTGGACTATCGCTATGCCG ATTGCCAGTCTCTCCGTGACTGTGACGGCTGCTGCCCCGGTTCTCAGTATATCTCTCTCTTTTCCCGTTGCTGCCCCCAGTCCC TTCTCGGCTGTTATTCCCTGAAGCTGTGTTGTTGACTCCTTGGGCTCCGGCAGACGGGTAGGTCACAGGGGCACCACTGATGTT GCCAGTATTGCCAAAGCCTGGGATGCCCTTGGCGGCACTGGTGACGGGGCTGTCAGGACTGTTATGGCCCTGTTGTGCTGAGTT AGTTGGAACAGAATTCAAGCTCCCTGCACTAGTCCACCTGCCCCACTGCTTCTTCGCTTCTCTCTTGGAAAGTCCAGTCTCTCC TCGGCTTGCAATGGACCCCAACTGCTCCT.GCGCCGCTGGTGTCTCCTGCACCTGCGCTGGTTCCTGCAAGTGCAAAGAGTGCAA' ATGCACCTCCTGCAAGAAGAGCTGCTGCTCCTGCTGCCCCGTGGGCTGTAGCAAGTGTGCCCAGGGCTGTGTTTGCAAAGGGGC GTCAGAGAAGTGCAGCTGCTGCGACTGATGCCAGGACAACCTTTCTCCCAGATGTAAACAGAGAGACATGTACAAACCTGGATT TTTTTTTTATACCACCTTGACCCATTTGCTACATTCCTTTTCCTGTGAAATATGTGAGTGATAATTAAACACTTTAGACCTGAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
339
MTQT KYASRVFHRVRWAPELGASLGYREYHSARRSLADIPGPSTPSFLAELFCKGGLSRLHE QVQGAAHFGPV ASFGTVR TVYVAAPA¥EEL RQEGPRPERCSFSP TEHRRCRQRACGL TAEGEE QRLRSLLAPLLLRPQAAARYAGT NVVCDLVRR RRQRGRGTGPPA VRDVAGEFYKFGLEGIAAVLLGSR GCLEAQVPPDTETFIRAVGSVFVSTLLTMAMPHWLRHL¥PGPWGR CRDWDQMFAFAQRHVERREAEAAMR GGQPEKDLESGAHLTHFLFREELPAQSILGVTE LLAGVDTVSNTLS ALYE SRH PEVQTALHSEITAALSPGSSAYPSATVLSQ PLLKAWKEVLRLYPVVPGNSRVPDKDIHVGDYIIPKNTLVTLCHYATSRDPA QFPEPNSFRPARWLGEGPTPHPFASLPFGFGKRSCMGRRLAE ELQMALAQILTHFEVQPEPGAAPVRPKTRTVVPERSINLQ FLDR
340
GGGGTTGAGATATGATGCTCAGGAGAAGCGCTTTCTTTCGCGAGCACCCTGAACCAGACCATGACCCAGACGCTCAAGTACGCC TCCAGAGTGTTCCATCGCGTCCGCTGGGCGCCCGAGTTGGGCGCCTCCCTAGGCTACCGAGAGTACCACTCAGCACGCCGGAGC TTGGCAGACATCCCAGGCCCCTCTACGCCCAGCTTTCTGGCCGAACTTTTCTGCAAGGGGGGGCTGTCGAGGCTACACGAGCTG CAGGTGCAGGGCGCCGCGCACTTCGGGCCGGTGTGGCTAGCCAGCTTTGGGACAGTGCGCACCGTGTACGTGGCTGCCCCTGCA CTCGTCGAGGAGCTGCTGCGACAGGAGGGACCCCGGCCCGAGCGCTGCAGCTTCTCGCCCTGGACGGAGCACCGCCGCTGCCGC CAGCGGGCTTGCGGACTGCTCACTGCGGAAGGCGAAGAATGGCAAAGGCTCCGCAGTCTCCTGGCCCCGCTCCTCCTCCGGCCT CAAGCGGCCGCCCGCTACGCCGGAACCCTGAACAACGTAGTCTGCGACCTTGTGCGGCGTCTGAGGCGCCAGCGGGGACGTGGC ACGGGGCCGCCCGCCCTGGTTCGGGACGTGGCGGGGGAATTTTACAAGTTCGGACTGGAAGGCATCGCCGCGGTTCTGCTCGGC TCGCGCTTGGGCTGCCTGGAGGCTCAAGTGCCACCCGACACGGAGACCTTCATCCGCGCTGTGGGCTCGGTGTTTGTGTCCACG
- CTGTTGACCATGGC.GATGCCCCACTGGCTGCGCCACCTTGTGCCTGGGCCCTGGGGCCGCCTCTGCCGAGACTGGGACCAGATG
TTTGCATTTGCTCAGAGGCACGTGGAGCGGCGAGAGGCAGAGGCAGCCATGAGGAACGGAGGACAGCCCGAGAAGGACCTGGAG
TCTGGGGCGCACCTGACCCACTTCCTGTTCCGGGAAGAGTTGCCTGCCCAGTCCATCCTGGGAAATGTGACAGAGTTGCTATTG GCGGGAGTGGACACGGTGTCCAACACGCTCTCTTGGGCTCTGTATGAGCTCTCCCGGCACCCCGAAGTCCAGACAGCACTCCAC TCAGAGATCACAGCTGCCCTGAGCCCTGGCTCCAGTGCCTACCCCTCAGCCACTGTTCTGTCCCAGCTGCCCCTGCTGAAGGCG GTGGTCAAGGAAGTGCTAAGACTGTACCCTGTGGTACCTGGAAATTCTCGTGTCCCAGACAAAGACATTCATGTGGGTGACTAT ATTATCCCCAAAAATACGCTGGTCACTCTGTGTCACTATGCCACTTCAAGGGACCCTGCCCAGTTCCCAGAGCCAAATTCTTTT 5 CGTCCAGCTCGCTGGCTGGGGGAGGGTCCCACCCCCCACCCATTTGCATCTCTTCCCTTTGGCTTTGGCAAGCGCAGCTGTATG GGGAGACGCCTGGCAGAGCTTGAATTGCAAATGGCTTTGGCCCAGATCCTAACACATTTTGAGGTGCAGCCTGAGCCAGGTGCG GCCCCAGTTAGACCCAAGACCCGGACTGTCCTGGTACCTGAAAGGAGCATCAACCTACAGTTTTTGGACAGATAGTCCCATGGA AAGAGACTGTCATCATCACCCTTTCATTCATCATAGGGATAAGATTTTTTGTAGGCACAAGACCAAGGTATACATCTTCCCCTA ATGCCTATCTGACCAAACTGGATAGAACCACCATAGTGAAGTGTGAGGCGGCCCTGACCAATGTGTGAAGTATGCACTTGGCCT 0 GACTCAGGAAGCCAGGTGAGAAAACCATGGTCTCTCTGCTTGCTTGGCCCTTCTGATCATGTATGCATCCCCCAAGGATGAAAT CAGATTTTAACTAATAATGCTGGATGGCCTGAGGAAAGATTCAACTGCCTCTCTTTTTGGGCTTTCATAGTGTTCATTGATGCT GCTGGCTAAGCATTTATCAAAGCATAAGCTCAGTAACTGTGCATCTGGTCTGTACCTGGTTGGTCCTTCGTCTTTGCATGTAAG CTCTTTGAGAGGAAGGGTGAAGCCTTATTTGTTTTTTATGTCCCCTGCCAGGGCCTGTCTCTGACTAGGTGTCACCATACACAT TCTTAGATTGAATCTGAACCATGTGGCAGAAGGGATAAGCAGCTTACTTAGTAGGCTCTGTCTACCCCCTTCCTTCTTTGTCTT 5 GCCCCTAGGAAGGTGAATCTGCCCTAGCCTGGTTTACGGTTTCTTATAACTCTCCTTTGCTCTCTGGCCACTATTAAGTGGGTT TGCCCCATCACTTAGTTCTCAGGCAGAGACATCTTTGGGCCTGTCCCTGCCCAGGCCTCTGGCTTTTTATATTGAAAATTTTTA AATATTCACAAATTTTAGAATAAATCAAATATTCCATTCTT
341
MRRAHEGREIPSLGGARRREVLQAGRSQRAAGRRRRRQELELGVGSGRPGGPPPGPGRRGTCAAALPPEWPRRRTGLPRRGPRP 0 PLAMAK NKYFSLGNSKTKSPPQPPRPDYREQRRRGERPSQPPQA¥PQASSAASASCGPATASCFSASSGS PDDSGSTSDLI RAYRAQKERHFQDPYNGPGSS RK RAMCRLDYCGGSGEPGGVQRAFSASSASGAAGCCCASSGAGAAASSSSSSGSPH YRSS SERRPATPAE¥RYISPKHRLIK¥ESAAGGGAGDPLGGACAGGRT SPTACGGKKLLNKCAASAAEESGAGKKDKVTIADDYSDP FDAKNDLKSKAGKGESAGYMEPYEAQRIMTEFQRQESVRSQHKGIQLYDTPYEPEGQSVDSDSESTVSPRRESKLPQDDDRPA DEYDQP EWNRVTSPALAAQF.NGNEKRQSSPSPSRDRRRQ RAPGGGFKPIKHGSPEFCGILGERVDPAVPLEKQIWYHGAISR 5 GDAEN LRLCKECSYLVR SQTSKHDYP SLRSNQGFMHMKLAKTKEKYVGQNSPPFDSVPEVIHYYTTRKLPIKGAEHLSLL YPVA¥RTL
342
CGGGCCGCCGGGACGGGCACGGGCGCGCGGGCTCCGGCGGGCGCCGGCTGCCTTCCTCCGTCGCTCGCTGTCTCTCCCGGCCGC ATTCTCCTCCGCTGCGGGGCCGAGCTCTCCCCAGCGCTCGCAGGAAGGAAGAAGGGAGCCGAGGACGCCGAGAAGTTCCCGCGG 0 CAGCCGCGGATCCCGGCCAAGGCGGAGGCTGCGGCTCCGACGGGGCAGGAGCGCGATCCACGGCGAGGGGCGTACGGCCAAAGG GTCCGCGGCGTGGAGCGCTCGGACCTTCCGCTCTCCCCCGGGCGTGGGCCGGGACCCCATGAGACGCGCCCACGAGGGGCGCGA GATTCCTAGCTTGGGCGGCGCTAGGCGGAGGGAGGTGTTGCAGGCCGGCCGGAGCCAGAGAGCTGCCGGCAGGAGGCGGCGGCG GCAAGAACTTGAACTTGGCGTCGGGAGCGGGCGCCCCGGAGGCCCCCCGCCGGGGCCGGGGCGCCGAGGGACCTGCGCCGCAGC
• ■ GCTGGCCCCCGAATGGCCGCGGCGGCGGACCGGGCTCCCGCGCCGCGGCCCTAGGCCGCCTCTCGCCATGGCCAAGTGGCTAAA 5 CAAGTACTTCAGCTTGGGCAACAGCAAGACCAAGAGCCCCCCGCAGCCGCCGCGGCCAGACTACCGCGAGCAGCGGCGCCGAGG CGAGCGGCCTTCGCAGCCCCCCCAGGCCGTGCCGCAGGCCTCCTCCGCCGCCTCGGCGTCCTGCGGTCCGGCCACCGCCTCCTG CTTCTCAGCCTCTTCGGGCTCGCTGCCCGACGACAGCGGCAGCACCAGCGACCTCATCCGCGCCTACCGCGCGCAGAAGGAGCG ACACTTCCAGGACCCCTACAACGGGCCTGGCTCGTCGCTGCGCAAACTGCGCGCCATGTGCCGCCTGGACTACTGCGGCGGCAG CGGGGAGCCAGGCGGGGTCCAGCGCGCCTTCTCGGCCTCGTCCGCGTCGGGCGCCGCGGGCTGTTGCTGCGCCTCCTCGGGCGC 0 GGGCGCCGCCGCGTCCTCGTCCTCGTCCTCCGGCTCTCCGCATCTCTACCGCAGCAGCAGCGAGCGGCGGCCCGCCACGCCGGC CGAGGTGCGCTACATCTCCCCCAAGCACCGCCTCATCAAAGTGGAGAGCGCCGCGGGCGGTGGGGCCGGGGACCCCCTGGGGGG CGCCTGCGCGGGCGGCCGCACCTGGAGCCCGACGGCCTGCGGAGGCAAGAAACTGCTCAACAAGTGCGCCGCCTCAGCCGCGGA GGAGAGCGGGGCCGGCAAGAAGGACAAGGTGACCATAGCCGATGACTACTCAGATCCCTTTGATGCCAAGAATGATCTCAAGAG CAAAGCAGGAAAGGGGGAGAGTGCTGGCTACATGGAGCCCTATGAGGCACAGAGGATCATGACAGAATTTCAGAGGCAGGAAAG 5 TGTCCGGTCCCAGCATAAAGGTATCCAGTTATATGACACCCCTTACGAACCTGAAGGCCAAAGTGTTGACTCGGACTCGGAGAG eACAGTCAGCCCCCGACTGCGGGAGAGCAAGCTGCCCCAGGATGACGACAGGCCCGCCGATGAGTACGACCAGCCTTGGGAGTG GAACCGGGTCACCAGCCCAGCCCTGGCAGCACAGTTTAATGGCAACGAGAAGCGGCAGTCATCCCCCTCACCTTCGCGGGACCG GCGGCGCCAGCTTCGTGCCCCTGGAGGGGGCTTTAAGCCTATCAAACATGGGAGCCCTGAGTTCTGCGGGATCCTAGGAGAAAG GGTGGATCCTGCCGTCCCCCTGGAGAAGCAAATATGGTATCACGGAGCCATCAGCAGAGGAGACGCCGAGAACCTGCTGCGACT 0 CTGCAAGGAGTGTAGCTACCTTGTCCGGAACAGCCAGACCAGCAAGCATGACTACCCCCTCTCCCTGAGGAGCAACCAGGGTTT TATGCACATGAAACTGGCCAAAACCAAAGAGAAATACGTTCTGGGTCAGAACAGCCCTCCGTTCGACAGTGTCCCGGAAGTCAT CCACTACTACACCACCAGAAAGCTACCCATCAAAGGGGCTGAGCACTTGTCCCTCCTCTATCCCGTGGCTGTGAGGACCCTGTG AGCGGACCAGACCTGCCCTGCTCTGTGACAGAGCCTGGAGACTTGGAGGTGCCAGAGGCCCCCCACCAACCAGCCCCCAGCCAC TGTTGCTGGCTGTGTCGTTTGTGTTGTGTGTATGGTACTAGCACACCACTGCATGTCTCTAGAATGCTGTTGCCACTTACGGGG GCTGGAGGCCTGGATAAAGACAGAAGGGCGGCAACACC
343
MASVLSRR GKRSLLGARVLGPSASEGPSAAPPSEP LEGAAPQPFTTSDDTPCQEQPKEVLKAPSTSGLQQVAFQPGQKVYVW YGGQECTGLVEQHSWMEGQVTVWLLEQKLQVCCRVEEVWLAELQGPCPQAPPLEPGAQALAYRPVSRNIDVPKRKSDAVEMDEM MAA VLTSLSCSPWQSPPGTEANFSASRAACDP KESGDISDSGSSTTSGH SGSSGVSTPSPPHPQASPKY GDAFGSPQTD HGFETDPDPFLLDEPAPRKRKNSVKVMYKCLWPNCGKVLRSIVGIKRHVKALHLGDT¥DSDQFKREEDFYYTEVQ KEESAAAA AAAAAGTPVPGTPTSEPAPTPSMTGLPLSA PPPLHKAQSSGPEHPGPESSLPSGA SKSAPGSFWHIQADHAYQALPSFQIPV SPHIYTSVS AAAPSAACSLSPVRSRSI-SFSEPQQPAPAMKSHLIVTSPPRAQSGARKARGEAKKCRKVYGIEHRDQWCTACRW KKACQRFLD
344 AAGTGCGCATGTGCGCGAGGAGTCGCTCGGGCACTTATTGAGCGCCGACTGTCTACGGGCGGCCGGGGGTGATGGGCAGAGGCT
TCAGTGTCCCCTTCGCCTCCGCAGGAGAGGAGAGGCAGCAGCATGGCGAGTGTCCTGTCCCGACGCCTTGGAAAGCGGTCCCTC
CTGGGAGCCCGGGTGTTGGGACCCAGTGCCTCGGAGGGGCCCTCGGCTGCCCCACCCTCGGAGCCACTGCTAGAAGGGGCCGCT CCCCAGCCTTTCACCACCTCTGATGACACCCCCTGCCAGGAGCAGCCCAAGGAAGTCCTTAAGGCTCCCAGCACCTCGGGCCTT
CAGCAGGTGGCCTTTCAGCCTGGGCAGAAGGTTTATGTGTGGTACGGGGGTCAAGAGTGCACAGGACTGGTGGAGCAGCACAGC TGGATGGAGGGTCAGGTGACCGTCTGGCTGCTGGAGCAGAAGCTGCAGGTCTGCTGCAGGGTGGAGGAGGTGTGGCTGGCAGAG CTGCAGGGCCCCTGTCCCCAGGCACCACCCCTGGAGCCCGGAGCCCAGGCCCTGGCCTACAGGCCCGTCTCCAGGAACATCGAT GTCCCAAAGAGGAAGTCGGACGCAGTGGAAATGGATGAGATGATGGCGGCCATGGTGCTGACGTCCCTGTCCTGCAGCCCTGTT GTACAGAGTCCTCCCGGGACCGAGGCCAACTTCTCTGCTTCCCGTGCGGCCTGCGACCCATGGAAGGAGAGTGGTGACATCTCG GACAGCGGCAGCAGCACTACCAGCGGTCACTGGAGTGGGAGCAGTGGTGTCTCCACCCCCTCGCCCCCCCACCCCCAGGCCAGC CCCAAGTATTTGGGGGATGCTTTTGGTTCTCCCCAAACTGATCATGGCTTTGAGACCGATCCTGACCCTTTCCTGCTGGACGAA CCAGCTCCACGAAAAAGAAAGAACTCTGTGAAGGTGATGTACAAGTGCCTGTGGCCAAACTGTGGCAAAGTTCTGCGCTCCATT GTGGGCATCAAACGACACGTCAAAGCCCTCCATCTGGGGGACACAGTGGACTCTGATCAGTTCAAGCGGGAGGAGGATTTCTAC TACACAGAGGTGCAGCTGAAGGAGGAATCTGCTGCTGCTGCTGCTGCTGCTGCCGCAGGCACCCCAGTCCCTGGGACTCCCACC TCCGAGCCAGCTCCCACCCCCAGCATGACTGGCCTGCCTCTGTCTGCTCTTCCACCACCTCTGCACAAAGCCCAGTCCTCCGGC CCAGAACATCCTGGCCCGGAGTCCTCCCTGCCCTCAGGGGCTCTCAGCAAGTCAGCTCCTGGGTCCTTCTGGCACATTCAGGCA GATCATGCATACCAGGCTCTGCCATCCTTCCAGATCCCAGTCTCAGCACACATCTACACCAGTGTCAGCTGGGCTGCTGCCCCC TCCGCCGCCTGCTCTCTCTCTCCGGTCCGGAGCCGGTCGCTAAGCTTCAGCGAGCCCCAGCAGCCAGCACCTGCGATGAAATCT CATCAGATCGTCACTTCTCCACCCCGGGCCCAGAGTGGTGCCAGGAAAGCCCGAGGGGAGGCTAAGAAGTGCCGCAAGGTGTAT GGCATCGAGCACCGGGACCAGTGGTGCACGGCCTGCCGGTGGAAGAAGGCCTGCCAGCGCTTTCTGGACTGAGCTGTGCTGCAG GTTCTACTCTGTTCCTGGCCCTGCCGGCAGCCACTGACAAGAGGCCAGTGTGTCACCAGCCCTCAGCAGAAACCGAAAGAGAAA GAACGGAAACACGGAGTTTGGGCTCTGTTGGCTAAGGTGTAACACTTAAAGCAATTTTCTCCCATTGTGCGAACATTTTATTTT TTAAAAAAAAGAAACAAAAATATTTTTCCCCCTAAAATAGGAGAGAGCCAAAACTGACCAAGGCTATTCAGCAGTGAACCAGTG ACTAAAGAATTAATTACCCTCCGTTTCCCACATCCCCACTCTCTAGGGGATTAGCTTGTGCGTGTCAAAAGAAGGAACAGCTCG TTCTGCTTCCTGCTGAGTCGGTGAATTCTTTGCTTTCTAAACTCTTCCAGAAAGGACTGTGAGCAAGATGAATTTACTTTTCTT 345
MAMHFIFSDTAVLLFDFWSVHSPAGMA SVLVLL LAVLYEGIKVGKAKLLNQVL LPTSISQQTIAETDGDSAGSDSFPVGR THHRWYLCHFGQSLIHVIQWIGYFIMLAVMSYNTWIFLGWLGSAVGYY AYP LSTA
346
TCGGCACAGGAGCGAGGAGACCCGAGAGCAGACGCGCCCTGGCGCCCGCCCTGCGCAGTCACCATGGCGATGCATTTCATCTTC TCAGATACAGCGGTGCTTCTGTTTGATTTCTGGAGTGTCCACAGTCCTGCTGGCATGGCCCTTTCGGTGTTGGTGCTCCTGCTT CTGGCTGTACTGTAT.GAAGGCATCAAGGTTGGCAAAGCCAAGCTGCTCAACCAGGTACTGGTGAACCTGCCAACCTCCATCAGC CAGCAGACCATCGCAGAGACAGACGGGGACTCTGCAGGCTCAGATTCATTCCCTGTTGGCAGAACCCACCACAGGTGGTACTTG TGTCACTTTGGCCAGTCTCTAATCCATGTCATCCAGGTGGTCATCGGCTACTTCATCATGCTGGCCGTAATGTCCTACAACACC TGGATTTTCCTTGGTGTGGTCTTGGGCTCTGCTGTGGGCTACTACCTAGCTTACCCACTTCTCAGCACAGCTTAGATGGTGAGG AACGTGCAGGCACTGAGGCTGGAGGGACATGGAGCCCCCTCTTCCAGACACTATACTTCCAACTGCCCTTTCTTCTGATGGCTA TTCCTCCACCTTATTCCCAGCCCCTGGAAACTTTGAGCTGAAGCCAGCACTTGCTCCCTGGAGTTCGGAAGCCATTGCAGCAAC CTTCCTTCTCAGCCAGCCTACGTAGGGCCCAGGCATGGTCTTGTGTCTTAAGACAGCTGCTGTGACCAAAGGGAGAATGGAGAT AACAGGGGTGGCAGGGTTACTGAGCCCATGACAATGCTTCTCTGTGACTCAAACCAGGAATTTCCAAAGATTTCAAGCCAGGGA GAAGGGTTCTTGGTGATGCAGGGCATGGAACCTGGACACCCTCAGCTCTCCTGCTTTGTGCCTTATCTACAGGAGCATCGCCCA TTGGACTTCCTGACCTCTTCTGTCTTTGAGGGACAGAGACCAAGCTAGATCCTTTTTCTCACCTTTCTGCCTTTGGAACACATG AAGATCATCTCGTCTATGGATCATGTTGACAAACTAAGTTTTTTTTATTTTTCCCATTGAACTCCTAGTTGGCAATTTTGCACA TTCATACAAAAAAATTTTTAATGAAATGATTTCATTGATTCATGATGGATGGCAGAAACTGCTGAGACCTATTTCCCTTTCTTG GGGAGAGAATAAGTGACAGCTGATTAAAGGCAGAGACACAGGACTGCTTTCAGGCTCCTGGTTTATTCTCTGATTGACTGAGCT CCTTCCACCAGAAGGCACTGCCTGCAGGAAGAAGATGATCTGATGGCCGTGGGTGTCTGGGAAGCTCTTCGTGGCCTCAATGCC CTCCTTTATCCTCATCTTTCTTCTATGCAGAACAAAAAGCTGCATCTAATAATGTTCAATACTTAATATTCTCTATTTATTACT TACTGCTTACTCGTAATGATCTAGTGGGGAAACATGATTCATTCACTTAAAATACTGATTAAGCCATGGGCAGGTACTGACTGA AGATGCAATCCAACCAAAGCCATTACATTTTTTGAGTTAGATGGGACTCTCTGGATAGTTGAACCTCTTCACTTTATAAAAAAG GAAAGAGAGAAAATCACTGCTGTATACTAAATACCTCACAGATTAGATGAAAAGATGGTTGTAAGCTTTGGGAATTAAAAACAA ATACATTTTAGTAAATAT
347 SRFVQDLSKAMSQDGASQFQEVIRQELE SVKKELEKI TTASSHEFEHTKKDLDGFRKLFHRFLQEKGPSVDWGKIQRPPED SIQPYEKIKARGLPDNISSVLNKLVWKLNGGLGTSMGCKGPKSLIGVR ENTF DLTVQQIEH NKTYNTDVPLV M SFNTD EDTKKILQKYNHCRVKIYTFNQSRYPRINKES RPVAKDVSYSGENTEAWYPPGHGDIYASFYNSGL DTFIGEGKEYIFVSNI DNLGATVDLYILNH INPPNGKRCEFV-.EVTNKTRADVKGGTLTQYEGK R VEIAQVPKAHVDEFKSVSKFKIFNTMLWISL AAVKRLQEQNAIDMEIIVNAKTLDGGLNVIQLETA¥GAAIKSFENSLGINVPRSRFLPVKTTSDLLLVMSNLYSLNAGSLTMSE KREFPTVPLVK GSSFTKVQDY RRFESIPDMLE DHLTVSGDVTFGKWSLKGTVIIIA HGDRIDIPPGAVLENKIVSGNLR ILDH 348
AGGAGAGGAAGAGAGACCTGCCCTGTAGCGTGACTCCTCTAGAAAAAAAAAAAAAAAGCCGGAGTATTTTACTAAGCCCCTAAA ATGTCGAGATTTGTACAAGATCTTAGCAAAGCAATGTCTCAAGATGGTGCTTCTCAGTTCCAAGAAGTCATTCGGCAAGAGCTA GAATTATCTGTGAAGAAGGAACTAGAAAAAATACTCACCACAGCATCATCACATGAATTTGAGCACACCAAAAAAGACCTGGAT- GGATTTCGGAAGCTATTTCATAGATTTTTGCAAGAAAAGGGGCCTTCTGTGGATTGGGGAAAAATCCAGAGACCCCCTGAAGAT TCGATTCAACCCTATGAAAAGATAAAGGCCAGGGGCCTGCCTGATAATATATCTTCCGTGTTGAACAAACTAGTGGTGGTGAAA CTCAATGGTGGTTTGGGAACCAGCATGGGCTGCAAAGGCCCTAAAAGTCTGATTGGTGTGAGGAATGAGAATACCTTTCTGGAT CTGACTGTTCAGCAAATTGAACATTTGAACAAAACCTACAATACAGATGTCCCTCTTGTTTTAATGAACTCTTTTAACACGGAT GAAGATACCAAAAAAATACTACAGAAGTACAATCATTGTCGTGTGAAAATCTACACTTTCAATCAAAGCAGGTACCCGAGGATT AATAAAGAATCTTTACGGCCTGTAGCAAAGGACGTGTCTTACTCAGGGGAAAATACAGAAGCTTGGTACCCTCCAGGTCATGGT GATATTTACGCCAGTTTCTACAACTCTGGATTGCTTGATACCTTTATAGGAGAAGGCAAAGAGTATATTTTTGTGTCTAACATA GATAATCTGGGTGCCACAGTGGATCTGTATATTCTTAATCATCTAATCAACCCACCCAATGGAAAACGCTGTGAATTTGTCATG GAAGTCACAAATAAAACACGTGCAGATGTAAAGGGCGGGACACTCACTCAATATGAAGGCAAACTGAGACTGGTGGAAATTGCT CAAGTGCCAAAAGCACATGTTGACGAGTTCAAGTCTGTATCAAAGTTCAAAATATTTAATACAAACAACCTATGGATTTCTCTT GCAGCAGTTAAAAGACTGCAGGAGCAAAATGCCATTGACATGGAAATCATTGTGAATGCAAAGACTTTGGATGGAGGCCTGAAT GTCATTCAATTAGAAACTGCAGTAGGGGCTGCCATCAAAAGCTTTGAGAATTCTCTAGGTATTAATGTGCCAAGGAGCCGTTTT CTGCCTGTCAAAACCACATCAGATCTCTTGCTGGTGATGTCAAACCTCTATAGTCTTAATGCAGGATCTCTGACAATGAGTGAA AAGCGGGAATTTCCTACAGTGCCCTTGGTTAAATTAGGCAGTTCTTTTACGAAGGTTCAAGATTATCTAAGAAGATTTGAAAGT ATACCAGATATGCTTGAATTGGATCACCTCACAGTTTCAGGAGATGTGACATTTGGAAAAAATGTTTCATTAAAGGGAACGGTT ATCATCATTGCAAATCATGGTGACAGAATTGATATCCCACCTGGAGCAGTATTAGAGAACAAGATAGTGTCTGGAAACCTTCGC ATCTTGGACCACTGAAATGAAAAATACTGTGGACACTTAAATAATGGGCTAGTTTCTTACAATGAAATGTTCTCTAGGATTTAG GCACTAAAAGGTACTTTACTATGTTACTGTACCCTGCAGTGTTGATTT.TTAAAATAGAGTTTTCTGCAGTATGCTTTTAGTCTA AGAAAAGCACAGATGGTGCAATACTTTCCTTCTTTGAAGAGATCCCAAAGTTAGTTACTCTTAAGTGC
349 MKLWSA L WFGV SCVQAEFFTSIGHMTD IYAEKELVQSLKEYI VEEAK SKIKS ANKMEALTSKSAADAEGYLAHPV NAYKLVKRLNTDWPALEDLVLQDSAAGFIANLSVQRQFFPTDEDEIGAAKAMRLQDTYR DPGTISRGE PGTKYQAMLSVDD CFGMGRSAY EGDYYHTVLWMEQVKQ DAGEEATTTKSQVLDYLSYA¥FQLGDLHRA ELTRR LSLDPSHERAGGNLRYFEQ LEEEREKTLTNQTEAELATPEGIYERPVDYLPERDVYES CRGEGVKLTPRRQKRLFCRYHHGNRAPQLLIAPFKEEDE DSP HIVRYYDVMSDEEIERIKEIAKPKLARATVRDPKTGV TVASYR¥SKSSWLEEDDDPVVARV RRMQHITGLTVKTAE QVAN YGVGGQYEPHFDFSRNDERDTFKHLGTGNRVATFLNYMSDVEAGGAT¥FPDLGAAIWPKKGTAVFWY L RSGEGDYRTRHAAC P¥LVGCKWVSNKWFHERGQEFLRPCGSTEVD
350
GGGGAAGGAACACTGTAGGGGATAGCTGTCCACGGACGCTGTCTACAAGACCCTGGAGTGAGATAACGTGCCTGGTACTGTGCC CTGCATGTGTAAGATGCCCAGTTGACCTTCGCAGCAGGAGCCTGGATCAGGCACTTCCTGCCTCAGGTATTGCTGGACAGCCCA GACACTTCCCTCTGTGACCATGAAACTCTGGGTGTCTGCATTGCTGATGGCCTGGTTTGGTGTCCTGAGCTGTGTGCAGGCCGA ATTCTTCACCTCTATTGGGCACATGACTGACCTGATTTATGCAGAGAAAGAGCTGGTGCAGTCTCTGAAAGAGTACATCCTTGT GGAGGAAGCCAAGCTTTCCAAGATTAAGAGCTGGGCCAACAAAATGGAAGCCTTGACTAGCAAGTCAGCTGCTGATGCTGAGGG CTACCTGGCTCACCCTGTGAATGCCTACAAACTGGTGAAGCGGCTAAACACAGACTGGCCTGCGCTGGAGGACCTTGTCCTGCA GGACTCAGCTGCAGGTTTTATCGCCAACCTCTCTGTGCAGCGGCAGTTCTTCCCCACTGATGAGGACGAGATAGGAGCTGCCAA AGCCCTGATGAGACTTCAGGACACATACAGGCTGGACCCAGGCACAATTTCCAGAGGGGAACTTCCAGGAACCAAGTACCAGGC AATGCTGAGTGTGGATGACTGCTTTGGGATGGGCCGCTCGGCCTACAATGAAGGGGACTATTATCATACGGTGTTGTGGATGGA GCAGGTGCTAAAGCAGCTTGATGCCGGGGAGGAGGCCACCACAACCAAGTCACAGGTGCTGGACTACCTCAGCTATGCTGTCTT CCAGTTGGGTGATCTGCACCGTGCCCTGGAGCTCACCCGCCGCCTGCTCTCCCTTGACCCAAGCCACGAACGAGCTGGAGGGAA TCTGCGGTACTTTGAGCAGTTATTGGAGGAAGAGAGAGAAAAAACGTTAACAAATCAGACAGAAGCTGAGCTAGCAACCCCAGA AGGCATCTATGAGAGGCCTGTGGACTACCTGCCTGAGAGGGATGTTTACGAGAGCCTCTGTCGTGGGGAGGGTGTCAAACTGAC ACCCCGTAGACAGAAGAGGCTTTTCTGTAGGTACCACCATGGCAACAGGGCCCCACAGCTGCTCATTGCCCCCTTCAAAGAGGA GGACGAGTGGGACAGCCCGCACATCGTCAGGTACTACGATGTCATGTCTGATGAGGAAATCGAGAGGATCAAGGAGATCGCAAA ACCTAAACTTGCACGAGCCACCGTTCGTGATCCCAAGACAGGAGTCCTCACTGTCGCCAGCTACCGGGTTTCCAAAAGCTCCTG GCTAGAGGAAGATGATGACCCTGTTGTGGCCCGAGTAAATCGTCGGATGCAGCATATCACAGGGTTAACAGTAAAGACTGCAGA ATTGTTACAGGTTGCAAATTATGGAGTGGGAGGACAGTATGAACCGCACTTCGACTTCTCTAGGAATGATGAGCGAGATACTTT CAAGCATTTAGGGACGGGGAATCGTGTGGCTACTTTCTTAAACTACATGAGTGATGTAGAAGCTGGTGGTGCCACCGTCTTCCC TGATCTGGGGGCTGCAATTTGGCCTAAGAAGGGTACAGCTGTGTTCTGGTACAACCTCTTGCGGAGCGGGGAAGGTGACTACCG AACAAGACATGCTGCCTGCCCTGTGCTTGTGGGCTGCAAGTGGGTCTCCAATAAGTGGTTCCATGAACGAGGACAGGAGTTCTT GAGACCTTGTGGATCAACAGAAGTTGACTGACATCCTTTTCTGTCCTTCCCCTTCCTGGTCCTTCAGCCCATGTCAACGTGACA-- GACACCTTTGTATGTTCCTTGTATGTTCCTATCAGGCTGATTTTTGGAGAAATGAATGTTTGTCTGGAGCAGAGGGAGACCATA CTAGGGCGACTCCTGTGTGACTGAAGTCCCAGCCCTTCCATTCAGCCTGTGCCATCCCTGGCCCCAAGGCTAGGATCAAAGTGG CTGCAGCAGAGTTAGCTGTCTAGCGCCTAGCAAGGTGCCTTTGTACCTCAGGTGTTTTAGGTGTGAGATGTTTCAGTGAACCAA AGTTCTGATACCTTGTTTACATGTTTGTTTTTATGGCATTTCTATCTATTGTGGCTTTACCAAAAAATAAAATGTCCCTACCAG AAGCCTTAAA
351
MPAH LQDDISSSYTTTTTITAPPPGV QNGGDKLETMP Y EDDIRPDIKDDIYDPTYKDKEGPSPKVEYVWRNIILMSLLHL GALYGITLIPTCKFYTWLWGVFYYFVSALGITAGAHRLWSHRSYKARLPLR FLIIANTMAFQNDVYE ARDHRAHHKFSETHA DPHNSRRGFFFSHVGWL VRKHPAVKEKGSTLDLSDLEAEKLVMFQRRYYKPGLLMMCFILPTLVPWYF GETFQNSVFVATFL RYAWLNAT WS HLFGYRPYDK ISPRENI VSLGAVGEGFHNYHHSFPYDYSASEYR HINFNTFFIDMAALG TYDR KKVSKAAILARIKRTGDGNYKSG
352
GACGGTCACCCGTTGCCAGCTCTAGCCTTTAAATTCCCGGCTCGGGGACCTCCACGCACCGCGGCTAGCGCCGACAACCAGCTA GCGTGCAAGGCGCCGCGGCTCAGCGCGTACCGGCGGGTTTCGAAACCGCAGTCCTCCGGCGACCCCGAACTCCGCTCCGGAGCC TCAGCCCCCTGGAAAGTGATCCCGGCATCGGAGAGCCAAGATGCCGGCCCACTTGCTGCAGGACGATATCTCTAGCTCCTATAC CACCACCACCACCATTACAGCGCCTCCTCCAGGGGTCCTGCAGAATGGAGGAGATAAGTTGGAGACGATGCCCCTCTACTTGGA AGACGACATTCGCCCTGATATAAAAGATGATATATATGACCCCACCTACAAGGATAAGGAAGGCCCAAGCCCCAAGGTTGAATA TGTCTGGAGAAACATCATCCTTATGTCTCTGCTACACTTGGGAGCCCTGTATGGGATCACTTTGATTCCTACCTGCAAGTTCTA CACCTGGCTTTGGGGGGTATTCTACTATTTTGTCAGTGCCCTGGGCATAACAGCAGGAGCTCATCGTCTGTGGAGCCACCGCTC TTACAAAGCTCGGCTGCCCCTACGGCTCTTTCTGATCATTGCCAACACAATGGCATTCCAGAATGATGTCTATGAATGGGCTCG TGACCACCGTGCCCACCACAAGTTTTCAGAAACACATGCTGATCCTCATAATTCCCGACGTGGCTTTTTCTTCTCTCACGTGGG TTGGCTGCTTGTGCGCAAACACCCAGCTGTCAAAGAGAAGGGGAGTACGCTAGACTTGTCTGACCTAGAAGCTGAGAAACTGGT GATGTTCCAGAGGAGGTACTACAAACCTGGCTTGCTGATGATGTGCTTCATCCTGCCCACGCTTGTGCCCTGGTATTTCTGGGG TGAAACTTTTCAAAACAGTGTGTTCGTTGCCACTTTCTTGCGATATGCTGTGGTGCTTAATGCCACCTGGCTGGTGAACAGTGC TGCCCACCTCTTCGGATATCGTCCTTATGACAAGAACATTAGeCCCCGGGAGAATATCCTGGTTTCACTTGGAGCTGTGGGTGA GGGCTTCCACAACTACCACCACTCCTTTCCCTATGACTACTCTGCCAGTGAGTACCGCTGGCACATCAACTTCAACACATTCTT CATTGATTGGATGGCCGCCCTCGGTCTGACCTATGACCGGAAGAAAGTCTCCAAGGCCGCCATCTTGGCCAGGATTAAAAGAAC CGGAGATGGAAACTACAAGAGTGGCTGAGTTTGGGGTCCCTCAGGTTCCTTTTTCAAAAACCAGCCAGGCAGAGGTTTTAATGT CTGTTTATTAACTACTGAATAATGCTACCAGGATGCTAAAGATGATGATGTTAACCCATTCCAGTACAGTATTCTTTTAAAATT CAAAAGTATTGAAAGCCAAAAAAAAAAAAAAAAAAAAAAAAA
353
MEPRDGSPEARSSDSESASASSSGSERDAGPEPDKAPRRNKRRFPG RLFGHRKAITKSGLQHI-APPPPTPGAPCSESERQIR STVDWSESATYGEHIWFETIWSGDFCYVGEQYCVARMLKSVSRRKCAACKIVVHTPCIEQLEKINFRCKPSFRESGSRNVREPT
FVRHHWVHRRRQDGKCRHCGKGFQQKFTFHSKEIVAISCSWCKQAYHSK¥SCFMLQQIEEPCSLGVHAAVVIPPTWI RARRPQ
NTLKASKKKKRASFKRKSSKKGPEEGRWRPFIIRPTPSPL KPLLVFVNPKSGGNQGAKIIQSF WYLNPRQVFDLSQGGPKEA
LEMYRKVHNLRILACGGDGTVGWI ST DQLRLKPPPPVAILP GTGNDLARTLWGGGYTDEPVSKI SHVEEGNWQLDRWD HAEPNPEAGPEDRDEGATDRLPLDVFN YFSLGFDAHVTLEFHESREA PEKFNSRFRNKMFYAGTAFSDFLMGSSKD AKHI RWCDGMDLTPKIQDLKPQCWF NIPRYCAGTMP GHPGEHHDFEPQRHDDGY EVIGFTMTSLAALQVGGHGER TQCREVV
LTTSKAIPVQVDGEPCKLAASRIRIALRNQATMVQKAKRRSAAPLHSDQQP¥PEQLRIQVSR¥SMHDYEALHYDKEQ KEASVP
LGTVVVPGDSDLELCRAHIERLQQEPDGAGAKSPTCQKLSPK CFLDATTASRFYRIDRAQEHNYVTEIAQDEIYILDPEL G
ASARPDLPTPTSPLPTSPCSPTPRSLQGDAAPPQGEELIEAAKRDFCK QELHRAGGDLMHRDEQSRT LHHAVSTGSKDVVR
YLLDHAPPEILDAVEENGETC HQAAALGQRTICHYIVEAGASLMKTDQQGDTPRQRAEKAQDTELAAYLENRQHYQMIQREDQ ETA¥
354
GCGGCGCGGAGCGGGCGTGCTGAGCCCCGGCCGCCGGCCCGGCATGGGCGTCTCCCGCGGGCCCTCCGCCGGCCGGGGCTAGGG CCGGATGGAGCCGCGGGACGGTAGCCCCGAGGCCCGGAGCAGCGACTCCGAGTCGGCTTCCGCCTCGTCCAGCGGCTCCGAGCG CGACGCCGGTCCCGAGCCGGACAAGGCGCCGCGGCGACTCAACAAGCGGCGCTTCCCGGGGCTGCGGCTCTTCGGGCACAGGAA AGCCATCACCAAGTCGGGCCTCCAGCACCTGGCCCCCCCTCCGCCCACCCCTGGGGCCCCGTGCAGCGAGTCAGAGCGGCAGAT CCGGAGTACAGTGGACTGGAGCGAGTCAGCGACATATGGGGAGCACATCTGGTTCGAGACCAACGTGTCCGGGGACTTCTGCTA CGTTGGGGAGCAGTACTGTGTAGCCAGGATGCTGAAGTCAGTGTCTCGAAGAAAGTGCGCAGCCTGCAAGATTGTGGTGCACAC GCCCTGCATCGAGCAGCTGGAGAAGATAAATTTCCGCTGTAAGCCGTCCTTCCGTGAATCAGGCTCCAGGAATGTCCGCGAGCC AACCTTTGTACGGCACCACTGGGTACACAGACGACGCCAGGACGGCAAGTGTCGGCACTGTGGGAAGGGATTCCAGCAGAAGTT CACCTTCCACAGCAAGGAGATTGTGGCCATCAGCTGCTCGTGGTGCAAGCAGGCATACCACAGCAAGGTGTCCTGCTTCATGCT GCAGCAGATCGAGGAGCCGTGCTCGCTGGGGGTCCACGCAGCCGTGGTCATCCCGCCCACCTGGATCCTCCGCGCCCGGAGGCC CCAGAATACTCTGAAAGCAAGCAAGAAGAAGAAGAGGGCATCCTTCAAGAGGAAGTCCAGCAAGAAAGGGCCTGAGGAGGGCCG CTGGAGACCCTTCATCATCAGGCCCACCCCCTCCCCGCTCATGAAGCCCCTGCTGGTGTTTGTGAACCCCAAGAGTGGGGGCAA CCAGGGTGCAAAGATCATCCAGTCTTTCCTCTGGTATCTCAATCCCCGACAAGTCTTCGACCTGAGCCAGGGAGGGCCCAAGGA GGCGCTGGAGATGTACCGCAAAGTGCACAACCTGCGGATCCTGGCGTGCGGGGGCGACGGCACGGTGGGCTGGATCCTCTCCAC CCTGGACCAGCTACGCCTGAAGCCGCCACCCCCTGTTGCCATCCTGCCCCTGGGTACTGGCAACGACTTGGCCCGAACCCTCAA CTGGGGTGGGGGCTACACAGATGAGCCTGTGTCCAAGATCCTCTCCCACGTGGAGGAGGGGAACGTGGTACAGCTGGACCGCTG GGACCTCCACGCTGAGCCCAACCCCGAGGCAGGGCCTGAGGACCGAGATGAAGGCGCCACCGACCGGTTGCCCCTGGATGTCTT CAACAACTACTTCAGCCTGGGCTTTGACGCCCACGTCACCCTGGAGTTCCACGAGTCTCGAGAGGCCAACCCAGAGAAATTCAA CAGCCGCTTTCGGAATAAGATGTTCTACGCCGGGACAGCTTTCTCTGACTTCCTGATGGGCAGCTCCAAGGACCTGGCCAAGCA CATCCGAGTGGTGTGTGATGGAATGGACTTGACTCCCAAGATCCAGGACCTGAAACCCCAGTGTGTTGTTTTCCTGAACATCCC CAGGTACTGTGCGGGCACCATGCCCTGGGGCCACCCTGGGGAGCACCACGACTTTGAGCCCCAGCGGCATGACGACGGCTACCT CGAGGTCATTGGCTTCACCATGACGTCGTTGGCCGCGCTGCAGGTGGGCGGACACGGCGAGCGGCTGACGCAGTGTCGCGAGGT GGTGCTCACCACATCCAAGGCCATCCCGGTGCAGGTGGATGGCGAGCCCTGCAAGCTTGCAGCCTCACGCATCCGCATCGCCCT GCGCAACCAGGCCACCATGGTGCAGAAGGCCAAGCGGCGGAGCGCCGCCCCCCTGCACAGCGACCAGCAGCCGGTGCCAGAGCA GTTGCGCATCCAGGTGAGTCGCGTCAGCATGCACGACTATGAGGCCCTGCACTACGACAAGGAGCAGCTCAAGGAGGCCTCTGT GCCGCTGGGCACTGTGGTGGTCCCAGGAGACAGTGACCTAGAGCTCTGCCGTGCCCACATTGAGAGACTCCAGCAGGAGCCCGA TGGTGCTGGAGCCAAGTCCCCGACATGCCAGAAACTGTCCCCCAAGTGGTGCTTCCTGGACGCCACCACTGCCAGCCGCTTCTA CAGGATCGACCGAGCCCAGGAGCACCTCAACTATGTGACTGAGATCGCACAGGATGAGATTTATATCCTGGACCCTGAGCTGCT 5 GGGGGCATCGGCCCGGCCTGACCTCCCAACCCCCACTTCCCCTCTCCCCACCTCACCCTGCTCACCCACGCCCCGGTCACTGCA AGGGGATGCTGCACCCCCTCAAGGTGAAGAGCTGATTGAGGCTGCCAAGAGGAACGACTTCTGTAAGCTCCAGGAGCTGCACCG AGCTGGGGGCGACCTCATGCACCGAGACGAGCAGAGTCGCACGCTCCTGCACCACGCAGTCAGCACTGGCAGCAAGGATGTGGT CCGCTACCTGCTGGACCACGCCCCCCCAGAGATCCTTGATGCGGTGGAGGAAAACGGGGAGACCTGTTTGCACCAAGCAGCGGC CCTGGGCCAGCGCACCATCTGCCACTACATCGTGGAGGCCGGGGCCTCGCTCATGAAGACAGACCAGCAGGGCGACACTCCCCG 10 GCAGCGGGCTGAGAAGGCTCAGGACACCGAGCTGGCCGCCTACCTGGAGAACCGGCAGCACTACCAGATGATCCAGCGGGAGGA CCAGGAGACGGCTGTGTAGCGGGCCGCCCACGGGCAGCAGGAGGGACAATGCGGCCAGGGGACGAGCGCCTTCCTTGCCCACCT CACTGCCACATTCCAGTGGGACGGCCACGGGGGGACCTAGGCCCCAGGGAAAGAGCCCCATGCCGCCCCCTAAGGAGCCGCCCA GACCTAGGGCTGGACTCAGGAGCTGGGGGGGCCTCACCTGTTCCCCTGAGGACCCCGCCGGACCCGGAGGCTCACAGGGAACAA GACACGGCTGGGTTGGATATGCCTTTGCCGGGGTTCTGGGGCAGGGCGCTCCCTGGCCGCAGCAGATGCCCTCCCAGGAGTGGA ' 15 GGGGCTGGAGAGGGGGAGGCCTTCGGGAAGAGGCTTCCTGGGCCCCCTGGTCTTCGGCCGGGTCCCCAGCCCCCGCTCCTGCCC CACCCCACCTCCTCCGGGCTTCCTCCCGGAAACTCAGCGCCTGCTGCACTTGCCTGCCCTGGCTTGCTTGGCACCCGCTCCGGC GACCCTCCCCGCTCCCCTGTCATTTCATCGCGGACTGTGCGGCCTGGGGGTGGGGGGCGGGACTCTCACGGTGACATGTTTACA GCTGGGTGTGACTCAGTAAAGTGGATTTTTTTTTCTTTAAAAAAAA
355
20 MQIPRAALLPL LLL AAPASAQLSRAGRSAPLAAGCPDRCEPARCPPQPEHCEGGRARDACGCCEVCGAPEGAACGLQEGPCG EGLQCWPFGVPASATVRRRAQAG CVCASSEPVCGSDA TYAN CQLRAASRRSER HRPPVIVLQRGACGQGQEDPNSLRHK YNFIADVVEKIAPAWHIELFRKLPFSKREVPVASGSGFIVSEDGLIVTNAHWTNKHRVKVELKNGATYEAKIKDVDEKADIA LIKIDHQGK PV LGRSSE RPGEFVVAIGSPFSLQNTVTTGI¥STTQRGGKELGLR SDMDYIQTDAIINYGNSGGPLV LD GEVIGINT KVTAGISFAIPSDKIKKFLTESHDRQAKGKAITKKKYIGIR MSLTSSKAKELKDRHRDFPD¥ISGAYIIEVIPD
25 TPAEAGGLKENDVIISINGQSVVSA DVSDVIKRESTLMVVRRGNEDIMITVIPEEIDP
356
CCGGCCCTCGCCCTGTCCGCCGCCACCGCCGCCGCCGCCAGAGTCGCCATGCAGATCCCGCGCGCCGCTCTTCTCCCGCTGCTG CTGCTGCTGCTGGCGGCGCCCGCCTCGGCGCAGCTGTCCCGGGCCGGCCGCTCGGCGCCTTTGGCCGCCGGGTGCCCAGACCGC TGCGAGCCGGCGCGCTGCCCGCCGCAGCCGGAGCACTGCGAGGGCGGCCGGGCCCGGGACGCGTGCGGCTGCTGCGAGGTGTGC
30 GGCGCGCCCGAGGGCGCCGCGTGCGGCCTGCAGGAGGGCCCGTGCGGCGAGGGGCTGCAGTGCGTGGTGCCCTTCGGGGTGCCA GCCTCGGCCACGGTGCGGCGGCGCGCGCAGGCCGGCCTCTGTGTGTGCGCCAGCAGCGAGCCGGTGTGCGGCAGCGACGCCAAC ACCTACGCCAACCTGTGCCAGCTGCGCGCCGCCAGCCGCCGCTCCGAGAGGCTGCACCGGCCGCCGGTCATCGTCCTGCAGCGC GGAGCCTGCGGCCAAGGGCAGGAAGATCCCAACAGTTTGCGCCATAAATATAACTTTATCGCGGACGTGGTGGAGAAGATCGCC CCTGCCGTGGTTCATATCGAATTGTTTCGCAAGCTTCCGTTTTCTAAACGAGAGGTGCCGGTGGCTAGTGGGTCTGGGTTTATT
35 GTGTCGGAAGATGGACTGATCGTGACAAATGCCCACGTGGTGACCAACAAGCACCGGGTCAAAGTTGAGCTGAAGAACGGTGCC
ACTTACGAAGCCAAAATCAAGGATGTGGATGAGAAAGCAGACATCGCACTCATCAAAATTGACCACCAGGGCAAGCTGCCTGTC
CTGCTGCTTGGCCGCTCCTCAGAGCTGCGGCCGGGAGAGTTCGTGGTCGCCATCGGAAGCCCGTTTTCCCTTCAAAACACAGTC
ACCACCGGGATCGTGAGCACCACCCAGCGAGGCGGCAAAGAGCTGGGGCTCCGCAACTCAGACATGGACTACATCCAGACCGAC
. GCCATCATCAACTATGGAAACTCGGGAGGCCCGTTAGTAAACCTGGACGGTGAAGTGATTGGAATTAACACTTTGAAAGTGACA
40 GCTGGAATCTCCTTTGCAATCGCATCTGATAAGATTAAAAAGTTCCTCACGGAGTCCCATGACCGACAGGCCAAAGGAAAAGCC ATCACCAAGAAGAAGTATATTGGTATCCGAATGATGTCACTCACGTCCAGCAAAGCCAAAGAGCTGAAGGACCGGCACCGGGAC TTCCCAGACGTGATCTCAGGAGCGTATATAATTGAAGTAATTCCTGATACCCCAGCAGAAGCTGGTGGTCTCAAGGAAAACGAC GTCATAATCAGCATCAATGGACAGTCCGTGGTCTCCGCCAATGATGTCAGCGACGTCATTAAAAGGGAAAGCACCCTGAACATG GTGGTCCGCAGGGGTAATGAAGATATCATGATCACAGTGATTCCCGAAGAAATTGACCCATAGGCAGAGGCATGAGCTGGACTT
'45 CATGTTTCCCTCAAAGACTCTCCCGTGGATGACGGATGAGGACTCTGGGCTGCTGGAATAGGACACTCAAGACTTTTGACTGCC ATTTTGTTTGTTCAGTGGAGACTCCCTGGCCAACAGAATCCTTCTTGATAGTTTGCAGGCAAAACAAATGTAATGTTGCAGATC CGCAGGCAGAAGCTCTGCCCTTCTGTATCCTATGTATGCAGTGTGCTTTTTCTTGCCAGCTTGGGCCATTCTTGCTTAGACAGT CAGCATTTGTCTCCTCCTTTAACTGAGTCATCATCTTAGTCCAACTAATGCAGTCGATACAATGCGTAGATAGAAGAAGCCCCA CGGGAGCCAGGATGGGACTGGTCGTGTTTGTGCTTTTCTCCAAGTCAGCACCCAAAGGTCAATGCACAGAGACCCCGGGTGGGT GAGCGCTGGCTTCTCAAACGGCCGAAGTTGCCTCTTTTAGGAATCTCTTTGGAATTGGGAGCACGATGACTCTGAGTTTGAGCT ATTAAAGTACTTCTTACAAA
357
MALETICRPSGRKSSKMQAFRIWDV QKTFY RMQLVAGYLQGPNVN EEKIDWPIEPHA FLGIHGGKMCLSCVKSGDETR LQLEAV ITDLSENRKQDKRFAFIRSDSGPTTSFESAACPG FLCTAMEADQPVSLTN PDEGVMVTKFYFQEDE
358
AGCTCCACCCTGGGAGGGACTGTGGCCCAGGTACTGCCCGGGTGCTACTTTATGGGCAGCAGCTCAGTTGAGTTAGAGTCTGGA AGACCTCAGAAGACCTCCTGTCCTATGAGGCCCTCCCCATGGCTTTAGAGACGATCTGCCGACCCTCTGGGAGAAAATCCAGCA' AGATGCAAGCCTTCAGAATCTGGGATGTTAACCAGAAGACCTTCTATCTGAGGAACAACCAACTAGTTGCTGGATACTTGCAAG GACCAAATGTCAATTTAGAAGAAAAGATAGATGTGGTACCCATTGAGCCTCATGCTCTGTTCTTGGGAATCCATGGAGGGAAGA TGTGCCTGTCCTGTGTCAAGTCTGGTGATGAGACCAGACTCCAGCTGGAGGCAGTTAACATCACTGACCTGAGCGAGAACAGAA AGCAGGACAAGCGCTTCGCCTTCATCCGCTCAGACAGTGGCCCCACCACCAGTTTTGAGTCTGCCGCCTGCCCCGGTTGGTTCC TCTGCACAGCGATGGAAGCTGACCAGCCCGTCAGCCTCACCAATATGCCTGACGAAGGCGTCATGGTCACCAAATTCTACTTCC AGGAGGACGAGTAG 359
MIPNGY MFEDENFIESSVAK NA RKSGQFCDVRLQ¥CGHEMLAHRAVLACCSPYLFEIFNSDSDPHGISHVKFDDLNPEAVE VLNYAYTAQLKADKELVKDVYSAAKE KMDRVKQVCGDYLLSRMD¥TSCISYRNFASCMGDSHL NKVDAYIQEHL QISEEE EF KLPRLKLEVMLEDNVC PSNGKLYTKVI WVQRSIWENGDSLEELMEEVQTLYYSADHK LDGNL DGQAEVFGSDDDHIQ FVQKKPPRENGHKQISSSSTGCLSSPNATVQSPKHEWKIVASEKTSNNTYLCLAVLDGIFCVIF HGRNSPQSSPTSTPKLSKS SFEMQQDELIEKPMSP QYARSGLGTAEMNGKLIAAGGYNREEC RT¥ECYNPHTDHWSF APMRTPRARFQMAVLMGQLYVV GGSNGHSDD SCGEMYDSNIDDWIPVPE RTNRCNAG¥CALNGKLYIVGGSDPYGQKGLKNCD¥FDPVTKWTSCAP NIRRHQ SAVCELGGYLYIIGGAESMCLNTVERYNPEraT TLIAPMWARRGAGVAVLNGK FVCGGFDGSHAISCVEMYDPTRNEWKM MGHMTSPRSNAGIATVGNTIYAVEDSMAMNF •
360 AGTGTCTCCCGGTCGCGGGTGGAGGTCGGTCGCTCAGAGCTGCTGGGCGCAGTTTCTCCGCCTGCTGCTTCGGCGCGGCTGTAT CGGCGAGCGAGCGAGTTCCCGCGAGTTCTCGGTGGCGCTCCCCCTTCCTTTCAGTCTCCACGGACTGGCCCCTCGTCCTTCTAC TTGACCGCTCCCGTCTTCTGCCGCCTTCTGGCGCTTTCCGTTGGGCCGATTCCCGCCCGCTTCCTCCTGCTTCCCATCGAAGCT CTAGAAATGAATGTTTCCATCTCTTCAGAGATGAACCAGATTATGATGCATCATTATCACAGAAGAAATTCGTGTCTATAGCTT TTAAGGACTTGATTACATCATTTTCAAGCCTGATAGTTTTGGAATCACCATTAGAG.CTTAAGACACACCTGCCTTCATTTCAAC CACCTGTCTTCATACCCTGACGAAGTGCACCTTTTAACACTCCTTTGTCCTTGGATTACTTAAGAGTTCCCAGAAATACATTTG CCACCAACAGAGTAGCCAAATTTATAAGGAAAAATGATTCGCAATGGATATTTGATGTTTGAGGATGAAAATTTTATTGAGTCT TCTGTTGCCAAATTAAATGCCCTGAGGAAAAGTGGCCAGTTCTGTGATGTTCGACTTCAGGTCTGTGGCCATGAAATGTTAGCA CACAGAGCAGTGCTAGCTTGCTGCAGTCCCTATTTATTTGAAATCTTTAATAGTGATAGTGATCCTCATGGAATTTCTCACGTT AAATTTGATGATCTCAATCCAGAAGCTGTTGAAGTCTTGTTGAATTATGCCTACACTGCTCAGTTGAAAGCAGATAAGGAATTG GTAAAAGATGTTTATTCTGCAGCAAAAGAGCTGAAGATGGATCGAGTAAAGCAGGTTTGTGGTGATTATTTACTGTCTAGAATG GATGTTACCAGCTGCATCTCTTACCGAAATTTTGCAAGTTGTATGGGAGACTCCCATTTGTTGAATAAGGTTGATGCTTATATT CAGGAGCATTTGTTACAAATTTCTGAAGAGGAGGAGTTTCTTAAGCTTCCAAGGCTAAAGTTGGAGGTAATGCTTGAAGATAAT GTTTGCTTGCCCAGCAATGGCAAATTATATACAAAGGTAATCAACTGGGTGCAGCGTAGCATCTGGGAGAATGGAGACAGTCTG GAAGAGCTGATGGAAGAGGTTCAAACCTTGTACTACTCAGCTGATCACAAGCTGCTTGATGGGAACCTACTAGATGGACAGGCT GAGGTGTTTGGCAGTGATGATGACCACATTCAGTTTGTGCAGAAAAAGCCACCACGTGAGAATGGCCATAAGCAGATAAGTAGC AGTTCAACTGGATGTCTCTCTTCTCCAAATGCTACAGTACAAAGCCCTAAGCATGAGTGGAAAATCGTTGCTTCAGAAAAGACT TCAAATAACACTTACTTGTGCCTGGCTGTGCTGGATGGTATATTCTGTGTCATTTTTCTTCATGGGAGAAACAGCCCACAGAGC TCACCAACAAGTACTCCAAAACTAAGTAAGAGTTTAAGCTTTGAGATGCAACAAGATGAGCTAATCGAAAAGCCCATGTCTCCT ATGCAGTACGCACGATCTGGTCTGGGAACAGCAGAGATGAATGGCAAACTCATAGCTGCAGGTGGCTATAACAGAGAGGAATGT CTTCGAACAGTCGAATGCTATAATCCACATACAGATCACTGGTCCTTTCTTGCTCCCATGAGAACACCAAGAGCCCGATTTCAA ATGGCTGTACTCATGGGCCAGCTCTATGTGGTAGGTGGATCAAATGGCCACTCAGATGACCTGAGTTGTGGAGAGATGTATGAT TCAAACATAGATGACTGGATTCCTGTTCCAGAATTGAGAACTAACCGTTGTAATGCAGGAGTGTGTGCTCTGAATGGAAAGTTA TACATCGTTGGTGGCTCTGATCCATATGGTCAAAAAGGACTGAAAAATTGTGATGTATTTGATCCTGTAACAAAGTTGTGGACA AGCTGTGCCCCTCTTAACATTCGGAGACACCAGTCTGCAGTCTGTGAGCTTGGTGGTTATTTGTACATAATCGGAGGTGCAGAA TCTTGGAATTGTCTGAACACAGTAGAACGATACAATCCTGAAAATAATACCTGGACTTTAATTGCACCCATGAATGTGGCTAGG CGAGGAGCTGGAGTGGCTGTTCTTAATGGAAAACTGTTTGTATGTGGTGGCTTTGATGGTTCTCATGCCATCAGTTGTGTGGAA ATGTATGATCCAACTAGAAATGAATGGAAGATGATGGGACATATGACTTCACCAAGGAGCAATGCTGGGATTGCAACTGTAGGG AACACCATTTATGCAGTGGAGGATTCGATGGCAATGAATTTCTGAATACGGCGGAAGTCTATAACCTTGAGTCAAATGAATGGA GCCCCTATACAAAGATTTTCCAGTTTTAACGGGTTTAAGACCCTCTCAAACTAACAGGCTTAGTGATGTAATTATGGTTAGCAG AGGTACACTTGTGAATAAAGAGGGTGGGTGGGGATAGATGTTGCTAACAGCAACACAAAGCTTTTGCATATTGCATACTATTAA ACATGCTGTACATACTTTTTGGGTTTATTTGGGAAGGAATGCAAAGATGAAGGTCTGTTTGTGTACTTTTAAGACTTTGGTTAT TTTACTTTTTGGAAAAGATAAACCAAGAATTGATTGGGCACATCAAAAAAAAAAAAAAAAAAAA 361
MVDGVMILPVLIMIA PSPSMEDEKPK¥NPKLYMCVCEGLSCGNEDHCEGQQCFSSLSINDGFHVYQKGCFQVYEQGKMTCKTP PSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLEVGLIILSWFAVCLLACLLGVALRKFKRRNQERNPRDVEYGTIE G ITTNVGDSTLADLLDHSCTSGSGSGLPF VQRTVARQIT LECVGKGRYGEVWRGSWQGENVAVKIFSSRDEKSWFRETE Y. NTVMLRHENILGFIASDMTSRHSSTQLWLITHYHEMGSLYDY QLTTLDTVSCLRIVLSIASGLAH HIEIFGTQGKPAIAHRD LKSKNIL¥KKNGQCCIADLGA HSQSTNQLDVGraPRVGTKRYMAPEVLDETIQVDCFDSYKRVDIWAFGL¥LWEVARRMVS NGIVEDYKPPFYDVVPNDPSFEDMRKWCVDQQRPNIPNR FSDPTLTS AKLMKECWYQNPSARLTALRIKKT TKIDNSLDK KTDC
362
GAAGCGAATAGCGTTTTCAGAGATATTGGGCGGCTCAAGGGTCTTACTCTGTCGCCCAGTCTGTAATGCAGTGCTGTGACCATA GCCCACTGCAGCCTCCACCTCCCAGGCTCAAGCAGTCCTTCCCCCCTCGCCCTCATGAATAGCTGGGACTACAGCCTGGAGCAT TGGTAAGCGTCACACTGCCAAAGTGAGAGCTGCTGGAGAACTCATAATCCCAGGAACGCCTCTTCTACTCTCCGAGTACCCCAG TGACCAGAGTGAGAGAAGCTCTGAACGAGGGCACGCGGCTTGAAGGACTGTGGGCAGATGTGACCAAGAGCCTGCATTAAGTTG TACAATGGTAGATGGAGTGATGATTCTTCCTGTGCTTATCATGATTGCTCTCCCCTCCCCTAGTATGGAAGATGAGAAGCCCAA GGTCAACCCCAAACTCTACATGTGTGTGTGTGAAGGTCTCTCCTGCGGTAATGAGGACCACTGTGAAGGCCAGCAGTGCTTTTC CTCACTGAGCATCAACGATGGCTTCCACGTCTACCAGAAAGGCTGCTTCCAGGTTTATGAGCAGGGAAAGATGACCTGTAAGAC CCCGCCGTCCCCTGGCCAAGCTGTGGAGTGCTGCCAAGGGGACTGGTGTAACAGGAACATCACGGCCCAGCTGCCCACTAAAGG AAAATCCTTCCCTGGAACACAGAATTTCCACTTGGAGGTTGGCCTCATTATTCTCTCTGTAGTGTTCGCAGTATGTCTTTTAGC CTGCCTGCTGGGAGTTGCTCTCCGAAAATTTAAAAGGCGCAACCAAGAACGCCTCAATCCCCGAGACGTGGAGTATGGCACTAT CGAAGGGCTCATCACCACCAATGTTGGAGACAGCACTTTAGCAGATTTATTGGATCATTCGTGTACATCAGGAAGTGGCTCTGG TCTTCCTTTTCTGGTACAAAGAACAGTGGCTCGCCAGATTACACTGTTGGAGTGTGTCGGGAAAGGCAGGTATGGTGAGGTGTG GAGGGGCAGCTGGCAAGGGGAAAATGTTGCCGTGAAGATCTTCTCCTCCCGTGATGAGAAGTCATGGTTCAGGGAAACGGAATT GTACAACACTGTGATGCTGAGGCATGAAAATATCTTAGGTTTCATTGCTTCAGACATGACATCAAGACACTCCAGTACCCAGCT GTGGTTAATTACACATTATCATGAAATGGGATCGTTGTACGACTATCTTCAGCTTACTACTCTGGATACAGTTAGCTGCCTTCG AATAGTGCTGTCCATAGCTAGTGGTCTTGCACATTTGCACATAGAGATATTTGGGACCCAAGGGAAACCAGCCATTGCCCATCG AGATTTAAAGAGCAAAAATATTCTGGTTAAGAAGAATGGACAGTGTTGCATAGCAGATTTGGGCCTGGCAGTCATGCATTCCCA GAGCACCAATCAGCTTGATGTGGGGAACAATCCCCGTGTGGGCACCAAGCGCTACATGGCCCCCGAAGTTCTAGATGAAACCAT CCAGGTGGATTGTTTCGATTCTTATAAAAGGGTCGATATTTGGGCCTTTGGACTTGTTTTGTGGGAAGTGGCCAGGCGGATGGT GAGCAATGGTATAGTGGAGGATTACAAGCCACCGTTCTACGATGTGGTTCCCAATGACCCAAGTTTTGAAGATATGAGGAAGGT AGTCTGTGTGGATCAACAAAGGCCAAACATACCCAACAGATGGTTCTCAGACCCGACATTAACCTCTCTGGCCAAGCTAATGAA AGAATGCTGGTATCAAAATCCATCCGCAAGACTCACAGCACTGCGTATCAAAAAGACTTTGACCAAAATTGATAATTCCCTCGA CAAATTGAAAACTGACTGTTGACATTTTCATAGTGTCAAGAAGGAAGATTTGACGTTGTTGTCATTGTCCAGCTGGGACCTAAT GCTGGCCTGACTGGTTGTCAGAATGGAATCCATCTGTCTCCCTCCCCAAATGGCTGCTTTGACAAGGCAGACGTCGTACCCAGC CATGTGTTGGGGAGACATCAAAACCACCCTAACCTCGCTCGATGACTGTGAACTGGGCATTTCACGAACTGTTCACACTGCAGA GACTAATGTTGGACAGACACTGTTGCAAAGGTAGGGACTGGAGGAACACAGAGAAATCCTAAAAGAGATCTGGGCATTAAGTCA GTGGCTTTGCATAGCTTTCACAAGTCTCCTAGACACTCCCCACGGGAAACTCAAGGAGGTGGTGAATTTTTAATCAGCAATATT GCCTGTGCTTCTCTTCTTTATTGCACTAGGAATTCTTTGCATTCCTTACTTGCACTGTTACTCTTAATTTTAAAGACCCAACTT GCCAAAATGTTGGCTGCGTACTCCACTGGTCTGTCTTTGGATAATAGGAATTCAATTTGGCAAAACAAAATGTAATGTCAGACT TTGCTGCATTTTACACATGTGCTGATGTTTACAATGATGCCGAACATTAGGAATTGTTTATACACAACTTTGCAAATTATTTAT TACTTGTGCACTTAGTAGTTTTTACAAAACTGCTTTGTGCATATGTTAAAGCTTATTTTTATGTGGTCTTATGATTTTATTACA GAAATGTTTTTAACACTATACTCTAAAATGGACATTTTCTTTTATTATCAGTTAAAATCACATTTTAAGTGCTTCACATTTGTA TGTGTGTAGACTGTAACTTTTTTTCAGTTCATATGCAGAACGTATTTAGCCATTACCCACGTGACACCACCGAATATATTATCG ATTTAGAAGCAAAGATTTCAGTAGAATTTTAGTCCTGAACGCTACGGGGAAAATGCATTTTCTTCAGAATTATCCATTACGTGC ATTTAAACTCTGCCAGAAAAAAATAACTATTTTGTTTTAATCTACTTTTTGTATTTAGTAGTTATTTGTATAAATTAAATAAAC TGTTTTCAAGTC 363
MYQVPLPLDRDGTLVRLRFTMVALVTVCCP VAF FCILWSLLFHFKETTATHCGATPCRMFSAASQPLDPDGTLFRLRFTAMV AITFPVFGFFFCIIWSLVFHFEYTVATDCGVPNYLPSVSSAIGGEVPQRYVWRFCIGLHSAPRFLVAFAY HYLSCTSPCS CYRPLCR NFGL WEN ALLVLTYVSSSEDFTIHENAFIVFIASSLGHMLLTCILWRLTKKHTVSQEDRKSYSWKQRLFIINF ISFFSALAWFRHMYCEAGVYTIFAILEYTVVLT MAFHMTA DFGNKELLITSQPEEKRF 364
GGCCTTACCAATCGCGAAAACCCGCCGTTCGCGCTCTGACCAGCCCGCAGAGCCAGCCCCCGACCCCGGGCCACCTGGGCCCCC GGGTTCCGCCGGCACTCTCGCCACCACCGCGTGGGTCTGACAAGATGTACCAGGTCCCACTACCACTGGATCGGGATGGGACCC TGGTACGGCTCCGCTTCACCATGGTGGCCCTGGTCACGGTCTGCTGTCCACTTGTCGCCTTCCTCTTCTGCATCCTCTGGTCCC TGCTCTTCCACTTCAAGGAGACAACGGCCACACACTGTGGGGCCACGCCCTGCAGGATGTTCTCTGCGGCCTCCCAGCCTTTGG ACCCCGATGGGACCTTGTTCCGGCTTCGCTTCACAGCCATGGTCTGGTGGGCCATCACTTTTCCTGTGTTCGGCTTCTTCTTCT GCATCATCTGGTCCCTGGTGTTCCACTTTGAGTACACGGTGGCCACTGACTGTGGGGTGCCCAATTACCTGCCCTCGGTGAGCT CAGCCATCGGCGGGGAGGTGCCCCAGCGCTACGTGTGGCGTTTCTGCATCGGCCTGCACTCGGCGCCTCGCTTCTTGGTGGCCT TCGCCTACTGGAACCACTACCTCAGCTGCACCTCCCCGTGTTCCTGCTATCGCCCGCTCTGCCGCCTCAACTTCGGCCTCAATG TCGTGGAGAACCTCGCGTTGCTAGTGCTCACTTATGTCTCCTCCTCCGAGGACTTCACCATCCACGAAAATGCTTTCATTGTGT TCATTGCCTCATCCCTCGGGCACATGCTCCTCACCTGCATTCTCTGGCGGTTGACCAAGAAGCACACAGTAAGTCAGGAGGATC GCAAGTCCTACAGCTGGAAACAGCGGCTCTTCATCATCAACTTCATCTCCTTCTTCTCGGCGCTGGCTGTCTACTTTCGGCACA ACATGTATTGTGAGGCTGGAGTGTACACCATCTTTGCCATCCTGGAGTACACTGTTGTCTTAACCAACATGGCGTTCCACATGA CGGCCTGGTGGGACTTCGGGAACAAGGAGCTGCTCATAACCTCTCAGCCTGAGGAAAAGCGATTCTGAACCCTTCAGTCCTGCT TGGGAGGACGCAGCCCACTGCCCAGAAACAAGAAACACGATACCATTCTGGCCTTCCCCACCCCAeATCCTCTCTTGGCCTTAC TGAAGATGGGGGAAGGGTAAGAAGGAAGGGTGTAGGCCAAGGCTCACCCCAGTGCTGCTGGCTTCTCCTCTCCACCCCTCATAT GGGCGTGGGGTCCTCAAACATCACCTTTACCTGAGAGGCCCCAAGAAGCTGAGCTGGCAGAGAGCTCCACCATTTGGTGCTAAA AAAAAAAACGTCCTGAGGTTCATGACCACCATCCAGTTTCTGGCCTTTACACAGTCACCTTTCACTGAGGTCAGGAGCCCCTGA GCAGTGGCTGCTCCCTGACAACCACAGCCATTTCTCTGCACGGGGGTCATTCATAGGACTAATGTATTTCATGATCTACTGTGC ACATCCAGGCCTGTGGCCACAGTCCCCTGCTAAAGTTGCTCAGGTGTTCTAGTCCTGACTTCACCTTTTTGATTTGGTGTGTGC CCTAGGGTATGTACCCTTCCCCATCTGAGCCTCGGTGTGTCCATGTGTCTGGCGGGGGATGGGTGGACTGTATGATTTCCAAGG ACTCTACCAGTCAGTGGTTCTGATGTCATCGGGTGGAGGTGGTGTTCTATACCTAAAGGATGACCTGCTCCAGAAACAGCACCA GCACAGCATGTATTTTCTTCTCTTCTGAAAGTTCTGGCTTGTAGACCCCTCCCCTCCTTTGCAAAGGTATGGGATAGAGGGGTC AGATGCAGATCTCTACTGTAAAATGGGCTCCCTGGTATCTCCTGTCTTCCCTACTGCTCCAAAeCCTAAATTTTGGTTGTACAT TTTATTTTGA GGAA TA TTTTTTTTTTGGGCC CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAA
365
MM SL LQNIIYNPVIPFVGTIPDQLDPGT IVIRGHVPSDADRFQ¥D QNGSSMKPRADVAFHFNPRFKRAGCIVCNTLINE KWGREEITYDTPFQKEKKSFEIVIMVKAKFQVAVNGKHT LYGHRIGPEKIDT GIYGKV IHSIGFSFSSDLQSTQASSLE TEISRENVPKSGTPQLRLPFAARLNTPMGPGRTV¥VKGEWANAKSF VD LAGKSKDIALHNPRLNIKAFVRNSFLQESWGE EERNITSFPFSPGMYFE IIYCDVREFK¥AV GVHSLEYKHRFKE SSIDTLEINGDIHLLEVRS
366
ACACAGAAGAGACTCCAATCGACAAGAAGCTGGAAAAGAATGATGTTGTCCTTAAACAACCTACAGAATATCATCTATAACCCG GTAATCCCGTTTGTTGGCACCATTCCTGATCAGCTGGATCCTGGAACTTTGATTGTGATACGTGGGCATGTTCCTAGTGACGCA GACAGATTCCAGGTGGATCTGCAGAATGGCAGCAGCATGAAACCTCGAGCCGATGTGGCCTTTCATTTCAATCCTCGTTTCAAA AGGGCCGGCTGCATTGTTTGCAATACTTTGATAAATGAAAAATGGGGACGGGAAGAGATCACCTATGACACGCCTTTCCAAAAA GAGAAAAAGTCTTTTGAGATCGTGATTATGGTGCTGAAGGCCAAATTCCAGGTGGCTGTAAATGGAAAACATACTCTGCTCTAT GGCCACAGGATCGGCCCAGAGAAAATAGACACTCTGGGCATTTATGGCAAAGTGAATATTCACTCAATTGGTTTTAGCTTCAGC TCGGACTTACAAAGTACCCAAGCATCTAGTCTGGAACTGACAGAGATAAGTAGAGAAAATGTTCCAAAGTCTGGCACGCCCCAG CTTAGGCTGCCATTCGCTGCAAGGTTGAACACCCCCATGGGCCCTGGACGAACTGTCGTCGTTAAAGGAGAAGTGAATGCAAAT GCCAAAAGCTTTAATGTTGACCTACTAGCAGGAAAATCAAAGGATATTGCTCTACACTTGAACCCACGCCTGAATATTAAAGCA TTTGTAAGAAATTCTTTTCTTCAGGAGTCCTGGGGAGAAGAAGAGAGAAATATTACCTCTTTCCCATTTAGTCCTGGGATGTAC TTTGAGATGATAATTTATTGTGATGTTAGAGAATTCAAGGTTGCAGTAAATGGCGTACACAGCCTGGAGTACAAACACAGATTT AAAGAGCTCAGCAGTATTGACACGCTGGAAATTAATGGAGACATCCACTTACTGGAAGTAAGGAGCTGGTAGCCTACCTACACA GCTGCTACAAAAACCAAAATACAGAATGGCTTCTGTGATACTGGCCTTGCTGAAACGCATCTCACTGTCATTCTATTGTTTATA TTGTTAAAATGACCT
367
MMLTRDPQFQK QQ YREHRSELNLRRLFD KDRFNHFSLTLNTNHGHILVDYSK LVTEDVMRML¥DLAKSRGVEAARERM FNGEKI TEGRAVLH¥ALMRSNTPIL¥DGKD PEV KV DKMKSFCQRVRSGDWKGYTGKTITDVINIGIVGSDLGPLMVT EA KPYSSGGPRV YVSNIDGTHIAKT AQ NPESSLFIIASKTFTTQETITNAETAKE FLQAAKDPSAVAKHFVALSTNTTK VKEFGIDPQmFEFWD VGGRYSLWSAIG SIALH¥GFDNFEQLLSGAHWMDQHFRTTPLEKNAPVLLA GI YINCFGCETH AMLPYDQY HRFAAYFQQGDMESNGKYITKSGTRVDHQTGPIVWGEPGTNGQHAFYQLIHQGTKMIPCDF IPVQTQ'HPIRKGL- HHKILLA FLAQTEALMRGKSTEEARKELQAAGKSPEDLERLLPHKVFEGNRPTNSIVFTKLTPFMLGA ¥AMYEHKIF¥QGII WDINSFDQWGVELGKQLAKKIEPE DGSAQVTSHDASTNGLINFIKQQREARVQ '
368
CTCGAGAGCTCCGCCATGGCCGCTCTCACCCGGGACCCCCAGTTCCAGAAGCTGCAGCAATGGTACCGCGAGCACCGCTCCGAG CTGAACCTGCGCCGCCTCTTCGATGCCAACAAGGACCGCTTCAACCACTTCAGCTTGACCCTCAACACCAACCATGGGCATATC CTGGTGGATTACTCCAAGAACCTGGTGACGGAGGACGTGATGCGGATGCTGGTGGACTTGGCCAAGTCCAGGGGCGTGGAGGCC GCCCGGGAGCGGATGTTCAATGGTGAGAAGATCAACTACACCGAGGGTCGAGCCGTGCTGCACGTGGCTCTGCGGAACCGGTCA AACACACCCATCCTGGTAGACGGCAAGGATGTGATGCCAGAGGTCAACAAGGTTCTGGACAAGATGAAGTCTTTCTGCCAGCGT GTCCGGAGCGGTGACTGGAAGGGGTACACAGGCAAGACCATCACGGACGTCATCAACATTGGCATTGTCGGCTCCGACCTGGGA CCCCTCATGGTGACTGAAGCCCTTAAGCCATACTCTTCAGGAGGTCCCCGCGTCTGGTATGTCTCCAACATTGATGGAACTCAC ATTGCCAAAACCCTGGCCCAGCTGAACCCGGAGTCCTCCCTGTTCATCATTGCCTCCAAGACCTTTACTACCCAGGAGACCATC ACGAATGCAGAGACGGCGAAGGAGTGGTTTCTCCAGGCGGCCAAGGATCCTTCTGCAGTGGCGAAGCACTTTGTTGCCCTGTCT ACTAACACAACCAAAGTGAAGGAGTTTGGAATTGACCCTCAAAACATGTTCGAGTTCTGGGATTGGGTGGGAGGACGCTACTCG CTGTGGTCGGCCATCGGACTCTCCATTGCCCTGCACGTGGGTTTTGACAACTTCGAGCAGCTGCTCTCGGGGGCTCACTGGATG GACCAGCACTTCCGCACGACGCCCCTGGAGAAGAACGCCCCCGTCTTGCTGGCGCTGCTGGGTATCTGGTACAT'CAACTGCTT'T GGGTGTGAGACACACGCCATGCTGCCCTATGACCAGTACCTGCACCGCTTTGCTGCGTACTTCCAGCAGGGCGACATGGAGTCC AATGGGAAATACATCACCAAATCTGGAACCCGTGTGGACCACCAGACAGGCCCCATTGTGTGGGGGGAGCCAGGGACCAATGGC CAGCATGCTTTTTACCAGCTCATCCACCAAGGCACCAAGATGATACCCTGTGACTTCCTCATCCCGGTCCAGACCCAGCACCCC ATACGGAAGGGTCTGCATCACAAGATCCTCCTGGCCAACTTCTTGGCCCAGACAGAGGCCCTGATGAGGGGAAAATCGACGGAG GAGGCCCGAAAGGAGCTCCAGGCTGCGGGCAAGAGTCCAGAGGACCTTGAGAGGCTGCTGCCACATAAGGTCTTTGAAGGAAAT CGCCCAACCAACTCTATTGTGTTCACCAAGCTCACACCATTCATGCTTGGAGCCTTGGTCGCCATGTATGAGCACAAGATCTTC GTTCAGGGCATCATCTGGGACATCAACAGCTTTGACCAGTGGGGAGTGGAGCTGGGAAAGCAGCTGGCTAAGAAAATAGAGCCT GAGCTTGATGGCAGTGCTCAAGTGACCTCTCACGACGCTTCTACCAATGGGCTCATCAACTTCATCAAGCAGCAGCGCGAGGCC AGAGTCCAATAAACTCGTGCTCATCTGCAGCCTCCTCTGTGACTCCCCTTTCTCTTCTCGTCCCTCCTCCCCGGAGCCGGCACT GCATGTTCCTGGACACCACCCAGAGCACCCTCTGGTTGTGGGCTTGGACCACGAGCCCTTAGCAGGGAAGGCTGGTCTCCCCCA GCCTAACCCCCAGCCCCTCCATGTCTATGCTCCCTCTGTGTTAGAATTGGCTGAAGTGTTTTTGTGCAGCTGACTTTTCTGACC CATGTTCACGTTGTTCACATCCCATGTAGAAAAACAAAGATGCCACGGAGGAGGT
369
MKKEHVLHCQFSAWYPFFRG¥TIKSVI PLPQN¥KDYLLDDGTLV¥SGRDDPPTHSQPDSDDEAEEIQWSDDENTATLTAPEFP
EFATKVQEPINS GGSVFPKLNWSAPRDAY IAMNSS KCKTLSDIFLLFKSSDFITRDFTQPFIHCTDDSPDPCIEYE VLRK
WCELIPGAEFRCFVKENKLIGISQRDYTQYYDHISKQKEEIRRCIQDFFKKHIQYKFLDEDFVFDIYRDSRGKVWLIDFNPFGE VTDSL FT EELISENNLNGDFSEVDAQEQDSPAFRCTNSEVT¥QPSPYLSYRLPKDFVDLSTGRDAHK IDFLKLKRNQQEDD
370
TGCGTTTAGGGCGAAGACGGAGTTGTAAACTTCTTAAAATTCCTCTCTCGACACTTCGGTAATTCCTCTTTCGAGACTAAAGCT CTTTTTGTATGCGTGTGTGTCAAGCGTATGCCCCGGGATTCTCCTCCGCTTCCTTTTCTCGGTCTTCCTTCTTGCTTTAGGGAC CGGAAGAGTCCTTGAACCAAAATAGCTCGGCGGGCACTTCCGGGGCCGGCGCCCAGAGTTCCGGGAGGGTGCAGGCAGGAGAGG GAAAGGCAGCAGCGGCGGCAGCTGGAGGATGAAGAAGGAGCATGTGCTTCACTGCCAGTTCTCCGCGTGGTACCCGTTCTTCCG AGGCGTTACCATCAAGAGTGTCATTCTTCCACTTCCTCAGAATGTGAAGGATTATTTACTCGATGATGGAACTCTGGTGGTTTC AGGAAGGGATGATCCACCAACACATTCTCAGCCAGACAGTGATGATGAAGCAGAAGAAATACAGTGGTCTGATGATGAGAACAC AGCCACGCTTACGGCACCAGAATTTCCTGAGTTTGCCACTAAAGTCCAGGAACCTATCAATTCCCTCGGGGGCAGTGTCTTTCC TAAGCTTAATTGGAGTGCCCCAAGGGATGCGTATTGGATAGCAATGAATAGTTCTCTGAAATGTAAAACCCTCAGCGACATCTT TCTGCTTTTCAAGAGTTCCGATTTCATCACTCGTGACTTCACTCAGCCGTTTATTCATTGTACTGATGATTCTCCAGATCCATG TATAGAATATGAGCTCGTTCTCCGAAAATGGTGTGAATTGATTCCTGGGGCTGAGTTTCGATGTTTTGTCAAGGAAAACAAGCT TATTGGTATTTCTCAAAGAGACTACACACAATACTATGATCATATTTCTAAACAAAAGGAAGAAATTCGCAGATGCATACAAGA CTTTTTCAAGAAACACATACAGTACAAATTCTTAGATGAAGACTTTGTGTTCGATATATACAGAGACAGTAGGGGGAAGGTGTG GCTCATTGACTTTAATCCATTTGGTGAAGTCACAGATTCACTGCTGTTCACCTGGGAAGAACTGATATCTGAGAACAACTTAAA CGGCGATTTTAGTGAAGTTGACGCTCAAGAGCAGGATTCCCCAGCTTTCCGTTGCACAAACAGTGAAGTGACAGTCCAGCCCAG CCCCTATTTGAGTTACCGGCTACCCAAGGACTTTGTAGACCTCTCTACTGGGAGGGACGCTCACAAGCTAATAGACTTCCTTAA GCTGAAGAGAAATCAGCAGGAGGACGACTGATGAGCGTACTGTAACTGGAGAAGAGGAGGCCCCGCCCCACCGCTCCGGGAGCT ' GCTCATCAGCCGCAACTTCCTGCCGACCCTGATGCGGGTGGGCCGAGCAGTGTGGACATCAGCCACTTTTTATATTCATGTACA TTCACCTGGGGAAAAAAACGGAGGGACTTTGCTACTTGTAAAAATAACATAATAAATAGATCTTAAACATAGGAAAACCATACT GTTCTGATAATAAAATGCTTTCTATGAAAT
371
MERIPSAQPPPACLPKAPGLEHGDLPGMYPAHMYQVYKSRRGIKRSEDSKETYKLPHRLIEKKRRDRINECIAQLKDL PEH K LTTLGHLEKAWLELT KH¥KALTNLIDQQQQKI-IA QSGLQAGELSGRVETGQEMFGSGFQTCAREVQYLAKHENTRDLKS SQ VTHLHRWSELLQGGTSRKPSDPAPKVMDFKEKPSSPAKGSEGPGK-.CVPVIQRTFAHSSGEQSGSDTDTDSGYGGESEKG DLRSEQPCFKSDHGRRFTMGERIGA1KQESEEPPTKKNRMQLSDDEGHFTSSDLISSPFLGPHPHQPPFCLPFY IPPSATAYL PMLEKCWYPTSVPVLYPGLNASAAA SSFMNPDKISAPLLMPQR PSPLPAHPSVDSSVLLQALKPIPPN ETKD
372 GGACACCGGGCCATGCACGCCCCCAACTGAAGCTGCATCTCAAAGCCGAAGATTCCAGCAGCCCAGGGGATTTCAAAGAGCTCA GACTCAGAGGAACATCTGCGGAGAGACCCCCGAAGCCCTCTCCAGGGCAGTCCTCATCCAGACGCTCCGCTAGTGCAGACAGGA GCGCGCAGTGGCCCCGGCTCGCCGCGCCATGGAGCGGATCCCCAGCGCGCAACCACCCCCCGCCTGCCTGCCCAAAGCACCGGG ACTGGAGCACGGAGACCTACCAGGGATGTACCCTGCCCACATGTACCAAGTGTACAAGTCAAGACGGGGAATAAAGCGGAGCGA GGACAGCAAGGAGACCTACAAATTGCCGCACCGGCTCATCGAGAAAAAGAGACGTGACCGGATTAACGAGTGCATCGCCCAGCT GAAGGATCTCCTACCCGAACATCTCAAACTTACAACTTTGGGTCACTTGGAAAAAGCAGTGGTTCTTGAACTTACCTTGAAGCA TGTGAAAGCACTAACAAACCTAATTGATCAGCAGCAGCAGAAAATCATTGCCCTGCAGAGTGGTTTACAAGCTGGTGAGCTGTC AGGGAGAAATGTCGAAACAGGTCAAGAGATGTTCTGCTCAGGTTTCCAGACATGTGCCCGGGAGGTGCTTCAGTATCTGGCCAA GCACGAGAACACTCGGGACCTGAAGTCTTCGCAGCTTGTCACCCACCTCCACCGGGTGGTCTCGGAGCTGCTGCAGGGTGGTAC CTCCAGGAAGCCATCAGACCCAGCTCCCAAAGTGATGGACTTCAAGGAAAAACCCAGCTCTCCGGCCAAAGGTTCGGAAGGTCC TGGGAAAAACTGCGTGCCAGTCATCCAGCGGACTTTCGCTCACTCGAGTGGGGAGCAGAGCGGCAGCGACACGGACACAGACAG TGGCTATGGAGGAGAATCGGAGAAGGGCGACTTGCGCAGTGAGCAGCCGTGCTTCAAAAGTGACCACGGACGCAGGTTCACGAT GGGAGAAAGGATCGGCGCAATTAAGCAAGAGTCCGAAGAACCCCCCACAAAAAAGAACCGGATGCAGCTTTCGGATGATGAAGG CCATTTCACTAGCAGTGACCTGATCAGCTCCCCGTTCCTGGGCCCACACCCACACCAGCCTCCTTTCTGCCTGCCCTTCTACCT GATCCCACCTTCAGCGACTGCCTACCTGCCCATGCTGGAGAAGTGCTGGTATCCCACCTCAGTGCCAGTGCTATACCCAGGCCT CAACGCCTCTGCCGCAGCCCTCTCTAGCTTCATGAACCCAGACAAGATCTCGGCTCCCTTGCTCATGCCCCAGAGACTCCCTTC TCCCTTGCCAGCTCATCCGTCCGTCGACTCTTCTGTCTTGCTCCAAGCTCTGAAGCCAATCCCCCCTTTAAACTTAGAAACCAA AGACTAAACTCTCTAGGGGATCCTGCTGCTTTGCTTTCCTTCCTCGCTACTTCCTAAAAAGCAACAAAAAAGTTTTTGTGAATG CTGCAAGATTGTTGCATTGTGTATACTGAGATAATCTGAGGCATGGAGAGCAGATTCAGGGTGTGTGTGTGTGTGTGTGTGTGT GTGTGTATGTGCGTGTGCGTGCACATGTGTGCCTGCGTGTTGGTATAGGACTTTAAAGCTCCTTTTGGCATAGGGAAGTCACGA AGGATTGCTTGACATCAGGAGACTTGGGGGGGATTGTAGCAGACGTCTGGGCTTTTCCCCACCCAGAGAATAGCCCCCTTCGAT ACACATCAGCTGGATTTTCAAAAGCTTCAAAGTCTTGGTCTGTGAGTCACTCTTCAGTTTGGGAGCTGGGTCTGTGGCTTTGAT CAGAAGGTACTTTCAAAAGAGGGCTTTCCAGGGCTCAGCTCCCAACCAGCTGTTAGGACCCCACCCTTTTGCCTTTATTGTCGA CGTGACTCACCAGACGTCGGGGAGAGAGAGCAGTCAGACCGAGCTTTCTGCTAACATGGGGAGGTAGCAGGCACTGGCATAGCA CGGTAGTGGTTTGGGGAGGTTTCCGCAGGTCTGCTCCCCACCCCTGCCTCGGAAGAATAAAGAGAATGTAGTTCCCTACTCAGG CTTTCGTAGTGATTAGCTTACTAAGGAACTGAAAATGGGCCCCTTGTACAAGCTGAGCTGCCCCGGAGGGAGGGAGGAGTTCCC TGGGCTTCTGGCACCTGTTTCTAGGCCTAACCATTAGTACTTACTGTGCAGGGAACCAAACCAAGGTCTGAGAAATGCGGACAC CCCGAGCGAGCACCCCAAAGTGCACAAAGCTGAGTAAAAAGCTGCCCCCTTCAAACAGAACTAGACTCAGTTTTCAATTCCATC CTAAAACTCCTTTTAACCAAGCTTAGCTTCTCAAAGGCCTAACCAAGCCTTGGCACCGCCAGATCCTTTCTGTAGGCTAATTCC TCTTGCCCAACGGCATATGGAGTGTCCTTATTGCTAAAAAGGATTCCGTCTCCTTCAAAGAAGTTTTATTTTTGGTCCAGAGTA CTTGTTTTCCCGATGTGTCCAGCCAGCTCCGCAGCAGCTTTTCAAGATGCACTATGCCTGATTGCTGATCGTGTTTTAACTTTT TCTTTTCCTGTTTTTATTTTGGTATTAAGTCGTTGCCTTTATTTGTAAAGCTGTTATAAATATATATTATATAAATATATTAAA AAGGAAAATGTTTCAGATGTTTATTTGTATAATTACTTGATTCACACAGTGAGAAAAAATGAATGTATTCCTGTTTTTGAAGAG AAGAATAATTTTTTTTTCTCTAGGGAGAGGTACAGTGTTTATATTTTGGAGCCTTCCTGAAGGTGTAAAATTGTAAATATTTTT ATCTATGAGTAAATGTTAAGTAGTTGTTTTAAAATACTTAATAAAATAATTCTTTTCCTGTGGAAG 373 KTYDYLFKLLLIGDSGVGKTC LFRFSEDAFNTTFISTIGIDFKIRTIE DGKKIK QI DTAGQERFRTITTAYYRGAMGI MLWDITNEKSFDNIKMIMIEEHASSDVERMILGNKCDMNDKRQVSKERGEKLAIDYGIKFLETSAKSSANVEEAFFT ARD IMTKLNRKMNDSNSAGAGGP¥KITENRSKKTSFFRCSL
374 ATTGGCGGGCACGCCCCCTCGCCCGCGGCCCCCTCCCCGCCTCTCTCCACCGCCTCCTCTGGCTCCCCGGTCAGAGGGCCGGAG CGAGAAGATGGCGAAGACGTACGATTATCTCTTCAAGCTCCTGCTGATCGGCGACTCGGGGGTAGGCAAGACCTGCCTCCTGTT CCGCTTCTCAGAGGACGCCTTCAACACCACCTTCATCTCCACCATCGGAATTGATTTTAAAATTAGAACGATAGAACTAGATGG AAAGAAAAT.TAAGCTTCAGATATGGGACACAGCGGGTCAGGAAAGATTCCGAACAATCACGACAGCGTACTACAGAGGAGCCAT GGGCATTATGCTGGTCTATGACATCACAAATGAAAAATCCTTTGACAATATTAAAAATTGGATCAGAAACATTGAAGAGCATGC CTCTTCCGATGTCGAAAGAATGATCCTGGGTAACAAATGTGATATGAATGACAAAAGACAAGTGTCAAAAGAAAGAGGGGAGAA GCTAGCAATTGACTATGGGATTAAATTCTTGGAGACAAGCGCAAAATCCAGTGCAAATGTAGAAGAGGCATTTTTTACACTTGC ACGAGATATAATGACAAAACTCAACAGAAAAATGAATGACAGCAATTCAGCAGGAGCAGGTGGACCAGTGAAAATAACAGAAAA CCGATCAAAGAAGACCAGTTTCTTTCGTTGCTCGCTACTTTGATGAACTCTTTCTGAGAGACTGCAGCACACCTAGAGGGCCCT TTCCTGCTTCTCTGAAAGCACAGGTCACCCAGCCTCAGAATCACACCTCCCGGCTGCTGCTGAGAGCACCACTGAACTTAGACC TCTCAACACAGTATGCCAAGTGGATTCCAGCCTCATGGCCTAGCAAAAGAACAGACTCCCTTTTTCAAACATGGAAGCAATGAA GTGGAGACACATGCAGGACCTAACTCGTTTTTTCCTTGTTTTATTACCTGTTGCAGAAGCGGTTATCTTTCTTTTTTACTTTGC ACATCAGTGTTAGCCTTTCCCTATTTCAGCACAATCTTAGACTCATATTTGCACACTTTTGTGTCGTGAAGTTCTAGACAAATT TGTACATGTGGCAATGTTAAAAGAGCATTTACAGCAGAGGTTAATATACTAAAATTAAAGGGTATTTGGTCTGGTTCATATGGT CAAATATTACTGCCTTGGTAGCATTTATTTAAGGGCTTTTTCTTAAATAAGAATCATTAAAGTCATTAAAAAATTTACTGAAAT GCCCA
375
MPGMFFSAWPKELKGTTHSLLDDKMQKRRPKTFGMDMKAYLRSMIPHLESGMKSSKSKDVLSAAEVMQ SQSLEKLLANQTGQN VFGSFLKSEFSEENIEFWLACEDYKKTESD LPCKAEEIYKAFVΗSDAAKQINIDFRTRESTAKKIKAPTPTCFDEAQKVIYT MEKDSYPRFLKSHIYLNLLNDLQA SLK 376
•GGGAGTTAGACAAAATGCCAGGAATGTTCTTCTCTGCTAACCCAAAGGAATTGAAAGGAACCACTCATTCACTTCTAGACGACA AAATGCAAAAAAGGAGGCCAAAGACTTTTGGAATGGATATGAAAGCATACCTGAGATCTATGATCCCACATCTGGAATCTGGAA TGAAATCTTCCAAGTCCAAGGATGTACTTTCTGCTGCTGAAGTAATGCAATGGTCTCAATCTCTGGAAAAACTTCTTGCCAACC AAACTGGTCAAAATGTCTTTGGAAGTTTCCTAAAGTCTGAATTCAGTGAGGAGAATATTGAGTTCTGGCTGGCTTGTGAAGACT ATAAGAAAACAGAGTCTGATCTTTTGCCCTGTAAAGCAGAAGAGATATATAAAGCATTTGTGCATTCAGATGCTGCTAAACAAA
TCAATATTGACTTCCGCACTCGAGAATCTACAGCCAAGAAGATTAAAGCACCAACCCCCACGTGTTTTGATGAAGCACAAAAAG
TCATATATACTCTTATGGAAAAGGACTCTTATCCCAGGTTCCTCAAATCACATATTTACTTAAATCTTCTAAATGACC.TGCAGG CTAATAGCCTAAAGTGACTGGTCCCTGGCTGAAGGGAATTAACAGATAGTATCAGCGCAGAAGGAATGTGCCAGTATGGATCCC
TGGGTGAACAGCTTGGCCTTTTTTGGGTGTCTTGACAGGCCAAGAAGAACAAATGACTCAGAACCGGATTAACATGAAAGTTAT CCAGGCGCAGAGTTGAAGAAGCATAAGCAAGCAAGACAAAAACAGAGAGACCGCAAGGAGGAAGATCTGTGGTACTGTCATAAA AAAGAGTGGAGCTCTGTATTAGAAAAGCCCCTCAGAACTGGGAAGGCCAGGTAACTCTAGTTACACAGAAACTGGTACTAAAGT CTATCAAACTGATTACACAGACTGTAAGAATTCAAAGTCAACTGACATCTATGCTACATATATTATATAGTTTGTACTTGACTA TGAGCCATTAACTTAAAGCATATGTTTCAAATAGCCATTGCTACTATTCCTTGTCCGGTGTAATTTTATTTTATTGTTTTTACT TTGGAAGAGATGAACTGTGTATTTAACTTAAGCTATTGCTCTTAAAACCAGGGAGTCAGATATATTTGTAAGGTTAAATCATTG GTGCAATAATAAATGTGGATTTTGTATTAAAATATATATGAAGCAAAAAAA
377
MQIFVKT TGKTIT EVEPSDTIE VKAKIQDKEG1PPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTL TGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTIT E VEPSDTIE VKAKIQDKEGIPPDQQRLIFAGKQ EDGRTLSDYNIQKESTLHLVLR RGGMQIFVKTIiTGKTIT EVEPSDTIE NVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDY-.IQKESTLHLV R RGGMQIFVKTLTGKTITLE¥EPSDTIENVKAKIQD KEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIF¥KTLTGKTITLEVEPSDTIEVKAKIQDKEGIPPDQ QRLIFAGKQLEDGRTLSDYNIQKEST HVLRLRGGMQIF¥KTLTGKTITLEVEPSDTIE VKAKIQDKEGIPPDQQRLIFAGK QLEDGRTLSDY IQKESTLHLVRLRGGMQIFVKT TGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTL SDYNIQKESTLHV R RGG QIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRT SDYNIQKE STLHLVLRLRGGV
378
TAGTTCCGTCGCAGCCGGGATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGATCTTCGTGA AGACTCTGACTGGTAAGACCATCACCCTCGAGGTTGAGCCCAGTGACACCATCGAGAATGTCAAGGCAAAGATCCAAGATAAGG AAGGCATCCCTCCTGACCAGCAGAGGCTGATCTTTGCTGGAAAACAGCTGGAAGATGGGCGCACCCTGTCTGACTACAACATCC AGAAAGAGTCCACCCTGCACCTGGTGCTCCGTCTCAGAGGTGGGATGCAAATCTTCGTGAAGACACTCACTGGCAAGACCATCA CCCTTGAGGTGGAGCCCAGTGACACCATCGAGAACGTCAAAGCAAAGATCCAGGACAAGGAAGGCATTCCTCCTGACCAGCAGA GGTTGATCTTTGCCGGAAAGCAGCTGGAAGATGGGCGCACCCTGTCTGACTACAACATCCAGAAAGAGTCTACCCTGCACCTGG TGCTCCGTCTCAGAGGTGGGATGCAGATCTTCGTGAAGACCCTGACTGGTAAGACCATCACCCTCGAGGTGGAGCCCAGTGACA CCATCGAGAATGTCAAGGCAAAGATCCAAGATAAGGAAGGCATTCCTCCTGATCAGCAGAGGTTGATCTTTGCCGGAAAACAGC TGGAAGATGGTCGTACCCTGTCTGACTACAACATCCAGAAAGAGTCCACCTTGCACCTGGTACTCCGTCTCAGAGGTGGGATGC AAATCTTCGTGAAGACACTCACTGGCAAGACCATCACCCTTGAGGTCGAGCCCAGTGACACTATCGAGAACGTCAAAGCAAAGA TCCAAGACAAGGAAGGCATTCCTCCTGACCAGCAGAGGTTGATCTTTGCCGGAAAGCAGCTGGAAGATGGGCGCACCCTGTCTG ACTACAACATCCAGAAAGAGTCTACCCTGCACCTGGTGCTCCGTCTCAGAGGTGGGATGCAGATCTTCGTGAAGACCCTGACTG GTAAGACCATCACCCTCGAAGTGGAGCCGAGTGACACCATTGAGAATGTCAAGGCAAAGATCCAAGACAAGGAAGGCATCCCTC CTGACCAGCAGAGGTTGATCTTTGCCGGAAAACAGCTGGAAGATGGTCGTACCCTGTCTGACTACAACATCCAGAAAGAGTCCA CCTTGCACCTGGTGCTCCGTCTCAGAGGTGGGATGCAGATCTTCGTGAAGACCCTGACTGGTAAGACCATCACTCTCGAGGTGG AGCCGAGTGACACCATTGAGAATGTCAAGGCAAAGATCCAAGACAAGGAAGGCATCCCTCCTGATCAGCAGAGGTTGATCTTTG CTGGGAAACAGCTGGAAGATGGACGCACCCTGTCTGACTACAACATCCAGAAAGAGTCCACCCTGCACCTGGTGCTCCGTCTTA GAGGTGGGATGCAGATCTTCGTGAAGACCCTGACTGGTAAGACCATCACTCTCGAAGTGGAGCCGAGTGACACCATTGAGAATG TCAAGGCAAAGATCCAAGACAAGGAAGGCATCCCTCCTGACCAGCAGAGGTTGATCTTTGCTGGGAAACAGCTGGAAGATGGAC GCACCCTGTCTGACTACAACATCCAGAAAGAGTCCACCCTGCACCTGGTGCTCCGTCTTAGAGGTGGGATGCAGATCTTCGTGA AGACCCTGACTGGTAAGACCATCACTCTCGAAGTGGAGCCGAGTGACACCATTGAGAATGTCAAGGCAAAGATCCAAGACAAGG AAGGCATCCCTCCTGACCAGCAGAGGTTGATCTTTGCTGGGAAACAGCTGGAAGATGGACGCACCCTGTCTGACTACAACATCC AGAAAGAGTCCACCCTGCACCTGGTGCTCCGTCTCAGAGGTGGGATGCAGATCTTCGTGAAGACCCTGACTGGTAAGACCATCA CCCTCGAGGTGGAGCCCAGTGACACCATCGAGAATGTCAAGGCAAAGATCCAAGATAAGGAAGGCATCCCTCCTGATCAGCAGA GGTTGATCTTTGCTGGGAAACAGCTGGAAGATGGACGCACCCTGTCTGACTACAACATCCAGAAAGAGTCCACTCTGCACTTGG TCCTGCGCTTGAGGGGGGGTGTCTAAGTTTCCCCTTTTAAGGTTTCAACAAATTTCATTGCACTTTCGTTTCAATAAAGTTGTT GCATTCCC •
379
MGSRTPESP HAVQLRGPRRRPPLVPL LLLVPPPPRVGGFN DAEAPAVLSGPPGSFFGFSVEFYRPGTDGVSVLVGAPKA TSQPGVLQGGAVYLCP GASPTQCTPIEFDSKGSRLLESSLSSSEGEEPVEYKSLQWFGATVRAHGSSILACAPLYS RTEKEP LSDPVGTCYLSTDNFTRILEYAPCRSDFSWAAGQGYCQGGFSAEFTKTGRVVLGGPGSYF QGQILSATQEQIAESYYPEY IN LVQGQLQTRQASSIYDDSYLGYSVAVGEFSGDDTEDFVAGVPKGNLTYGYVTILNGSDIRS Y FSGEQMASYFGYAVAATDV GDGLDDLLVGAPLLMDRTPDGRPQEVGRVYVYLQHPAGIEPTPTLTLTGHDEFGRFGSSLTPLGDLDQDGYWDVAIGAPFGGET QQGVVFVFPGGPGGLGSKPSQVLQPLWAASHTPDFFGSALRGGRDLDGNGYPD IVGSFGVDKAVVYRGRPIVSASASLTIFPA MFNPEERSCSLEGNPVACINLSFC NASGKHVADSIGFTVELQLD QKQKGGVRRALFLASRQATLTQTLLIQNGAREDCREMK IYLRNESEFRDK SPIHIALNFSLDPQAPVDSHGLRPALHYQSKSRIEDKAQIL DCGEDNICVPDLQ EVFGEQNHVY GDKN ALNLTFHAQNVGEGGAYEAE RVTAPPEAEYSGLVRHPGNFSSLSCDYFAV QSRLVCDLGNPMKAGAS GGLRFTVPHLRD TKKTIQFDFQILSKNL NSQSDVVSFRLSVEAQAQVTLNGVSKPEAV FPVSDWHPRDQPQKEEDLGPAVHHVYELINQGPSSI SQGVLELSCPQA EGQQLLY¥TRVTGLNCTTNHPINPKGLELDPEGSLHHQQKREAPSRSSASSGPQILKCPEAECFR RCELG P HQQESQSLQLHFRV AKTFLQREHQPFSLQCEAVYKALKMPYRILPRQLPQKERQVATAVQWTKAEGSYGVPLWIII AI F GLL LGLLIYILYKLGFFKRSLPYGTAMEKAQLKPPATSDA
380
CAGGACAGGGAAGAGCGGGCGCTATGGGGAGCCGGACGCCAGAGTCCCCTCTCCACGCCGTGCAGCTGCGCTGGGGCCCCCGGC GCCGACCCCCGCTCGTGCCGCTGCTGTTGCTGCTCGTGCCGCCGCCACCCAGGGTCGGGGGCTTCAACTTAGACGCGGAGGCCC CAGCAGTACTCTCGGGGCCCCCGGGCTCCTTCTTCGGATTCTCAGTGGAGTTTTACCGGCCGGGAACAGACGGGGTCAGTGTGC TGGTGGGAGCACCCAAGGCTAATACCAGCCAGCCAGGAGTGCTGCAGGGTGGTGCTGTCTACCTCTGTCCTTGGGGTGCCAGCC CCACACAGTGCACCCCCATTGAATTTGACAGCAAAGGCTCTCGGCTCCTGGAGTCCTCACTGTCCAGCTCAGAGGGAGAGGAGC CTGTGGAGTACAAGTCCTTGCAGTGGTTCGGGGCAACAGTTCGAGCCCATGGCTCCTCCATCTTGGCATGCGCTCCACTGTACA GCTGGCGCACAGAGAAGGAGCCACTGAGCGACCCCGTGGGCACCTGCTACCTCTCCACAGATAACTTCACCCGAATTCTGGAGT ATGCACCCTGCCGCTCAGATTTCAGCTGGGCAGCAGGACAGGGTTACTGCCAAGGAGGCTTCAGTGCCGAGTTCACCAAGACTG GCCGTGTGGTTTTAGGTGGACCAGGAAGCTATTTCTGGCAAGGCCAGATCCTGTCTGCCACTCAGGAGCAGATTGCAGAATCTT ATTACCCCGAGTACCTGATCAACCTGGTTCAGGGGCAGCTGCAGACTCGCCAGGCCAGTTCCATCTATGATGACAGCTACCTAG GATACTCTGTGGCTGTTGGTGAATTCAGTGGTGATGACACAGAAGACTTTGTTGCTGGTGTGCCCAAAGGGAACCTCACTTACG GCTATGTCACCATCCTTAATGGCTCAGACATTCGATCCCTCTACAACTTCTCAGGGGAACAGATGGCCTCCTACTTTGGCTATG CAGTGGCCGCCACAGACGTCAATGGGGACGGGCTGGATGACTTGCTGGTGGGGGCACCCCTGCTCATGGATCGGACCCCTGACG GGCGGCCTCAGGAGGTGGGCAGGGTCTACGTCTACCTGCAGCACCCAGCCGGCATAGAGCCCACGCCCACCCTTACCCTCACTG GCCATGATGAGTTTGGCCGATTTGGCAGCTCCTTGACCCCCCTGGGGGACCTGGACCAGGATGGCTACAATGATGTGGCCATCG GGGCTCCCTTTGGTGGGGAGACCCAGCAGGGAGTAGTGTTTGTATTTCCTGGGGGCCCAGGAGGGCTGGGCTCTAAGCCTTCCC AGGTTCTGCAGCCCCTGTGGGCAGCCAGCCACACCCCAGACTTCTTTGGCTCTGCCCTTCGAGGAGGCCGAGACCTGGATGGCA ATGGATATCCTGATCTGATTGTGGGGTCCTTTGGTGTGGACAAGGCTGTGGTATACAGGGGCCGCCCCATCGTGTCCGCTAGTG CCTCCCTCACCATCTTCCCCGCCATGTTCAACCCAGAGGAGCGGAGCTGCAGCTTAGAGGGGAACCCTGTGGCCTGCATCAACC TTAGCTTCTGCCTCAATGCTTCTGGAAAACACGTTGCTGACTCCATTGGTTTCACAGTGGAACTTCAGCTGGACTGGCAGAAGC AGAAGGGAGGGGTACGGCGGGCACTGTTCCTGGCCTCCAGGCAGGCAACCCTGACCCAGACCCTGCTCATCCAGAATGGGGCTC GAGAGGATTGCAGAGAGATGAAGATCTACCTCAGGAACGAGTCAGAATTTCGAGACAAACTCTCGCCGATTCACATCGCTCTCA ACTTCTCCTTGGACCCCCAAGCCCCAGTGGACAGCCACGGCCTCAGGCCAGCCCTACATTATCAGAGCAAGAGCCGGATAGAGG ACAAGGCTCAGATCTTGCTGGACTGTGGAGAAGACAACATCTGTGTGCCTGACCTGCAGCTGGAAGTGTTTGGGGAGCAGAACC ATGTGTACCTGGGTGACAAGAATGCCCTGAACCTCACTTTCCATGCCCAGAATGTGGGTGAGGGTGGCGCCTATGAGGCTGAGC TTCGGGTCACCGCCCCTCCAGAGGCTGAGTACTCAGGACTCGTCAGACACCCAGGGAACTTCTCCAGCCTGAGCTGTGACTACT TTGCCGTGAACCAGAGCCGCCTGCTGGTGTGTGACCTGGGCAACCCCATGAAGGCAGGAGCCAGTCTGTGGGGTGGCCTTCGGT TTACAGTCCCTCATCTCCGGGACACTAAGAAAACCATCCAGTTTGACTTCCAGATCCTCAGCAAGAATCTCAACAACTCGCAAA GCGACGTGGTTTCCTTTCGGCTCTCCGTGGAGGCTCAGGCCCAGGTCACCCTGAACGGTGTCTCCAAGCCTGAGGCAGTGCTAT TCCCAGTAAGCGACTGGCATCCCCGAGACCAGCCTCAGAAGGAGGAGGACCTGGGACCTGCTGTCCACCATGTCTATGAGCTCA TCAACCAAGGCCCCAGCTCCATTAGCCAGGGTGTGCTGGAACTCAGCTGTCCCCAGGCTCTGGAAGGTCAGCAGCTCCTATATG TGACCAGAGTTACGGGACTCAACTGCACCACCAATCACCCCATTAACCCAAAGGGCCTGGAGTTGGATCCCGAGGGTTCCCTGC ACCACCAGCAAAAACGGGAAGCTCCAAGCCGCAGCTCTGCTTCCTCGGGACCTCAGATCCTGAAATGCCCGGAGGCTGAGTGTT TCAGGCTGCGCTGTGAGCTCGGGCCCCTGCACCAACAAGAGAGCCAAAGTCTGCAGTTGCATTTCCGAGTCTGGGCCAAGACTT TCTTGCAGCGGGAGCACCAGCCATTTAGCCTGCAGTGTGAGGCTGTGTACAAAGCCCTGAAGATGCCCTACCGAATCCTGCCTC GGCAGCTGCCCCAAAAAGAGCGTCAGGTGGCCACAGCTGTGCAATGGACCAAGGCAGAAGGCAGCTATGGCGTCCCACTGTGGA TCATCATCCTAGCCATCCTGTTTGGCCTCCTGCTCCTAGGTCTACTCATCTACATCCTCTACAAGCTTGGATTCTTCAAACGCT CCCTCCCATATGGCACCGCCATGGAAAAAGCTCAGCTCAAGCCTCCAGCCACCTCTGATGCCTGAGTCCTCCCAATTTCAGACT CCCATTCCTGAAGAACCAGTCCCCCCACCCTCATTCTACTGAAAAGGAGGGGTCTGGGTACTTCTTGAAGGTGCTGACGGCCAG GGAGAAGCTCCTCTCCCCAGCCCAGAGACATACTTGAAGGGCCAGAGCCAGGGGGGTGAGGAGCTGGGGATCCCTCCCCCCCAT GCACTGTGAAGGACCCTTGTTTACACATACCCTCTTCATGGATGGGGGAACTCAGATCCAGGGACAGAGGCCCAGCCTCCCTGA AGCCTTTGCATTTTGGAGAGTTTCCTGAAACAACTGGAAAGATAACTAGGAAATCCATTCACAGTTCTTTGGGCCAGACATGCC ACAAGGACTTCCTGTCCAGCTCCAACCTGCAAAGATCTGTCCTCAGCCTTGCCAGAGATCCAAAAGAAGCCCCCAGTAAGAACC TGGAACTTGGGGAGTTAAGACCTGGCAGCTCTGGACAGCCCCACCCTGGTGGGCCAACAAAGAACACTAACTATGCATGGTGCC CCAGGACCAGCTCAGGACAGATGCCACAAGGATAGATGCTGGCCCAGGGCCAGAGCCCAGCTCCAAGGGGAATCAGAACTCAAA TGGGGCCAGATCCAGCCTGGGGTCTGGAGTTGATCTGGAACCCAGACTCAGACATTGGCACCAATCCAGGCAGATCCAGGACTA TATTTGGGCCTGCTCCAGACCTGATCCTGGAGGCCCAGTTCACCCTGATTTAGGAGAAGCCAGGAATTTCCCAGGACCTGAAGG GGCCATGATGGCAACAGATCTGGAACCTCAGCCTGGCCAGACACAGGCCCTCCCTGTTCCCCAGAGAAAGGGGAGCCCACTGTC CTGGGCCTGCAGAATTTGGGTTCTGCCTGCCAGCTGCACTGATGCTGCCCCTCATCTCTCTGCCCAACCCTTCCCTCACCTTGG CACCAGACACCCAGGACTTATTTAAACTCTGTTGCAAGTGCAATAAATCTGACCCAGTGCCCCCACTGACCAGAACTAGAAAAA AAAA
381
MDHTEG PAEEPPAHAPSPGKFGERPPPKRLTREAMRYLKERGDQTVLILHAKVAQKSYGNEKRFFCPPPCVYLMGSGWKKKK EQMERDGCSEQESQPCAFIGIGNSDQEMQQLN EGKNYCTAKTLYISDSDKRKHFIFSVKMFYGNSDD1GVFLSKRIKVISKPS KKKQSLKNADLCIASGTKVALFNRLRSQTVSTRYLHVEGGNFHASSQQWGAFFIHLLDDDESEGEEFTVRDVYIHYGQTCKLVC SVTGMA PRLIIMKVDKHTALLDADDP¥SQLHKCAFYLKDTERMYLC SQERIIQFQATPCPKEPNKEMINDGASWTIISTDKA EYTFYEGMGPVAPVTPVPWESLQLNGGGDVAM ELTGQNFTPNLRVWFGDVEAETMYRCGESMLCVVPDISAFREGWRWVRQ PVQVPVTLVRNDGIIYSTSLTFTYTPEPGPRPHCSVAGAILPANSSQVPPNESNTNSEGSYTNASTNSTS¥TSSTATWS
382 ATCCCCTCCGGTTTTCCTCAGTCTCCACGTACGTCCCTCAAAGCGCGTCCTAAAACCCGGATAACCGGAGCGCTCCCCATGGAC CACACGGAGGGCTTGCCCGCGGAGGAGCCGCCTGCGCATGCTCCATCGCCTGGGAAATTTGGTGAGCGGCCTCCACCTAAACGA CTTACTAGGGAAGCTATGCGAAATTATTTAAAAGAGCGAGGGGATCAAACAGTACTTATTCTTCATGCAAAAGTTGCACAGAAG TCATATGGAAATGAAAAAAGGTTTTTTTGCCCACCTCCTTGTGTATATCTTATGGGCAGCGGATGGAAGAAAAAAAAAGAACAA ATGGAACGCGATGGTTGTTCTGAACAAGAGTCTCAACCGTGTGCATTTATTGGGATAGGAAATAGTGACCAAGAAATGCAGCAG CTAAACTTGGAAGGAAAGAACTATTGCACAGCCAAAACATTGTATATATCTGACTCAGACAAGCGAAAGCACTTCATTTTTTCT GTAAAGATGTTCTATGGCAACAGTGATGACATTGGTGTGTTCCTCAGCAAGCGGATAAAAGTCATCTCCAAACCTTCCAAAAAG AAGCAGTCATTGAAAAATGCTGACTTATGCATTGCCTCAGGAACAAAGGTGGCTCTGTTTAATCGACTACGATCCCAGACAGTT AGTACCAGATACTTGCATGTAGAAGGAGGTAATTTTCATGCCAGTTCACAGCAGTGGGGAGCCTTTTTTATTCATCTCTTGGAT GATGATGAATCAGAAGGAGAAGAATTCACAGTCCGAGATGTCTACATCCATTATGGACAAACATGCAAACTTGTGTGCTCAGTT ACTGGCATGGCACTCCCAAGATTGATAATTATGAAAGTTGATAAGCATACCGCATTATTGGATGCAGATGATCCTGTGTCACAA CTCCATAAATGTGCATTTTACCTTAAGGATACAGAAAGAATGTATTTGTGCCTTTCTCAAGAAAGAATAATTCAATTTCAGGCC ACTCCATGTCCAAAAGAACCAAATAAAGAGATGATAAATGATGGCGCTTCCTGGACAATCATTAGCACAGATAAGGCAGAGTAT ACATTTTATGAGGGAATGGGCCCTGTCCTTGCCCCAGTCACTCCTGTGCCTGTGGTAGAGAGCCTTCAGTTGAATGGCGGTGGG GACGTAGCAATGCTTGAACTTACAGGACAGAATTTCACTCCAAATTTACGAGTGTGGTTTGGGGATGTAGAAGCTGAAACTATG TACAGGTGTGGAGAGAGTATGCTCTGTGTCGTCCCAGACATTTCTGCATTCCGAGAAGGTTGGAGATGGGTCCGGCAACCAGTC CAGGTTCCAGTAACTTTGGTCCGAAATGATGGAATCATTTATTCCACCAGCCTTACCTTTACCTACACACCAGAACCAGGGCCA CGGCCACATTGCAGTGTAGCAGGAGCAATCCTTCCAGCCAATTCAAGCCAGGTGCCCCCTAACGAATCAAACACAAACAGCGAG GGAAGTTACACAAACGCCAGCACAAATTCAACCAGTGTCACATCATCTACAGCCACAGTGGTATCCTA
•383 EESEPERKRARTDEVLPEEAAPRRKMRTTRTTCPMCRYAAPQLL QKLLQRRRKGAAEEEQQDSGSEPRGDEDDIPLGPQSNV SLLDQHQH KEKAEARKESAKEKQLKEEEKILESVAEGRALMSVKEMAKGITYDDPIKTS TPPRYVLSMSEERHERVRKKYHI LVEGDGIPPPIKSFKEMKFPAAI RGLKKKGIHHPTPIQIQGIPTILSGRDMIGIAFTGSGKTLVFT PVIMFCLEQEKR PFS KREGPYGLIICPSRELARQTHGILEYYCRLLQEDSSP LRCALCIGGMSVKEQMETIRHGVHMMVATPGRLMDLLQKKMVS DI CRYALDEADMIDMGFEGDIRTIFSYFKGQRQTL FSATMPKKIQNFAKSALVKPVTI VGRAGAASI)DVIQEVEYVKEEAKM VY ECLQKTPPPVLIFAEKKADVDAIHEYLLLKGVEAVAIHGGKDQEERTKAIEAFREGKKDVVATDVASKGLDFPAIQHVI NYDMPEEIENYVHRIGRTGRSGNTGIATTFINKACDESVLMDLKALLLEAKQKVPPVLQVLHCGDESMLDIGGERGCAFCGGLG HRITDCPKLEA QTKQVSNIGRKDYLAHSSMDF
384
AATGGAGGAGTCGGAACCCGAACGGAAGCGGGCTCGCACCGACGAGGTGCTGCCGGAGGAAGCCGCTCCGAGGCGGAAGATGAG GACGACGAGGACTACGTGCCCTATGTGCCGTTACGCAGCGCCGCAGCTACTGCTCCAGAAGCTGCTGCAGCGAAGACGCAAGGG AGCTGCGGAGGAAGAGCAGCAGGACAGCGGTAGTGAACCCCGGGGAGATGAGGACGACATCCCGCTAGGCCCTCAGTCCAACGT CAGCCTCCTGGATCAGCACCAGCACCTTAAAGAGAAGGCTGAAGCGCGCAAAGAGTCTGCCAAGGAGAAGCAGCTGAAGGAAGA AGAGAAGATCCTGGAGAGTGTTGCCGAGGGCCGAGCATTGATGTCAGTGAAGGAGATGGCTAAGGGCATTACGTATGATGACCC CATCAAAACCAGCTGGACTCCACCCCGTTATGTTCTGAGCATGTCTGAAGAGCGACATGAGCGCGTGCGGAAGAAATACCACAT CCTGGTGGAGGGAGACGGTATCCCACCACCCATCAAGAGCTTCAAGGAAATGAAGTTTCCTGCAGCCATCCTGAGAGGCCTGAA GAAGAAAGGCATTCACCACCCAACACCCATTCAGATCCAGGGCATCCCCACCATTCTATCTGGCCGTGACATGATAGGCATCGC TTTCACGGGTTCAGGCAAGACACTGGTGTTCACGTTGCCCGTCATCATGTTCTGCCTGGAACAAGAGAAGAGGTTACCCTTCTC AAAGCGCGAGGGGCCCTATGGACTCATCATCTGCCCCTCGCGGGAGCTGGCCCGGCAGACCCATGGCATCCTGGAGTACTACTG CCGCCTGCTGCAGGAGGACAGCTCACCACTCCTGCGCTGCGCCCTCTGCATTGGGGGCATGTCCGTGAAAGAGCAGATGGAGAC CATCCGACACGGTGTACACATGATGGTGGCCACCCCGGGGCGCCTCATGGATTTGCTGCAGAAGAAGATGGTCAGCCTAGACAT CTGTCGCTACCTGGCCCTGGACGAGGCTGACCGCATGATCGACATGGGCTTCGAGGGTGACATCCGTACCATCTTCTCCTACTT CAAGGGCCAGCGACAGACCCTGCTCTTCAGTGCCACCATGCCGAAGAAGATTCAGAACTTTGCTAAGAGTGCCCTTGTAAAGCC TGTGACCATCAATGTGGGGCGCGCTGGGGCTGCCAGCCTGGATGTCATCCAGGAGGTAGAATATGTGAAGGAGGAGGCCAAGAT GGTGTACCTGCTCGAGTGCCTGCAGAAGACACCCCCGCCTGTACTCATCTTTGCAGAGAAGAAGGCAGACGTGGACGCCATCCA CGAGTACCTGCTGCTCAAGGGGGTTGAGGCCGTAGCCATCCATGGGGGCAAAGACCAGGAGGAACGGACTAAGGCCATCGAGGC ATTCCGGGAGGGCAAGAAGGATGTCCTAGTAGCCACAGACGTTGCCTCCAAGGGCCTGGACTTCCCTGCCATCCAGCACGTCAT CAATTATGACATGCCAGAGGAGATTGAGAACTATGTACACCGGATTGGCCGCACCGGGCGCTCGGGAAACACAGGCATCGCCAC TACCTTCATCAACAAAGCGTGTGATGAGTCAGTGCTGATGGACCTCAAAGCGCTGCTGCTAGAAGCCAAGCAGAAGGTGCCGCC CGTGCTGCAGGTGCTGCATTGCGGGGATGAGTCCATGCTGGACATTGGAGGAGAGCGCGGCTGTGCCTTCTGCGGGGGCCTGGG TCATCGGATCACTGACTGCCCCAAACTCGAGGCTATGCAGACCAAGCAGGTCAGCAACATCGGTCGCAAGGACTACCTGGCCCA CAGCTCCATGGACTTCTGAGCCGACAGTCTTCCCTTCTCTCCAAGAGGCCTCAGTCCCCAAGACTGCCACCAGTCTACACATAC AGCAGCCCCCTGGACAGAATCAGCATTTCAGCTCAGCTGGCCTGGAATGGGCCAGGCTGGTCCTGGCTGCCTGTTCCCTGTGCT CTTCAGAATTACTGTTTTTGTTTCCTTTTACCCCAGCTGCCATTAAAGCCCAAACCTCTAGCCCAAAAAAAAAA
385
MGKGDPNKPRGKMSSYAFFVQTCREEHKKKHPDSSWFAEFSKKCSERWKTMSAKEKSKFEDMAKSDKARYDREMK YVPPKGD KKGKKKDPNAPKRPPSAFFLFCSEHRPKIKSEHPG SIGDTAKKLGE WSEQSAKDKQPYEQKAAKLKEKYEKDIAAYRAKGKS EAGKKGPGRPTGSKKK EPEDEEEEEEEEDEDEEEEDEDEE 386
GATGTGGCCCGTGGCCTAGCTCGTCAAGTTGCCGTGGCGCGGAGAACTCTGCAAAACAAGAGGCTGAGGATTGCGTTAGAGATA AACCAGTTCACGCCGGAGCCCCGTGAGGGAAGCGTCTCCGTTGGGTCCGGCCGCTCTGCGGGACTCTGAGGAAAAGCTCGCACC AGGTGGACGCGGATCTGTCAACATGGGTAAAGGAGACCCCAACAAGCCGCGGGGCAAAATGTCCTCGTACGCCTTCTTCGTGCA GACCTGCCGGGAAGAGCACAAGAAGAAACACCCGGACTCTTCCGTCAATTTCGCGGAATTCTCCAAGAAGTGTTCGGAGAGATG GAAGACCATGTCTGCAAAGGAGAAGTCGAAGTTTGAAGATATGGCAAAAAGTGACAAAGGTCGCTATGACAGGGAGATGAAAAA
TTACGTTCCTCCCAAAGGTGATAAGAAGGGGAAGAAAAAGGACCCCAATGCTCCTAAAAGGCCACCATCTGCCTTCTTCCTGTT
TTGCTCTGAACATCGCCCAAAGATCAAAAGTGAACACCCTGGCCTATCCATTGGGGATACTGCAAAGAAATTGGGTGAAATGTG GTCTGAGCAGTCAGCCAAAGATAAACAACCATATGAACAGAAAGCAGCTAAGCTAAAGGAGAAATATGAAAAGGATATTGCTGC
ATATCGTGCCAAGGGCAAAAGTGAAGCAGGAAAGAAGGGCCCTGGCAGGCCAACAGGCTCAAAGAAGAAGAACGAACCAGAAGA TGAGGAGGAGGAGGAGGAAGAAGAAGATGAAGATGAGGAGGAAGAGGATGAAGATGAAGAATAAATGGCTATCCTTTAATGATG CGTGTGGAATGTGTGTGTGTGCTCAGGCAATTATTTTGCTAAGAATGTGAATTCAAGTGCAGCTCAATACTAGCTTCAGTATAA AAACTGTACAGATTTTTGTATAGCTGATAAGATTCTCTGTAGAGAAAATACTTTTAAAAAATGCAGGTTGTAGCTTTTTGATGG GCTACTCATACAGTTAGATTTTACAGCTTCTGATGTTGAATGTTCCTAAATATTTAATGGTTTTTTTAATTTCTGTGTGTATGG TAGCACAGCAAACTTGTAGGAATTAGTATCAATAGTAAATTTTGGGTTTTTTAGGATGTTGCATTTCGTTTTTTTAAAAAAAAT TTTGTAATAAAATTATGTATATTATTTCTATTGTCTTTGTCTTAATATGCTAAGTTAATTTTCACTTTAAAAAAGCCATTTGAA GACCAAAAAAAAAAAAA
387
MRSRLLLSVAH PTIRETTEEMLLGGPGQEPPPSPSLDDYVRSISRLAQPTSVLDKATAQGQPRPPHRPAQACRKGRPAVSLRD ITARFSGQQPTLPMADTVDPLD LFGESQEKQPSQRDLPRRTGPSAGL GPHRQMDSSKPMGAPRGRLCEARMPGHSLARPPQD GQQSSD RS TFGQSAQAMASRHRPRPSSVLRTLYSHLPVIHEI-
CACACTGCTCAGGGAAGAGCCTGCTACGGTGGACTGTGAGACTCAGTGCACTGTCCTCCTCCCAGCGACCCCACGCTGGACCCC CTGCCGGACCCTCCACCCTTCGGCCCCCAAGCTTCCCAGGGGCTTCCTTTGGACTGGACTGTCCCTGCTCATCCATTCTCCTGC CACCCCCAGACCTCCTCAGCTCCAGGTTGCCACCTCCTCTCGCCAGAGTGATGAGGTCCCGGCTTCTGCTCTCCGTGGCCCATC TGCCCACAATTCGGGAGACCACGGAGGAGATGCTGCTTGGGGGTCCTGGACAGGAGCCCCCACCCTCTCCTAGCCTGGATGACT ACGTGAGGTCTATATCTCGACTGGCACAGCCCACCTCTGTGCTGGACAAGGCCACGGCCCAGGGCCAACCCAGGCCACCCCACA GGCCAGCCCAGGCCTGCCGGAAGGGCCGCCCTGCTGTGTCCCTGCGAGACATCACCGCACGTTTCAGTGGCCAGCAGCCCACAC TGCCCATGGCTGATACTGTGGACCCCCTGGACTGGCTTTTTGGGGAGTCCCAGGAAAAGCAGCCAAGCCAGAGGGACCTGCCAA GGAGGACTGGCCCCTCTGCTGGCCTCTGGGGTCCACATAGACAGATGGACAGCAGCAAGCCCATGGGGGCCCCCAGAGGGAGGC TCTGTGAAGCCAGGATGCCTGGGCATTCCCTGGCAAGACCACCGCAGGATGGGCAGCAGAGCTCTGACCTAAGAAGCTGGACTT TTGGGCAGTCTGCCCAAGCCATGGCCTCCCGCCACCGCCCCCGCCCCAGCAGTGTCCTCAGAACACTCTACTCGCACCTCCCGG TGATCCATGAACTCTGACCCCTCCCCAGTAAAGGCTTCTGTAGAGAGCATGCTGGGTCTGCATCTCCTCTCGTCTCCTCCATGG TGGTCACTGCCCCTGGCAGGTCTCTGAAAGGGAAATGCTTTTCTGCAGAGGCCCCTTCTTGGGCAGTTCACAGTTAGACCCACC CCCTCTGAATATGATAACAGCCTGTTTCACATGAGGAGATGTTACCAATCCCGTTCGCTCTGACCCTTGCTGGCTGATCACCTT GAGCAACTTACTTAACATCTGTGTTCCTCAGTTTCTCATGGGTAATATAGGGATAATTACTGGCACCTGCCTCCCAGGCCATTC TGACGTGTACCGCATATAGGAGCCCACTGGCTGAGTAGCTACCATCATCGCTGGTGGGGAAACTGGTGGTAGGGGTGTGAGGGT AGTGGGGGTGTCAGCCCCCAGGTGTTTCAGAACAAGGCCTCGGGCACTCCCAAGTCTGCCTCTTGGCTCCCACCCTCAAAGCCC ATGTTCTGTGAGGCCCAAGAGAACACATGGAGTCTTAGCAAATGCACTAATGTATTCCGGGGGACTGTCACCTGGCACCACTGG GGCACTCTGCTGGCTACAACTCATACGTCCTGTGGTGGCATTGGGAGAGTTCCCCCATGATGAGGGCCAAGATAGAATCTGTAC CACTCAGTGCTACCATCCCCACCCCTACACCACTTCCACACAGGGGCCTCATGGCATGGTCAGGGTCCCAGCTGTGGGTGAGAG CAGGGCACTGTCCAGCTGTCCACTGGGGAAGTCAAGATGTCCTAAGGCCCAGGCCAGGGCATCTGGAGTCTGAAGGACCCTAGT TCCTAGAGGCATCTGGCAGCAAGAAGGTGAGGCATCAGGGAACGGGAATCAGGCTGGGACTGATCAGAGGTGAAGGGACAGAGA GAGGAGAGGAGGAAGATTGAGCTGGGGCAACAGCCAAGCTCACCTGGCAGGTCTCTGCCACCTCCTTCTCTGTGAGCTGTCAGT CTAGGTTATTCTCTTTTTTTGTGGCTATTTTTAATTGCTTTGGATTTGTTAAATGTTTTCTGTCTTCTGTTAAGTGTGTTTTCT CTGGAGATAGAATGTAAACCATATTAAAAGGAAAAAGTTTCAGACAAGCAATTACCCAGTTTCCTTATCTATAAAATGGGGACA TCAGCAATGTTCTTCACACCCTGCAAGGGCTGGGAATTGCGCATGTGAACTTGGAGCTGCATTTATGAGCACTGTAGACAAATG TTTGTATCTGTCAC 389
MQS MQAP IALGLLLATPAQAH KKPSQLSSFSWDNCDEGKDPA¥IRSLTLEPDPIVVPGVT SWGSTSVPLSSPLKVDL VLEKEVAGL IKIPCTDYIGSCTFEHFCDVLDM IPTGEPCPEPLRTYGLPCHCPFKEGTYSLPKSEFVVPD ELPSWLTTGNY RIESVLSSSGKRLGCIKIAASI-KGI
390 CTCAGCTTCTTTGCGTAACCAATACTGGAAGGCATTTAAAGGACCTCTGCCGCCTCAGACCTTGCAGTTAACTCCGCCCTGACC CACCCTTCCCGATGCAGTCCCTGATGCAGGCTCCCCTCCTGATCGCCCTGGGCTTGCTTCTCGCGACCCCTGCGCAAGCCCAdC TGAAAAAGCCATCCCAGCTCAGTAG.CTTTTCCTGGGATAACTGTGATGAAGGGAAGGACCGTGCGGTGATCAGAAGCCTGACTC TGGAGCCTGACCCCATCGTCGTTCCTGGAAATGTGACCCTCAGTGTCGTGGGCAGCACCAGTGTCCCCCTGAGTTCTCCTCTGA AGGTGGATTTAGTTTTGGAGAAGGAGGTGGCTGGCCTCTGGATCAAGATCCCATGCACAGACTACATTGGCAGCTGTACCTTTG AACACTTCTGTGATGTGCTTGACATGTTAATTCCTACTGGGGAGCCCTGCCCAGAGCCCCTGCGTACCTATGGGCTTCCTTGCC ACTGTCCCTTCAAAGAAGGAACCTACTCACTGCCCAAGAGCGAATTCGTTGTGCCTGACCTGGAGCTGCCCAGTTGGCTCACCA CCGGGAACTACCGCATAGAGAGCGTCCTGAGCAGCAGTGGGAAGCGTCTGGGCTGCATCAAGATCGCTGCCTCTCTAAAGGGCA TATAGCATGGCATCTGCCACAGCAGAATGGAGCGGTGTGAGGAAGGTCCCTTTTCCTCTGTTTTGTGTTTGCCAAGGCCAAACT CCCACTCTCTGCCCCCCTTTAATCCCCTTTCTACAGTGAGTCCACTACCCTCACTGAAAATCATTTTGTACCACTTACATTTTA GGCTGGGGCAAGCAGCCCTGACCTAAGGGAGAATGAGTTGGACAGTTCTTGATAGCCCAGGGCATCTGCTGGGCTGACCACGTT ACTCATCCCCGTTAACATTCTCTCTAAAGAGCCTCGTTCATTTCCAAAGCAGTTAAGGAATGGGAACAGAGTGTTTTAGGACCT GAAGAATCTTTATGACTCTCTCTCTTTCTCTCTTTTTTTTTTTGTCACTAAGTTAAAAGCGAAGTGAGAGTATTAACGTTTTTG TTCTCCTCCGGCCCCCTGTTACAATGAAGGGGCAAAAGTATTTGCTCTTAGTCTATTCCTCCCTTAACTTCTGTGACTAATTTT TATTTCCTTTCTAGATTTGCCCAATTAATACTAGGGTGCAGTGTATCCTGGAGAGGTAGGGTGTGTGGGGGAGGAATCCCTTGG GGGAGATATTAGGAGTGCTCTGTTGTTTACAAACTCAGGTACCCGCAGGGCCTAGCAAGAGACTTAAATGACTGATAAGAACCG TGAGAAACATGTTGCTTCCAGGCTTGATTTCGATTTTTCGCTTTTTTTTTTTGGGACGGAGTCTCGCTTTGTCACCAGGCTGGA GTGCAGTGGTGCAATCTCACCTCACTGCAACCTCCGCCTCCTGGGTTCAAGCAATTCTCCTGCCTCAGCCTCCCAAGTAGCTTG GACTACAGGCCCTGCCACCACGCCCGGCTAATTTGTGTATTTTTAGTAGAGATGGGGTTTCACCATGTTGGCCAGGATGGTCTC GATCTCTTGACCTCGTGATCCGTCCACCTTGGCCTTGCAAAGCGCTGGATTACAGGCATGAGCCACTACACCCAGCCGATTTTT CCTTTTTGATTAAAGATGCTATTACAATGTAAATATTTCTTACACAGAAAGTCACAGCACATGTGCCCATTGATACAAGGCTGC TGAGGCCTGGTCTCCAGTTGGAAATATAATTAAGGGTGGCAGGGACTGGAGTCAGTTGGAGAGTGCATAGCCAGTCTGTGAAGA CAACTGCCAGATACTGGCAATACTCCAGCCTGGTGACAGAGTGAGACTCTGTCTCAAAAAAAAAGTTTCAATGTTTACTCCTAG AGAAGCCAAAAATCCAGATTTGTATATGAAATCTTACCATTTTAAAAGATTGGCAGCTAATTATTTTTTTAAAAAGCTGTGCAG TGTGATGTGTCCCAAACGGACTGGCTCATGGGTGGCCACGTCACAACCTCTGATCTCAGACCGTGCATGCCTTGTCCTCTTAAG ACAACTCCTGTGGCACCGTTTCTCCCTCCACAGGGCCAAAGCCATAGTGTCCGGTCCCAAGGACAAGGCTCTTCCAGTGCTAGG AGAGGTATGAGCAGCCTCTCACCTGTGAGCTGTGGGGATCACAAGGCTGCCTGCCTCAGTCTTGGAGTCCTGTTGGGTGAATGA GGCAGATGGGAAAGAGCCTCACCAGCAGCTGCTTTTGGAGCAGGGGTCCAAGGAAGAGAGGGTGGCCTCGACATCAAACTGCCT GGATTTTTCTACCACCCTGTTACATCATAACAACTTCTGAAACACACACCAGCCCTGAGTTCTGGGCTCATTTGAAGCCTGGAA TAGCAATAAATCTTTTTAACTTGCAAAAAAAAAAAAAAAAAA 391
MPAALVENSQVICEVWASNLEEEMRKIREIVPSYSYIAMDTEFPGVVVRPIGEFRSSIDYQYQLLRCNVDL KIIQLGLTFTNE KGEYPSGINT QFNFKFNLTEDMYSQDSIDLLANSGLQFQKHEEEGIDTLHFAEL MTSGWLCDNVKLSFHSGYDFGY VKL LTDSRLPEEEHEFLHILN FSPSIYD¥KYLMKSCKNLKGGLQEVADQLDLQRIGRQHQAGSDSLLTGMAFFRMKELFFEDSIDD AKYCGRLYGGTGVAQKQNEDVDSAQEKMSILAIINNMQQ 392
GCACGAGGGGGTAGAGGGAAAAGAGCTCCGGGCCAGGGGCTGCCGTCGCCGCCGTCGGGGAGTCAGCCCGCCAGCCCGCCAGCT CGTCAGCCCGCCACCAGCTTCGCGGGCCCTGTCGGTCCCGGTAAGCGGGCCTGCGCTTACCGGAAAGAGGAGCGTAAGATGAAA GAGTATCAGACCAAACATTGTCTGGCTTGCACTGTAAAACTAGTTAGCTGAAGACGACTTCTCAGGTTTCTTCAGGATGCCTGC AGCACTTGTGGAGAATAGCCAGGTTATCTGTGAAGTGTGGGCCAGTAATCTAGAAGAAGAGATGAGGAAGATCCGAGAAATCGT GCCCAGTTACAGTTATATTGCCATGGACACAGAATTTCCAGGTGTTGTGGTGCGACCAATTGGTGAATTTCGTAGTTCCATAGA TTACCAATATCAGCTTCTGCGGTGCAATGTTGACCTTTTAAAAATTATCCAGCTGGGCCTTACATTCACAAATGAGAAGGGAGA GTATCCTTCTGGAATCAATACTTGGCAGTTCAATTTCAAATTTAACCTTACAGAGGACATGTACTCCCAGGATTCCATAGATCT CCTTGCTAACTCAGGACTACAGTTTCAGAAGCATGAAGAGGAAGGGATTGACACACTGCACTTTGCAGAGCTGCTTATGACATC AGGAGTGGTTCTCTGTGACAATGTCAAATGGCTTTCATTTCATAGTGGCTATGATTTTGGCTATATGGTAAAGTTGCTTACAGA TTCTCGTTTGCCAGAAGAGGAACATGAΑTTCTTACATATTCTGAACCTTTTCTCCCCATCCATTTATGATGTGAAATACCTGAT GAAGAGCTGCAAAAATCTTAAGGGAGGTCTTCAGGAAGTTGCTGATCAGTTGGATTTGCAGAGGATTGGAAGGCAGCACCAGGC AGGCTCAGACTCACTGCTGACAGGAATGGCTTTCTTTAGGATGAAAGAGTTGTTTTTTGAGGACAGCATTGATGATGCCAAGTA CTGTGGGCGGCTCTATGGCTTAGGCACAGGAGTGGCCCAGAAGCAGAATGAGGATGTGGACTCTGCCCAGGAGAAGATGAGCAT CCTGGCGATTATCAACAACATGCAGCAGTGATGGCGCCAGGCTCTGCAGGGTGGGCCTGATCCCAGAGTGGTGCTTACTGTGCT GACTGTGTACTTATCTTCCCCAAGAGAAAATGCTTCTTTTGAGCACACTGTACCTACCATCTGCATTGAGCAGAAAGACTTTTG TTTTACTGAAGACAAAAGATGTTTTTATTTTAGACCCAGAAGAGAGGAGTTTGCTCTGAATTTGTAAATAAGTCTTCCCCATTC CTCATACTCGAGCCTCTCCTCTCTGGTTGCCTCCTGCCACCAGCATCCATGGCTCATTTGACACCTTTTTAAATATCAGGACAA GTCTGAAACAAAGTAGTAAAATGTATATAACTCTTACCTGTTGTCATTCTTTTTCTTTTAAATTTGTTGCTAATCTCTGATAAT GAAGATTCTTACTCTGATTCTCAGCTGAGCTGTGAGGGCTTCCAGGGAAAATGGAACAAAATGGTGTTCTTAGGTAATGGGTTG TAGATACTGAGTCTTCCTTTCCTTTTCTGACCCTTCTCGAGGACATTTGCTTTCCTCACACTTTTGTAGTCTCTCTTTACATAT TACTATATGGAAATGAATTGCTCTGTGCTGAAATTTGAAGACCAGATAATGAAACTGAAAAGCAAACAATTTTTACTGAATCTG TCTACCTTCATTCATGAGAACTCCAGAATGAGTGTTGACCACTGAAGCATCTTTTAAGTCTGTGTTCCATTGTGCCATTCAGGT TTGCTGTCACATATGCATCATCTGAAATCATTTGAAATTTTTGTACAATAAAATATCCTGGATTTGATCCTGAAGGAAACTAGT AAGATCAGATTTTTGGGTCATGTCTGTTGTATTTTCAGTAATGTGATTTCAGATGGTCATCTGGATTCTCCCACTTCTCTACTC CATTATTTCTCTACTTTTCCTTCCAGCAAACCTTGAAACGTGAGGGAGATGGATTAATGTGAGTAACAGGAATGTGTCTTTAAA AAGCTAGAGTGGTTACATTTAATCAGGCAGTAAGATAATTTGGGTTCTTGAGTTGTTTTGGAGTAATATCCCACAACTGGGGTA GGAAGCTCAGGACTTTTTTCTTTAAAGCTAGTCATTT.CAAAAGCATATTGTATTTTTTTGAATGACTACAGTATGGACAATTTC AAAAACCAAAACCCACTTTGGATTGGTGGAAGTAAAAACTGGTAACTCACTCAAGTGAATGAATGGTCTTGCATTTTAAAAGCT TATGGGAAACTCAATTTGAAATGATTAGAAAATGTCAAGTATTATAAGCTGGTATTTAAGATGCTTGTAAATACTATTTATGTT TTTAATTTTGTAAAATAAAGATTTCTTTTTAAAAAAAAAAAAAAAAAAAAAAA
394
TCATCTTTCTCTTTATTCTGACAACATTATGACATTAAATAAAATCCAAGAGGTATTGGATTAGTCCTTGTTTGGTCTCTGGTG ATTTAGATAAGGCAGAACTGAGCCCCTCGGAATGTATTATCTCAAAGAGCTAGTAGCAGCTGCTATGCAAAGTTCTAAGGCCCG AGTCAAATCCTGGGCATCTCCACAGATGTGTGGTAGGGCACGGGCTCCAGCTCTTGTGTAAGAAAGAACAGGAATGAGAACAGC TTTATTTTGTAGCGCCAAGGTCTCACTATGCTCACACCTGTAATCCCAGCTTTGAGAAGAGGATCTGGCACCAGAAGGGTCTGG TAGAAGAAAGTGGGAAAGGTGAAGGACAGGGATCCTTTCCCTTCTGCTACAACCTAGGGACAGAGGCACTTGACTTCCGCAAGG GGGCCAAAGAAGGTAGCAGCTACTTGGGGTTTTGTGTGGGAGATGGCCGACCACTCCAAGGGAGGTCAAATGGCTTTTTTCAGG ACGTGGAATCTCGTCCAAAAAATGG 395
MKVSAAL CLLLIAATFIPQGLAQPDAINAPVTCCYFTNRKISVQRLASYRRITSSKCPKEAVIFKTIVAKEICADPKQKWVQ DSMDH DKQTQTPKT
396
CTAACCCAGAAACATCCAATTCTCAAACTGAAGCTCGCACTCTCGCCTCCAGCATGAAAGTCTCTGCCGCCCTTCTGTGCCTGC TGCTCATAGCAGCCACCTTCATTCCCCAAGGGCTCGCTCAGCCAGATGCAATCAATGCCCCAGTCACCTGCTGTTATAACTTCA CCAATAGGAAGATCTCAGTGCAGAGGCTCGCGAGCTATAGAAGAATCACCAGCAGCAAGTGTCCCAAAGAAGCTGTGATCTTCA AGACCATTGTGGCCAAGGAGATCTGTGCTGACCCCAAGCAGAAGTGGGTTCAGGATTCCATGGACCACCTGGACAAGCAAACCC AAACTCCGAAGACTTGAACACTCACTCCACAACCCAAGAATCTGCAGCTAACTTATTTTCCCCTAGCTTTCCCCAGACACCCTG TTTTATTTTATTATAATGAATTTTGTTTGTTGATGTGAAACATTATGCCTTAAGTAATGTTAATTCTTATTTAAGTTATTGATG TTTTAAGTTTATCTTTCATGGTACTAGTGTTTTTTAGATACAGAGACTTGGGGAAATTGCTTTTCCTCTTGAACCACAGTTCTA CCCCTGGGATGTTTTGAGGGTCTTTGCAAGAATCATTAATACAAAGAATTTTTTTTAACATTCCAATGCATTGCTAAAATATTA TTGTGGAAATGAATATTTTGTAACTATTACACCAAATAAATATATTTTTGTACAAAAAAAAAAAAAA
397
MDYLLMIFS LFVACQGAPETAVLGAELSA¥GENGGEKPTPSPPWRLRRSKRCSCSSLMDKECVYFCHLDII VNTPEHWPYG GSPRSKRALENLLPTKATDRENRCQCASQKDKKC FCQAGKELRAEDIMEKDW HKKGKDCSK GKKCIYQQL¥RGRKIRR SSEEH RQTRSETMR SVKSSFHDPKLKGKPSRERY¥THNRAHW
GGAGCTGTTTACCCCCACTCTAATAGGGGTTCAATATAAAAAGCCGGCAGAGAGCTGTCCAAGTCAGACGCGCCTCTGCATCTG CGCCAGGCGAACGGGTCCTGCGCCTCCTGCAGTCCCAGCTCTCCACCACCGCCGCGTGCGCCTGCAGACGCTCCGCTCGCTGCC TTCTCTCCTGGCAGGCGCTGCCTTTTCTCCCCGTTAAAGGGCACTTGGGCTGAAGGATCGCTTTGAGATCTGAGGAACCCGCAG CGCTTTGAGGGACCTGAAGCTGTTTTTCTTCGTTTTCCTTTGGGTTCAGTTTGAACGGGAGGTTTTTGATCCCTTTTTTTCAGA ATGGATTATTTGCTCATGATTTTCTCTCTGCTGTTTGTGGCTTGCCAAGGAGCTCCAGAAACAGCAGTCTTAGGCGCTGAGCTC AGCGCGGTGGGTGAGAACGGCGGGGAGAAACCCACTCCCAGTCCACCCTGGCGGCTCCGCCGGTCCAAGCGCTGCTCCTGCTCG TCCCTGATGGATAAAGAGTGTGTCTACTTCTGCCACCTGGACATCATTTGGGTCAACACTCCCGAGCACGTTGTTCCGTATGGA CTTGGAAGCCCTAGGTCCAAGAGAGCCTTGGAGAATTTACTTCCCACAAAGGCAACAGACCGTGAGAATAGATGCCAATGTGCT AGCCAAAAAGACAAGAAGTGCTGGAATTTTTGCCAAGCAGGAAAAGAACTCAGGGCTGAAGACATTATGGAGAAAGACTGGAAT AATCATAAGAAAGGAAAAGACTGTTCCAAGCTTGGGAAAAAGTGTATTTATCAGCAGTTAGTGAGAGGAAGAAAAATCAGAAGA AGTTCAGAGGAACACCTAAGACAAACCAGGTCGGAGACCATGAGAAACAGCGTCAAATCATCTTTTCATGATCCCAAGCTGAAA GGCAAGCCCTCCAGAGAGCGTTATGTGACCCACAACCGAGCACATTGGTGACAGACTTCGGGGCCTGTCTGAAGCCATAGCCTC CACGGAGAGCCCTGTGGCCGACTCTGCACTCTCCACCCTGGCTGGGATCAGAGCAGGAGCATCCTCTGCTGGTTCCTGACTGGC AAAGGACCAGCGTCCTCGTTCAAAACATTCCAAGAAAGGTTAAGGAGTTCCCCCAACCATCTTCACTGGCTTCCATCAGTGGTA ACTGCTTTGGTCTCTTCTTTCATCTGGGGATGACAATGGACCTCTCAGCAGAAACACACAGTCACATTCGAATTC
400
GTGTTGGAATCAATCAATGTCCATTTCAGGAAGCTTCTTGTCTGAATCCGAAGCACAGCTGTGTCTGTACCCTGCTCAGCAGCC TGGGGCCTGGGTTGTCTCCTTGTCCATCCACTGGTCCATTCTGCTCTGATTTTTTTGTTCCTCTTTTGGAGGTTCCACTTTGGG TTTGGGCTTTGAAATTATAGGGCTACAAGTACTTGTCAGCTCCTTAATTTTAGCTTCAATCTCTTTTGACTTGACAACTGGATC CATGGTCAAACTCTGCTTGTTCTGCAGATTTAGCTTGTTATTCATCCACTCCATTGCTTCATTTGTGCTTTTTTCTACCTTTGT CATGTCAGCAGCATCCAAATGATCATACTGGTCCCCCTGTTTTTGAAAGAGCCGATTATTTTCATATACTGTTGGATCTGTTTC CCTAGTTCT 401 MAMVSEF KQA FIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAALHKAIMVKGVDEATIIDI TKRMAQRQQIKAAY LQETGKPLDETLKKALTGHLEEWLALLKTPAQFDADELRAAMKGLGTDEDTLIEILASRTNKEIRDINRVYREELKRDLAKDI TSDTSGDFR A SLAKGDRSEDFGVNEDLADSDARALYEAGERRKGTDV VFNTILTTRSYPQLRRVFQKYTKYSKHDMNKV DLELKGDIEKCLTAIVKCATSKPAFFAEKLHQ KGVGTRHKA IRIJVIVSRSEIDMNDIKAFYQKMYGISLCQAI DETKGDYE KILVALCGGN
402
AGTGTGAAATCTTCAGAGAAGAATTTCTCTTTAGTTCTTTGCAAGAAGGTAGAGATAAAGACACTTTTTCAAAAATGGCAATGG TATCAGAATTCCTCAAGCAGGCCTGGTTTATTGAAAATGAAGAGCAGGAATATGTTCAAACTGTGAAGTCATCCAAAGGTGGTC CCGGATCAGCGGTGAGCCCCTATCCTACCTTCAATCCATCCTCGGATGTCGCTGCCTTGCATAAGGCCATAATGGTTAAAGGTG TGGATGAAGCAACCATCATTGACATTCTAACTAAGCGAAACAATGCACAGCGTCAACAGATCAAAGCAGCATATCTCCAGGAAA CAGGAAAGCCCCTGGATGAAACACTTAAGAAAGCCCTTACAGGTCACCTTGAGGAGGTTGTTTTAGCTCTGCTAAAAACTCCAG CGCAATTTGATGCTGATGAACTTCGTGCTGCCATGAAGGGCCTTGGAACTGATGAAGATACTCTAATTGAGATTTTGGCATCAA GAACTAACAAAGAAATCAGAGACATTAACAGGGTCTACAGAGAGGAACTGAAGAGAGATCTGGCCAAAGACATAACCTCAGACA CATCTGGAGATTTTCGGAACGCTTTGCTTTCTCTTGCTAAGGGTGACCGATCTGAGGACTTTGGTGTGAATGAAGACTTGGCTG ATTCAGATGCCAGGGCCTTGTATGAAGCAGGAGAAAGGAGAAAGGGGACAGACGTAAACGTGTTCAATACCATCCTTACCACCA GAAGCTATCCACAACTTCGCAGAGTGTTTCAGAAATACACCAAGTACAGTAAGCATGACATGAACAAAGTTCTGGACCTGGAGT TGAAAGGTGACATTGAGAAATGCCTCACAGCTATCGTGAAGTGCGCCACAAGCAAACCAGCTTTCTTTGCAGAGAAGCTTCATC AAGCCATGAAAGGTGTTGGAACTCGCCATAAGGCATTGATCAGGATTATGGTTTCCCGTTCTGAAATTGACATGAATGATATCA AAGCATTCTATCAGAAGATGTATGGTATCTCCCTTTGCCAAGCCATCCTGGATGAAACCAAAGGAGATTATGAGAAAATCCTGG TGGCTCTTTGTGGAGGAAACTAAACATTCCCTTGATGGTCTCAAGCTATGATCAGAAGACTTTAATTATATATTTTCATCCTAT AAGCTTAAATAGGAAAGTTTCTTCAACAGGATTACAGTGTAGCTACCTACATGCTGAAAAATATAGCCTTTAAATCATTTTTAT ATTATAACTCTGTATAATAGAGATAAGTCCATTTTTTAAAAATGTTTTCCCCAAACCATAAAACCCTATACAAGTTGTTCTAGT AACAATACATGAGAAAGATGTCTATGTAGCTGAAAATAAAATGACGTCACAAGAC
403 MPLVSFTNRNYDLDYDSVQPYFYCDEEENFYQQQQQSELQPPAPSEDIWKKFELLPTPPLSPSRRSGLCSPSYVAVTPFSLRG DNDGGGGSFSTADQLEWTELLGGDMVNQSFICDPDDETFIKNIIIQDCMWSGFSAAAKLVSEKLASYQAARKDSGSPNPARGH SVCSTSSLYLQDLSAAASECIDPSVVFPYPLNDSSSPKSCASQDSSAFSPSSDS LSSTESSPQGSPEPLVHEETPPTTSSDS EEEQEDEEEIDWSVEKRQAPGKRSESGSPSAGGHSKPPHSP VLKRCHVSTHQHNYAAPPSTRKDYPAAKRVKLDSVRVLRQI S RKCTSPRSSDTEE VKRRTHNVLERQRRNELKRSFFALRDQIPELE NEKAPKV¥ILKKATAYI S¥QAEEQKLISEEDLL RKRREQLKHKLE.QLR SCA
404
CTGCTCGCGGCCGCCACCGCCGGGCCCCGGCCGTCCCTGGCTCCCCTCCTGCCTCGAGAAGGGCAGGGCTTCTCAGAGGCTTGG CGGGAAAAAAGAACGGAGGGAGGGATCGCGCTGAGTATAAAAGCCGGTTTTCGGGGCTTTATCTAACTCGCTGTAGTAATTCCA GCGAGAGGCAGAGGGAGCGAGCGGGCGGCCGGCTAGGGTGGAAGAGCCGGGCGAGCAGAGCTGCGCTGCGGGCGTCCTGGGAAG GGAGATCCGGAGCGAATAGGGGGCTTCGCCTCTGGCCCAGCCCTCCCGCTTGATCCCCCAGGCCAGCGGTCCGCAACCCTTGCC GCATCCACGAAACTTTGCCCATAGCAGCGGGCGGGCACTTTGCACTGGAACTTACAACACCCGAGCAAGGACGCGACTCTCCCG ACGCGGGGAGGCTATTCTGCCCATTTGGGGACACTTCCCCGCCGCTGCCAGGACCCGCTTCTCTGAAAGGCTCTCCTTGCAGCT GCTTAGACGCTGGATTTTTTTCGGGTAGTGGAAAACCAGCAGCCTCCCGCGACGATGCCCCTCAACGTTAGCTTCACCAACAGG AACTATGACCTCGACTACGACTCGGTGCAGCCGTATTTCTACTGCGACGAGGAGGAGAACTTCTACCAGCAGCAGCAGCAGAGC GAGCTGCAGCCCCCGGCGCCCAGCGAGGATATCTGGAAGAAATTCGAGCTGCTGCCCACCCCGCCCCTGTCCCCTAGCCGCCGC TCCGGGCTCTGCTCGCCCTCCTACGTTGCGGTCACACCCTTCTCCCTTCGGGGAGACAACGACGGCGGTGGCGGGAGCTTCTCC ACGGCCGACCAGCTGGAGATGGTGACCGAGCTGCTGGGAGGAGACATGGTGAACCAGAGTTTCATCTGCGACCCGGACGACGAG ACCTTCATCAAAAACATCATCATCCAGGACTGTATGTGGAGCGGCTTCTCGGCCGCCGCCAAGCTCGTCTCAGAGAAGCTGGCC TCCTACCAGGCTGCGCGCAAAGACAGCGGCAGCCCGAACCCCGCCCGCGGCCACAGCGTCTGCTCCACCTCCAGCTTGTACCTG CAGGATCTGAGCGCCGCCGCCTCAGAGTGCATCGACCCCTCGGTGGTCTTCCCCTACCCTCTCAACGACAGCAGCTCGCCCAAG TCCTGCGCCTCGCAAGACTCCAGCGCCTTCTCTCCGTCCTCGGATTCTCTGCTCTCCTCGACGGAGTCCTCCCCGCAGGGCAGC CCCGAGCCCCTGGTGCTCCATGAGGAGACACCGCCCACCACCAGCAGCGACTCTGAGGAGGAACAAGAAGATGAGGAAGAAATC GATGTTGTTTCTGTGGAAAAGAGGCAGGCTCCTGGCAAAAGGTCAGAGTCTGGATCACCTTCTGCTGGAGGCCACAGCAAACCT CCTCACAGCCCACTGGTCCTCAAGAGGTGCCACGTCTCCACACATCAGCACAACTACGCAGCGCCTCCCTCCACTCGGAAGGAC TATCCTGCTGCCAAGAGGGTCAAGTTGGACAGTGTCAGAGTCCTGAGACAGATCAGCAACAACCGAAAATGCACCAGCCCCAGG TCCTCGGACACCGAGGAGAATGTCAAGAGGCGAACACACAACGTCTTGGAGCGCCAGAGGAGGAACGAGCTAAAACGGAGCTTT TTTGCCCTGCGTGACCAGATCCCGGAGTTGGAAAACAATGAAAAGGCCCCCAAGGTAGTTATCCTTAAAAAAGCCACAGCATAC ATCCTGTCCGTCCAAGCAGAGGAGCAAAAGCTCATTTCTGAAGAGGACTTGTTGCGGAAACGACGAGAACAGTTGAAACACAAA CTTGAACAGCTACGGAACTCTTGTGCGTAAGGAAAAGTAAGGAAAACGATTCCTTCTAACAGAAATGTCCTGAGCAATCACCTA TGAACTTGTTTCAAATGCATGATCAAATGCAACCTCACAACCTTGGCTGAGTCTTGAGACTGAAAGATTTAGCCATAATGTAAA CTGCCTCAAATTGGACTTTGGGCATAAAAGAACTTTTTTATGCTTACCATCTTTTTTTTTTCTTTAACAGATTTGTATTTAAGA ATTGTTTTTAAAAAATTTTAA 405
MGK KLLHPS VLL LVLPTDAS¥SGKPQYMVLVPSLLHTETTEKGCVLLSYNETVTVSASLESVRGNRSLFTDLEAENDVL HCVAFAVPKSSSNEEVMFLTVQVKGPTQEFKKRTTVMVKNEDSLVFVQTDKSIYKPGQTVKFRWSMDENFHPLNELIPLVYIQ DPKGNRIAQ QSFQLEGG KQFSFPLSSEPFQGSYKVVVQKKSGGRTEHPFTVEEFVLPKFEVQVTVPKIITILEEEMNVSVCG YTYGKPVPGHVTVSICRKYSDASDCHGEDSQAFCEKFSGQLNSHGCFYQQVKTKVFQ KRKEYEMKI-HTEAQIQEEGTVVELT GRQSSEITRTITKLSFVKVDSHFRQGIPFFGQVRLVDGKGVPIPNK¥IFIRGNEA YYSNATTDEHGLVQFSINTTVMGTSLT VRVNYKDRSPCYGYQWVSEEHEEAHHTAYLVFSPSKSFVHLEPMSHELPCGHTQTVQAHYI NGGTLLGLKKLSFYY IMAKGG IVRTGTHGLLVKQEDMKGHFSISIPVKSDIAPVAR IYAV PTGDVIGDSAKYDVENCLAKVD SFSPSQS PASHAHLRVT AAPQSVCALRAVDQSVLLMKPDAELSASSVYWLLPEKD TGFPGPLNDQDDEDCINRH VYINGITYTPVSSTNEKDMYSFLED MGLIU.FTNSKIRKPKMCPQ QQYEMHGPEGLRVGFYESDVMGRGHARLVHVEEPHTETVRKYFPET I DLV¥V SAGVAEVG¥ TVPDTITE KAGAFCLSEDAGLGISSTAS RAFQPFF¥ELTMPYSVIRGEAFTLKATVLNYLPKCIRVSVQLEASPAF AVP¥E KEQAPHCICAGRQTVSWA¥TPKSLGNV FT¥SAEALESQELCGTE¥PSVPEHGRKDTVIKPLLVEPEGLEKETTFNS LCPSG GEVSEELS KLPPNWEESARASVSVLGDI GS QNTQNLLQMPYGCGEQNMVLFAPNIYVLDYLNETQQ TPEVKSKAIGYL' NTGYQRQLNYKHYDGSYSTFGERYGRNQGNT LTAFVKTFAQARAYIFIDEAHITQA IWLSQRQKDNGCFRSSGSLL NAIK GG¥EDEVTLSAYITIAL EIP TVTHPVVRALFCLESAWKTAQEGDHGSHVYTKALLAYAFAAGNQDKRKEV KSLNEEAVK KDNS¥H ERPQKPKAPVGHFYEPQAPSAE¥EMTSYVL AY TAQPAPTSED TSATNIVKWITKQQNAQGGFSSTQDTWALHA LSKYG TFTRTGKAAQ¥TIQSSGTFSSKFQ¥DNNNRLLLQQVSLPELPGEYSMKVTGEGCVYLQTSLKYNILPEKEEFPFALG VQTLPQTCDEPKAHTSFQISLSVSYTGSRSASIMAIVD¥KMVSGFIPLKPTVKMLERSNH¥SRTEVSSNHV IYLDKVSNQTLS LFFTVQDVPVRDLKPAIVKVYDYYETDEFAIAEYNAPCSKD GNA
407 MKLCVTVLSLL V FCSPALSAPMGSDPPTACCFSYTARKLPRNFVVDYYETSSLCSQPAWFQTKRSKQVCADPSET VQE YVYDLELN
408
• AGCACAGGACACAGCTGGGTTCTGAAGCTTCTGAGTTCTGCAGCCTCACCTCTGAGAAAACCTCTTTTCCACCAATACCATGAA
GCTCTGCGTGACTGTCCTGTCTCTCCTCATGCTAGTAGCTGCCTTCTGCTCTCCAGCGCTCTCAGCACCAATGGGCTCAGACCC TCCCACCGCCTGCTGCTTTTCTTACACCGCGAGGAAGCTTCCTCGCAACTTTGTGGTAGATTACTATGAGACCAGCAGCCTCTG
CTCCCAGCCAGCTGTGGTATTCCAAACCAAAAGAAGCAAGCAAGTCTGTGCTGATCCCAGTGAGACCTGGGTCCAGGAGTACGT
GTATGACCTGGAACTGAACTGAGCTGCTCAGAGACAGGAAGTCTTCAGGGAAGGTCACCTGAGCCCGGATGCTTCTCCATGAGA
CACATCTCCTCCATACTCAGGACTCCTCTCCGCAGTTCCTGTCCCTTCTCTTAATTTAATCTTTTTTATGTGCCGTGTTATTGT
. ATTAGGTGTCATTTCCATTATTTATATTAGTTTAGCCAAAGGATAAGTGTCCCCTATGGGGATGGTCCACTGTCACTGTTTCTC TGCTGTTGCAAATACATGGATAACACATTTGATTCTGTGTGTTTTCATAATAAAACTTTAAAATAAAATGCAGACAGTT
409
MESRGPLATSRL LLLLL LLRHTRQG ALRPV PTQSAHDPPAVH SNGPGQEPIAVMTFDLTKITKTSSSFEVRTWDPEGVI FYGDTNPKDD FMLGLRDGRPEIQ HNHWAQLTVGAGPRLDDGRWHQVEVKMEGDSVLLEVDGEEVLRLRQVSGPLTSKRHPIM RIALGGLLFPASNLR PLVPA'LDGCLRRDS LDKQAEISASAPTS RSCDVESNPGIFLPPGTQAEFN RDIPQPHAEPWAFSL DLGLKQAAGSGH LALGTPENPSWLSLHLQDQK LSSGSGPG DLPLVLGLPLQLKLSMSRVVLSQGSKMKALALPPLG APL LNLWAKPQGRLFLGALPGEDSSTSFCLNG WAQGQRLDVDQAL RSHEI THSCPQSPGNGTDASH
410 ATGGAGAGCAGAGGCCCACTGGCTACCTCGCGCCTGCTGCTGTTGCTGCTGTTGCTACTACTGCGTCACACCCGCCAGGGATGG GCCCTGAGACCTGTTCTCCCCACCCAGAGTGCCCACGACCCTCCGGCTGTCCACCTCAGCAATGGCCCAGGACAAGAGCCTATC GCTGTCATGACCTTTGACCTCACCAAGATCACAAAAACCTCCTCCTCCTTTGAGGTTCGAACCTGGGACCCAGAGGGAGTGATT TTTTATGGGGATACCAACCCTAAGGATGACTGGTTTATGCTGGGACTTCGAGACGGCAGGCCTGAGATCCAACTGCACAATCAC TGGGCCCAGCTTACGGTGGGTGCTGGACCACGGCTGGATGATGGGAGATGGCACCAGGTGGAAGTCAAGATGGAGGGGGACTCT GTGCTGCTGGAGGTGGATGGGGAGGAGGTGCTGCGCCTGAGACAGGTCTCTGGGCCCCTGACCAGCAAACGCCATCCCATCATG AGGATTGCGCTTGGGGGGCTGCTCTTCCCCGCTTCCAACCTTCGGTTGCCGCTGGTTCCTGCCCTGGATGGCTGCCTGCGCCGG GATTCCTGGCTGGACAAACAGGCCGAGATCTCAGCATCTGCCCCCACTAGCCTCAGAAGCTGTGATGTAGAATCAAATCCCGGG ATATTTCTCCCTCCAGGGACTCAGGCAGAATTCAATCTCCGAGACATTCCCCAGCCTCATGCAGAGCCCTGGGCCTTCTCTTTG GACCTGGGACTCAAGCAGGCAGCAGGCTCAGGCCACCTCCTTGCTCTTGGGACACCAGAGAACCCATCTTGGCTCAGTCTCCAC CTCCAAGATCAAAAGGTGGTGTTGTCTTCTGGGTCGGGGCCAGGGCTGGATCTGCCCCTGGTCTTGGGACTCCCTCTTCAGCTG AAGCTGAGTATGTCCAGGGTGGTCTTGAGCCAAGGGTCGAAGATGAAGGCCCTTGCCCTGCCTCCCTTAGGCCTGGCTCCCCTC CTTAACCTCTGGGCCAAGCCTCAAGGGCGTCTCTTCCTGGGGGCTTTACCAGGAGAAGACTCTTCCACCTCTTTTTGCCTGAAT GGCCTTTGGGCACAAGGTCAGAGGCTGGATGTGGACCAGGCCCTGAACAGAAGCCATGAGATCTGGACTCACAGCTGCCCCCAG AGCCCAGGCAATGGCACTGACGCTTCCCATTAA.
411
MADK TRIAIVNHDKCKPKKCRQECKKSCPWRMGKLCIEVTPQSKIAWISETL'CIGCGICIKKCPFGA S'IV1.LPSNLEKETT HRYCA AFKLHRLPIPRPGEVLGLVGTNGIGKSAALKI AGKQKPNLGKYDDPPDWQEILTYFRGSE QNYFTKILEDDLKAII KPQYVARFLR AKGT¥GSILDRKDETKTQAIVCQQLD THLKERNVEDLSGGELQRFACAV¥CIQKADIFMFDEPSSYLDVKQR KAAITIRSLINPDRYIIWEHDLSVLDYLSDFICC YGVPSAYGWTMPFSVREGINIF DGYVPTENLRFRDASLVFKVAET EEEVKKMCMYKYPGMKKKMGEFELAIVAGEFTDSEIMVMLGENGTGKTTFIRM AGR KPDEGGE¥P¥LNVSYKPQKISPKS TGSVRQ LHEKIRDAYTHPQFVTDVMKPLQIENIIDQE¥QTLSGGELQRVRLRLC GKPADVY IDEPSAYLDSEQRLMAARW KRFILHAKKTAFWEHDFIMATYLADRVIVFDGVPSKNT¥ANSPQTLLAGM KFLSQLEITFRRDPNNYRPRINKLKSIKDVEQ KKSGNYFFLDD 412
CCGGTCCTGAGACACGCTGTGTGGCTGAAAAGTGAAGGCAAGAGCTCATTTGGCCTCTGTGCTCCCCTCCGCAAGGGATCGTTT CTCCAGAAGAGCTGGATATTCTTTCGCCCAGTTATGGCAGACAAGTTAACGAGAATTGCTATTGTCAACCATGACAAATGTAAA CCTAAGAAATGTCGACAGGAATGCAAAAAGAGTTGTCCTGTAGTTCGAATGGGAAAATTATGCATAGAGGTTACACCCCAGAGC AAAATAGCATGGATTTCCGAAACTCTTTGTATTGGTTGTGGTATCTGTATTAAGAAATGCCCCTTTGGCGCCTTATCAATTGTC AATCTACCAAGCAACTTGGAAAAAGAAACCACACATCGATATTGTGCCAATGCCTTCAAACTTCACAGGTTGCCTATCCCTCGT CCAGGTGAAGTTTTGGGATTAGTTGGAACTAATGGTATTGGAAAGTCAGCTGCTTTAAAAATTTTAGCAGGAAAACAAAAGCCA AACCTTGGAAAGTACGATGATCCTCCTGACTGGCAGGAGATTTTGACTTATTTCCGTGGATCTGAATTACAAAATTACTTTACA AAGATTCTAGAAGATGACCTAAAAGCCATCATCAAACCTCAATATGTAGCCAGATTCCTAAGGCTGGCAAAGGGGACAGTGGGA TCTATTTTGGACCGAAAAGATGAAACAAAGACACAGGCAATTGTATGTCAGCAGCTTGATTTAACCCACCTAAAAGAACGAAAT GTTGAAGATCTTTCAGGAGGAGAGTTGCAGAGATTTGCTTGTGCTGTCGTTTGCATACAGAAAGCTGATATTTTCATGTTTGAT GAGCCTTCTAGTTACCTAGATGTCAAGCAGCGTTTAAAGGCTGCTATTACTATACGATCTCTAATAAATCCAGATAGATATATC ATTGTGGTGGAACATGATCTAAGTGTATTAGACTATCTCTCCGACTTCATCTGCTGTTTATATGGTGTACCAAGCGCCTATGGA GTTGTCACTATGCCTTTTAGTGTAAGAGAAGGCATAAACATTTTTTTGGATGGCTATGTTCCAACAGAAAACTTGAGATTCAGA GATGCATCACTTGTTTTTAAAGTGGCTGAGACAGCAAATGAAGAAGAAGTTAAAAAGATGTGTATGTATAAATATCCAGGAATG AAGAAAAAAATGGGAGAATTTGAGCTAGCAATTGTAGCTGGAGAGTTTACAGATTCTGAAATTATGGTGATGCTGGGGGAAAAT GGAACGGGTAAAACGACATTTATCAGAATGCTTGCTGGAAGACTTAAACCTGATGAAGGAGGAGAAGTACCAGTTCTAAATGTC AGTTATAAGCCACAGAAAATTAGTCCCAAATCAACTGGAAGTGTTCGCCAGTTACTACATGAAAAGATAAGAGATGCTTATACT CACCCACAATTTGTGACCGATGTAATGAAGCCTCTGCAAATTGAAAACATCATTGATCAAGAGGTGCAGACATTATCTGGTGGT GAACTACAGCGAGTACGTTTACGCCTTTGCTTGGGCAAACCTGCTGATGTCTATTTAATTGATGAACCATCTGCATATTTGGAT TCTGAGCAAAGACTGATGGCAGCTCGAGTTGTCAAACGTTTCATACTCCATGCAAAAAAGACAGCCTTTGTTGTGGAACATGAC TTCATCATGGCCACCTATCTAGCGGATCGCGTCATCGTTTTTGATGGTGTTCCATCTAAGAACACAGTTGCAAACAGTCCTCAA ACCCTTTTGGCTGGCATGAATAAATTTTTGTCTCAGCTTGAAATTACATTCAGAAGAGATCCAAACAACTATAGGCCACGAATA AACAAACTTAATTCAATTAAGGATGTAGAACAAAAGAAGAGTGGAAACTACTTTTTCTTGGATGATTAGACTGACTCTGAGAAT ATTGATAAGCCATTTATTAAAAGGAGTATTTACTAGAATTTTTTGTCATATAAAACTTGAATCAGGATTTTATGCCCCACATAC TCTGGAACTTGAAGTATAATATACTTAATATAACATAAAAAGCCAGTTGGGTTCTAAATTGTAGTTGAAACACAGAAAATGCCA CTTTTCTGTTCCTGAAGAGGCTCTTTTGTGCATAATATTCTAAAATGAAGACATTTCAAGCTATACAAATTACTTCCAAGTTTT CATGATGTATGGGAAGATTTTCAGTAGGTGTATTATATTCACGGTACCAAATGCTGACCAGTGTTGCTCCATTTTTTAAATCTT GAAAAGGGTTTCTGTACTTACCTGGTTTGCCAAGTATGCCAGTGTAATGAAACTGCCCTTATTTTAAAAGCCAGTCAAAGATTC CACTGATTGACATTTGATAAATAAACATCAGGATTATGTTTATTGTTTGTTTTCAGTCTTTGCACTATATTACCAGTATATGGT TTCCGAGGAAGATTATCTACTGCAAAACACCACTGTTGGAAAAATAGGTATTTTTAAATTGTTTTTAATCCTTTTTTGGTGCTT TTAAACATGTTTAAGCAAAAACCAATTCAGTCCATTCCCCGCAAAAAACCCCTAACTTTACTCTGAACTTTTTTTGTTTTTGCA TTCCATGAGGTTCTGTATTCAGTCATTCTCTAGGTAATGTCATTTTTGTACACATATATTTATATAATCACTGATTGAGATTTA GGAAAAAGCATTTCTAAAGAATATTTGCTTCCCTTAGAACTACAGACTCGAAATCTTTAAAGATGGTGCCTAAGCATCTATGTA TTTTTTTTAAGTTCCACAGATTTTTCTGTTGGGCAGGCCAAGGATTATAAACCACTTCCCTAAAGGCAACATTAATGCAAAAGT CCCCAGATGGCAATACAAAGTATCCCCTGGTACCACATATATTCATTTGTGAGTTTGGATATAGAGCACATTATCTAAACCATT TTGTAGTTCCAAAAACCCATCTAAATTTCTTGAGTTCCTGAATTTTGAACAGGATTACCTGGAGCCTGGAGCCACTTTAAGTTG* TACTTCTGACTAAACTGGAATTATGAGTGAGGAAGAGTGTTTACTAAATAAATGACTGGGGCAAGCAAAATTGAGGAGGAAATT AGAAACTGTTTGACAAACTTTAAGAGCTACTTGAAATAACAGAAGTCTTGATTAATATGCAAATAATGGCTAGAAAGTATGGTT TAACTGGACCCTATTATGCCTTTTAAAAATAATTTCAGTAACCCATAAATACATGTTGTAAAAAATTCAAATATACAGAATGGA ATAAAAAAATGATCTCCCTTTATTACCCTCCCAAAGGTTACCAGCGTTTGAATTTAATAATGTATATTCTTTCATGCTTTTTTC TGTGCACTTACCTAAGTGTGAATATGTAAAGGGTTTGTTTTGTATACAAATGGGATTATACTAAAATAAGTAATGCCTATTTTT AAGGATAGGTTAAATTTGTGAATGATCATTTCAAATATATTGAATAAAATAAGCAAAAGCTATTGTTATTTACTGATCCTGAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 413
MMVKTLNPKAEVARAQ LAWIS RGLQDVLRTNLGPKGTMML¥SGAGDIKLTKDGNV LHEMQIQHPTASLIAKVATAQ DDITGDGTTSNV IIGE LKQAD YISEGLHPRIITEGFEAAKEKA QFLEEVKVSREMDRETLID¥ARTS RTKVHAE ADVL TEAWDSI AIKKQDEPID FMIEIMEMKHKSETDTSLIRGLVLDHGARHPDMKKR¥EDAYILTCN¥SLEYEKTEVNSGFFYKS AEEREK VKAERKFIEDRVKKIIELKRKVCGDSDKGFWINQKGIDPFS DA SKEGIVALRRAKRRNMER TLACGGVALNSF DD SPDC GHAGLVYEYTLGEEKFTFIEKCNNPRSVTLLIKGPNKHTLTQIKDAVRDGLRAVKNAIDDGCWPGAGAVEVAMAE A IKHKPSVKGRAQLGVQAFADALLIIPKV AQNSGFDLQET VKIQAEHSESGQLVGVD NTGEPMVAAEVGVWDNYCVKKQL HSCTVIATNILLVDEIMRAGMSS KG
414
CGAGAAGACCCGGATAGTTCCTCCCGGCCACGCCGCGCCGGCTCTGGGCACTCAGCATCGTTTCCTTTTCCTCCGCTGGAGCAG ■CTATGGCGGCGGTGAAGACCCTGAACCCCAAGGCCGAGGTGGCCCGAGCGCAGGCGGCGCTGGCGGTCAACATCAGCGCAGCGC GGGGTCTGCAGGACGTGCTAAGGACCAACCTGGGGCCCAAGGGCACCATGAAGATGCTCGTTTCTGGCGCTGGAGACATCAAAC TTACTAAAGACGGCAATGTGCTGCTTCACGAAATGCAAATTCAACACCCAACAGCTTCCTTAATAGCAAAGGTAGCAACAGCCC AGGATGATATAACTGGTGATGGTACGACTTCTAATGTCCTAATCATTGGAGAGCTGCTGAAACAGGCGGATCTCTACATTTCTG AAGGCCTTCATCCTAGAATAATCACTGAAGGATTTGAAGCTGCAAAGGAAAAGGCCCTTCAGTTTTTGGAAGAAGTCAAAGTAA GCAGAGAGATGGACAGGGAAACACTTATAGATGTGGCCAGAACATCTCTTCGTACTAAAGTTCATGCTGAACTTGCAGATGTCT TAACAGAGGCTGTAGTGGACTCCATTTTGGCCATTAAAAAGCAAGATGAACCTATTGATCTCTTCATGATTGAGATCATGGAGA TGAAACATAAATCTGAAACTGATACAAGCTTAATCAGAGGGCTTGTTTTGGACCACGGAGCACGGCATCCTGATATGAAGAAAA GGGTGGAGGATGCATACATCCTCACTTGTAACGTGTCATTAGAGTATGAGAAAACAGAAGTGAATTCTGGCTTTTTTTACAAGA GTGCAGAAGAGAGAGAAAAACTCGTGAAAGCTGAAAGAAAATTCATTGAAGATAGGGTTAAAAAAATAATAGAACTGAAAAGGA AAGTCTGTGGCGATTCAGATAAAGGATTTGTTGTTATTAATCAAAAGGGAATTGACCCCTTTTCCTTAGATGCTCTTTCAAAAG AAGGCATAGTCGCTCTGCGCAGAGCTAAAAGGAGAAATATGGAGAGGCTGACTCTTGCTTGTGGTGGGGTAGCCCTGAATTCTT TTGACGACCTAAGTCCTGACTGCTTGGGACATGCAGGACTTGTATATGAGTATACATTGGGAGAAGAGAAGTTTACCTTTATTG AGAAATGTAACAACCCTCGTTCTGTCACATTATTGATCAAAGGACCAAATAAGCACACACTCACTCAGATCAAAGATGCAGTGA GGGACGGCTTGAGGGCTGTCAAAAATGCTATTGATGATGGCTGTGTGGTTCCAGGTGCTGGTGCCGTGGAAGTGGCAATGGCAG ' AAGCCCTGATTAAACATAAGCCCAGTGTAAAGGGCAGGGCACAGCTTGGAGTCCAAGCATTTGCTGATGCATTGCTCATTATTC CCAAGGTTCTTGCTCAGAACTCTGGTTTTGACCTTCAGGAAACATTAGTTAAAATTCAAGCAGAACATTCAGAATCAGGTCAGC TTGTGGGTGTGGACCTGAACACAGGTGAGCCAATGGTGGCAGCAGAAGTAGGCGTATGGGATAACTATTGTGTAAAGAAACAGC TTCTTCACTCCTGCACTGTGATTGCCACCAACATTCTCTTGGTTGATGAGATCATGCGAGCTGGAATGTCTTCTCTGAAAGGTT GAATTGAAGCTTCCTCTGTATCTGAATCTTGAAGACTGCAAAGTGATCCTGAGGATTACAGCTGTGGAATTTTTGTCCAAGCTT CAAATAATTTTGAAAGAAATTTTCCCATATGAAAAAAGGAGAGAACACTGGCATCTGTTGAAATTTGGAAGTTCTGAAATTATA GTATTTTTAAAAATTGCACTGAAGTGTATACACATAAAGCAGGTCTTTTATCCAGTGAACAGGATGTTTTGCTTTAGCAGCAGT GACATAAAATTCCATGTTAGATAAGCATATGTTACTTACCTTGTTATTAAATATTTCTTGAAAAGCAGGCCACGAAGG
415
MTAPGAAGRCPPTTWLGSLLLLVC LASRSITEEVSEYCSHMIGSGHLQSLQRLIDSQMETSCQITFEFVDQEQLKDPVCYLKK AFLLVQDIMEDTMRFRDNTANPIAIVQ QE SLRLKSCFTKDYEEHDKACVRTFYETPLQLLEKVKNVFNETKN LDKDNIFS KNC SFAECSSQDVVTKPDCNCLYPKAIPSSDPASVSPHQPLAPSMAPVAG TWEDSEGTEGSSLLPGEQPLHTVDPGSAKQR PPRSTCQSFEPPETPWKDSTIGGSPQPRPSVGAFNPGMEDILDSAMGTMVPEEASGEASEIPVPQGTELSPSRPGGGSMQTE PARPSNF SASSPLPASAKGQQPADVTATALPRVGPVMPTGQD HTPQKTDHPSAL RDPPEPGSPRISSLRPQA SNPSTLS AQPQLSRSHSSGSVLP GELEGRRSTRDRTSPAEPEAAPASEGAARP PRFNSVPLTDTGHERQSEGSSSPQ QESVFHL VPS VI VL AVGGLLFYRWRRRSHQEPQRADSPLEQPEGSPLTQDDRQVEI-PV
416
CCTGGGTCCTCTCGGCGCCAGAGCCGCTCTCCGCATCCCAGGACAGCGGTGCGGCCCTCGGCCGGGGCGCCCACTCCGCAGCAG CCAGCGAGCCAGCTGCCCCGTATGACCGCGCCGGGCGCCGCCGGGCGCTGCCCTCCCACGACATGGCTGGGCTCCCTGCTGTTG TTGGTCTGTCTCCTGGCGAGCAGGAGTATCACCGAGGAGGTGTCGGAGTACTGTAGCCACATGATTGGGAGTGGACACCTGCAG TCTCTGCAGCGGCTGATTGACAGTCAGATGGAGACCTCGTGCCAAATTACATTTGAGTTTGTAGACCAGGAACAGTTGAAAGAT CCAGTGTGCTACCTTAAGAAGGCATTTCTCCTGGTACAAGACATAATGGAGGACACCATGCGCTTCAGAGATAACACCGCCAAT CCCATCGCCATTGTGCAGCTGCAGGAACTCTCTTTGAGGCTGAAGAGCTGCTTCACCAAGGATTATGAAGAGCATGACAAGGCC TGCGTCCGAACTTTCTATGAGACACCTCTCCAGTTGCTGGAGAAGGTCAAGAATGTCTTTAATGAAACAAAGAATCTCCTTGAC AAGGACTGGAATATTTTCAGCAAGAACTGCAACAACAGCTTTGCTGAATGCTCCAGCCAAGATGTGGTGACCAAGCCTGATTGC AACTGCCTGTACCCCAAAGCCATCCCTAGCAGTGACCCGGCCTCTGTCTCCCCTCATCAGCCCCTCGCCCCCTCCATGGCCCCT GTGGCTGGCTTGACCTGGGAGGACTCTGAGGGAACTGAGGGCAGCTCCCTCTTGCCTGGTGAGCAGCCCCTGCACACAGTGGAT CCAGGCAGTGCCAAGCAGCGGCCACCCAGGAGCACCTGCCAGAGCTTTGAGCCGCCAGAGACCCCAGTTGTCAAGGACAGCACC ATCGGTGGCTCACCACAGCCTCGCCCCTCTGTCGGGGCCTTCAACCCCGGGATGGAGGATATTCTTGACTCTGCAATGGGCACT AATTGGGTCCCAGAAGAAGCCTCTGGAGAGGCCAGTGAGATTCCCGTACCCCAAGGGACAGAGCTTTCCCCCTCCAGGCCAGGA GGGGGCAGCATGCAGACAGAGCCCGCCAGACCCAGCAACTTCCTCTCAGCATCTTCTCCACTCCCTGCATCAGCAAAGGGCCAA CAGCCGGCAGATGTAACTGCTACAGCCTTGCCCAGGGTGGGCCCCGTGATGCCCACTGGCCAGGACTGGAATCACACCCCCCAG AAGACAGACCATCCATCTGCCCTGCTCAGAGACCCCCCGGAGCCAGGCTCTCCCAGGATCTCATCACTGCGCCCCCAGGCCCTC AGCAACCCCTCCACCCTCTCTGCTCAGCCACAGCTTTCCAGAAGCCACTCCTCGGGCAGCGTGCTGCCCCTTGGGGAGCTGGAG GGCAGGAGGAGCACCAGGGATCGGACGAGCCCCGCAGAGCCAGAAGCAGCACCAGCAAGTGAAGGGGCAGCCAGGCCCCTGCCC CGTTTTAACTCCGTTCCTTTGACTGACACAGGCCATGAGAGGCAGTCCGAGGGATCCTCCAGCCCGCAGCTCCAGGAGTCTGTC TTCCACCTGCTGGTGCCCAGTGTCATCCTGGTCTTGCTGGCTGTCGGAGGCCTCTTGTTCTACAGGTGGAGGCGGCGGAGCCAT CAAGAGCCTCAGAGAGCGGATTCTCCCTTGGAGCAACCAGAGGGCAGCCCCCTGACTCAGGATGACAGACAGGTGGAACTGCCA GTGTAGAGGGAATTCTAAGCTGGACGCACAGAACAGTCTCTTCGTGGGAGGAGACATTATGGGGCGTCCACCACCACCCCTCCC TGGCCATCCTCCTGGAATGTGGTCTGCCCTCCACCAGAGCTCCTGCCTGCCAGGACTGGACCAGAGCAGCCAGGCTGGGGCCCC TCTGTCTCAACCCGCAGACCCTTGACTGAATGAGAGAGGCCAGAGGATGCTCCCCATGCTGCCACTATTTATTGTGAGCCCTGG AGGCTCCCATGTGCTTGAGGAAGGCTGGTGAGCCCGGCTCAGGACCCTCTTCCCTCAGGGGCTGCAGCCTCCTCTCACTCCCTT CCATGCCGGAACCCAGGCCAGGGACCCACCGGCCTGTGGTTTGTGGGAAAGCAGGGTGCACGCTGAGGAGTGAAACAACCCTGC ACCCAGAGGGCCTGCCTGGTGCCAAGGTATCCCAGCCTGGACAGGCATGGACCTGTCTCCAGACAGAGGAGCCTGAAGTTCGTG GGGCGGGACAGCCTCGGCCTGATTTCCCGTAAAGGTGTGCAGCCTGAGAGACGGGAAGAGGAGGCCTCTGCACCTGCTGGTCTG CACTGACAGCCTGAAGGGTCTACACCCTCGGCTCACCTAAGTCCCTGTGCTGGTTGCCAGGCCCAGAGGGGAGGCCAGCCCTGC CCTCAGGACCTGCCTGACCTGCCAGTGATGCCAAGAGGGGGATCAAGCACTGGCCTCTGCCCCTCCTCCTTCCAGCACCTGCCA GAGCTTCTCCAGCAGGCCAAGCAGAGGCTCCCCTCATGAAGGAAGCCATTGCACTGTGAACACTGTACCTGCCTGCTGAACAGC CTCCCCCCGTCCATCCATGAGCCAGCATCCGTCCGTCCTCCACTCTCCAGCCTCTCCCCAGCCTCCTGCACTGAGCTGGCCTCA CCAGTCGACTGAGGGAGCCCCTCAGCCCTGACCTTCTCCTGACCTGGCCTTTGACTCCCCGGAGTGGAGTGGGGTGGGAGAACC TCCTGGGCCGCCAGCCAGAGCCGCTCTTTAGGCTGTGTTCTTCGCCCAGGTTTCTGCATCTTCCACTTTGACATTCCCAAGAGG GAAGGGACTAGTGGGAGAGAGCAAGGGAGGGGAGGGCACAGACAGAGAGCCTACAGGGCGAGCTCTGACTGAAGATGGGCCTTT GAAATATAGGTATGCACCTGAGGTTGGGGGAGGGTCTGCACTCCCAAACCCCAGCGCAGTGTCCTTTCCCTGCTGCCGACAGGA ACCTGGGGCTGAGCAGGTTATCCCTGTCAGGAGCCCTGGACTGGGCTGCATCTCAGCCCCACCTGCATGGTATCCAGCTCCCAT CCACTTCTCACCCTTCTTTCCTCCTGACCTTGGTCAGCAGTGATGACCTCCAACTCTCACCCACCCCCTCTACCATCACCTCTA ACCAGGCAAGCCAGGGTGGGAGAGCAATCAGGAGAGCCAGGCCTCAGCTTCCAATGCCTGGAGGGCCTCCACTTTGTGGCCAGC CTGTGGTGCTGGCTCTGAGGCCTAGGCAACGAGCGACAGGGCTGCCAGTTGCCCCTGGGTTCCTTTGTGCTGCTGTGTGCCTCC TCTCCTGCCGCCCTTTGTCCTCCGCTAAGAGACCCTGCCCTACCTGGCCGCTGGGCCCCGTGACTTTCCCTTCCTGCCCAGGAA AGTGAGGGTCGGCTGGCCCCACCTTCCCTGTCCTGATGCCGACAGCTTAGGGAAGGGCACTGAACTTGCATATGGGGCTTAGCC TTCTAGTCACAGCCTCTATATTTGATGCTAGAAAACACATATTTTTAAATGGAAGAAAAATAAAAAGGCATTCCCCCTTCATCC CCCTACCTTAAACATATAATATTTTAAAGGTCAAAAAAGCAATCCAACCCACTGCAGAAGCTCTTTTTGAGCACTTGGTGGCAT CAGAGCAGGAGGAGCCCCAGAGCCACCTCTGGTGTCCCCCAGGCTACCTGCTCAGGAACCCCTTCTGTTCTCTGAGAACTCAAC AGAGGACATTGGCTCACGCACTGTGAGATTTTGTTTTTATACTTGCAACTGGTGAATTATTTTTTATAAAGTCATTTAAATATC TATTTAAAAGATAGGAAGCTGCTTATATATTTAATAATAAAAGAAGTGCACAAGCTGCCGTTGACGTAGCTCGAG
417 MSVPAFIDISEEDQAAELRAYLKSKGAEISEENSEGGLHVDLAQIIEACDVCLKEDDKDVESWNSWSL LI EPDKQEA IE SLCEKLVKFREGERPS R QLLSN FHGMDKNTPVRYTVYCS IEVVASCGAIQYIPTELDQVRKWISD TTEKKHT LR L YEALADCKKSDAASKVMVELLGSYTEDNASQARVDAHRCI¥EPLKDPNAFLFDHL TLKPVKFLEGELIHDLLTIFVSAKLASY VKFYQ KDFIDSLGLLHEQ KMRLLTFMG IENKEISFDTMQQE QIGADDVEAFVIDAVRTKWYCKIDQTQRKVVVSH STHRTFGKQR QQLYDTLNAWKQNLNKVKNSLLSLSDT 418
GGGTCGGCGTGGTCTTGCGAGTGGAGTGTCCGCTGTGCCCGGGCCTGCACCATGAGCGTCCCGGCCTTCATCGACATCAGTGAA GAAGATCAGGCTGCTGAGCTTCGTGCTTATCTGAAATCTAAAGGAGCTGAGATTTCAGAAGAGAACTCGGAAGGTGGACTTCAT GTTGATTTAGCTCAAATTATTGAAGCCTGTGATGTGTGTCTGAAGGAGGATGATAAAGATGTTGAAAGTGTGGTGAACAGTGTG GTATCCCTACTCTTGATCCTGGAACCAGACAAGCAAGAAGCTTTGATTGAAAGCCTATGTGAAAAGCTGGTCAAATTTCGCGAA GGTGAACGCCCGTCTCTGAGACTGCAGTTGTTAAGCAACCTTTTCCACGGGATGGATAAGAATACTCCTGTAAGATACACAGTG TATTGCAGCCTTATTGAAGTGGTAGCATCTTGTGGGGCCATCCAGTACATCCCAACTGAGCTGGATCAAGTTAGAAAATGGATT TCTGACTGGAATCTCACCACTGAAAAAAAGCACACCCTTTTAAGACTACTTTATGAGGCACTTGCGGATTGTAAGAAGAGTGAT GCTGCTTCAAAAGTCATGGTGGAATTGCTCGGAAGTTACACAGAGGACAATGCTTCCCAGGCTCGAGTTGATGCCCACAGGTGT ATTGTCGAACCATTGAAAGATCCAAATGCATTTCTTTTTGACCAGCTTCTTACTTTAAAACCAGTCAAGTTTTTGGAAGGCGAG CTTATTCATGATCTTTTAACCATTTTTGTGAGTGCTAAATTGGCATCATATGTCAAGTTTTATCAGAATAATAAAGACTTCATT GATTCACTTGGCCTGTTACATGAACAGAATATGGCAAAAAT.GAGACTACTTACTTTTATGGGAATGGCAATAGAAAATAAGGAA ATTTCTTTTGACACAATGCAGCAAGAACTTCAGATTGGAGCTGATGATGTTGAAGCATTTGTTATTGACGCCGTAAGAACTAAA ATGGTCTACTGCAAAATTGATCAGACCCAGAGAAAAGTAGTTGTCAGTCATAGCACACATCGGACATTTGGAAAACAGCGGTGG CAACAACTGTATGACACACTTAATGCCTGGAAACAAAATCTGAACAAAGTGAAAAACAGCCTTTTGAGTCTTTCCGATACCTGA GTTTTTATGCTTATAATTTTTGTTCTTTGAAAAAAAAGCCCTAAATCATAGTAAGACATTATAAACCAAAAAA
419 ' "
MSAATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVL HGLASLLGLVENGVILFVVGCRMRQTWTTVHLALSDLLASAS PFFTYF A¥GHS ELGTTFCKLHSSIFFLNMFASGFLLSAISLDRCLQWRPVWAQNHRTVAAAHKVCLVWALAVLNTVPYF¥ FRDTISRLDGRIMCYYNV LLNPGPDRDATCNSRQAALAVSKF LAFL¥PLAIIASSHAAVS R QHRGRRRPGRFVRLVAAW AAFALCWGPYHVFSLLEARAHANPGLRPVWRGLPFVTSLAFFNSVA P¥LYVLTCPD LRKLRRSLRTVLES¥VDDSELGGA GSSRRRRTSSTARSASP ALCSRPEEPRGPAR LGWL GSCAASPQTGPLNRA SSTSS
420
CAGCCTCCCTCTCCCACCTCTGTCTGCCCGCTGCCTCTTGTCTAGCTGeTGTCAGGAGCTGACTGCCTCCAGGGCTGGAATCCT GTGCTCCCTCTGTGCCCAGAGCCCCACGATGTCGGCCAACGCCACACTGAAGCCACTCTGCCCCATCCTGGAGCAGATGAGCCG TCTCCAGAGCCACAGCAACACCAGCATCCGCTACATCGACCACGCGGCCGTGCTGCTGCACGGGCTGGCCTCGCTGCTGGGCCT GGTGGAGAATGGAGTCATCCTCTTCGTGGTGGGCTGCCGCATGCGCCAGACCGTGGTCACCACCTGGGTGCTGCACCTGGCGCT GTCCGACCTGTTGGCCTCTGCTTCCCTGCCCTTCTTCACCTACTTCTTGGCCGTGGGCCACTCGTGGGAGCTGGGCACCACCTT CTGCAAACTGCACTCCTCCATCTTCTTTCTCAACATGTTCGCCAGCGGCTTCCTGCTCAGCGCCATCAGCCTGGACCGCTGCCT GCAGGTGGTGCGGCCGGTGTGGGCGCAGAACCACCGCACCGTGGCCGCGGCGCACAAAGTCTGCCTGGTGCTTTGGGCACTAGC GGTGCTCAACACGGTGCCCTATTTCGTGTTCCGGGACACCATCTCGCGGCTGGACGGGCGCATTATGTGCTACTACAATGTGCT GCTCCTGAACCCGGGGCCTGACCGCGATGCCACGTGCAACTCGCGCCAGGCGGCCCTGGCCGTCAGCAAGTTCCTGCTGGCCTT CCTGGTGCCGCTGGCGATCATCGCCTCGAGCCACGCGGCCGTGAGCCTGCGGTTGCAGCACCGCGGCCGCCGGCGGCCAGGCCG CTTCGTGCGCCTGGTGGCAGCCGTCGTGGCCGCCTTCGCGCTCTGCTGGGGGCCCTACCACGTGTTCAGCCTGCTGGAGGCGCG GGCGCACGCAAACCCGGGGCTGCGGCCGCTCGTGTGGCGCGGGCTGCCCTTCGTCACCAGCCTGGCCTTCTTCAACAGCGTGGC CAACCCGGTGCTCTACGTGCTCACCTGCCCCGACATGCTGCGCAAGCTGCGGCGCTCGCTGCGCACGGTGCTGGAGAGCGTGCT GGTGGACGACAGCGAGCTGGGTGGCGCGGGAAGCAGCCGCCGCCGCCGCACCTCCTCCACCGCCCGCTCGGCCTCCCCTTTAGC TCTCTGCAGCCGCCCGGAGGAACCGCGGGGCCCCGCGCGTCTCCTCGGCTGGCTGCTGGGCAGCTGCGCAGCGTCCCCGCAGAC GGGCCCCCTGAACCGGGCGCTGAGCAGCACCTCGAGTTAGAACCCGGCCCACGTAGGGCGGCACTCACACGCGAAAGTATCACC AGGGTGCCGCGGTTCAATTCGATATCCGGACTCCTGCCGCAGTGATCAAAGTCCGAGGGGCGGGACCCAGGCACCTGCATTTTA AAGCGCCCCGGGAGACTCTGAATCTTTTTCAGAAACAGTGAGTTAAAGCAGTGCTTCTCAAACCTTGATGTGCCTGTGAATCAC CTAGGGGTCTTGTTAAGTGCAGTCTGATCCAGGAGGCCGGGGCCGGGTACTGAGAGTCTGCACTTAACAAGCTCCCAGGCCGAG AAGCCAGTGCGGCAGGTTCACAGGCGAGGCCTGGAGTAACACAAAGTGAAACTCGTAATAGACTTCCCACTCTAGGGCAGTGGA GTCGGAAGGGCACACGGGGTGCGTCTCCCCGGAGTTCAGTTTTACCAGATGATGGGGGAGGGGGGAAGGAGTTTTATGTTAAAC CATCCATGTATTTTTGGAGAAGAGAGAGGAAAGGTTTGAGAAGCACTGTTCCAGCCTGCCCTCTTCATTTAGCCAATGCTTACT GCGCTAGACGCTTCATCCCACAATCTTAAGGGGCAGCTTCTATTAGCCAGTCTTTACAGCTGAGCACATTCTGGCTCAGGGAGG TTAAGTGACTTGCCCAGTTTCAGGGCTAACGACCACAGGGTCTGCACTCTAACCCTAGGCATCACATGCTCAATGACTCTCTGG TGAGCGAGGACATTCTCTGACCTACTCGAGGGACTTAAGATGCTACCTTGTGACCCAGCACTGCCCAAAGTGCTTCCAAGGCAG AAGCAGCAGGGGATGGCGTGGTCAAGCACTCGGGAAACCTGGGGCTAATCAAATCCAATGGGGGAAATGACTAAAAGTCTTCGG TCGTTAGAAGTTGAATGGGCACAGCAACTCTAAGACTACAGCACACGTCATTTCTTAGCTAAGCGGACCAGCCTCCCTGTCGGC CTGGTGTTCTGTGGGATCCCTCTGGGCACTGGTAATCCCAAGATCTGTGCAGCCCCGCCTCCAGGCCACATGGGGCTGGGCAGC TACCATTTCCCTTTTGCGGATGGGAGGGGTAACTTGCACCTCTGACCTATCACTTCCACTGCACCCCGTCTCATTCCTCCACCT GCCGTGGACTTGGGGTCAGAGACTGCTGTGTTTGAGCTCTGCAGCCCAGGGACCGAAAAGTTGGTGTCAATGAATTTTGCTTGG TGGATGAAATGTCAGTGGAAGAAGCAGATGAGAAACTCTTGAGATCTTGGTCCTGTGTTTTTTCTGCCACCAAAGGCCAGGGTC ACTGAAGGCCTGGCCCACAGCAGGTGCTGAGCAAAGGGAACAGTGAGGTGCCCAGCTAGCTGCAGAGCCACCCTGTGTTGACAC CTCGCCCCTGCTCCCTCCCATCCCTTCCCCCTTTACTCATAGCACTTCCCCCATTGGACACGTGGTGCATTTTGCTTGTTTATT ATGTTTTCTCTCCATCAGAATGAAAGCTCCTCGAGGGCAGGGACTTTGGTCTATTGTCTGTATTTGCCGGTGCCTAGGATTGTG CCTGTATGCAACAGGCACTCAATAAATATTTTTGCTGTAGACTGG 421
MASTSTTIRSHSSSRRGFSASSARLPGVSRSGFSSISVSRSRGSGGLGGACGGAGFGSRS YGLGGSKRISIGGGSCAISGGYG SRAGGSYGFGGAGSGFGFGGGAGIGFGLGGGAGLAGGFGGPGFPVCPPGGIQEVTVNQSLLTP NLQIDPAIQR¥RAEEREQIK T raKFASFIDK¥RFLEQQNKV DTK T LQEQGTKT¥RQNLEP FEQYIM RRQLDSI¥GERGRLDSELRNMQDLVED K K YEDEINKRTMENEFVT KKDVDMYMKVELQAKADTLTDEINF RALYDAELSQMQTHISDTS LSMDNMR LDLDSIIAE ¥I<-AQYEEIAQRSRAEAES YQTKYEELQVTAGRHGDDLRNTKQEIAEINRMIQR RSEIDHVKKQCA LQAAIADAEQRGEMAL KDArøKLEG EDALQKAKQDLAR LKEYQELMNVKLALD¥EIATYRKLLEGEECRLNGEGVGQVl\IISWQSTVSSGYGGASGVG SGLGLGGGSSYSYGSGLGVGGGFSSSSGRATGGG SSVGGGSSTIKYTTTSSSSRKSYKH
422
ATGGCCAGCACATCCACCACCATCAGGAGCCACAGCAGCAGCCGCCGGGGTTTCAGTGCCAGCTCAGCCAGGCTCCCTGGGGTC AGCCGCTCTGGCTTCAGCAGCATCTCCGTGTCCCGCTCCAGGGGCAGTGGTGGCCTGGGTGGCGCATGTGGAGGAGCTGGCTTT GGCAGCCGCAGTCTGTATGGCCTGGGGGGCTCCAAGAGGATCTCCATTGGAGGGGGCAGCTGTGCCATCAGTGGCGGCTATGGC AGCAGAGCCGGAGGCAGCTATGGCTTTGGTGGCGCCGGGAGTGGATTTGGTTTCGGTGGTGGAGCCGGCATTGGCTTTGGTCTG GGTGGTGGAGCCGGCCTTGCTGGTGGCTTTGGGGGCCCTGGCTTCCCTGTGTGCCCCCCTGGAGGCATCCAAGAGGTCACTGTC AACCAGAGTCTCCTGACTCCCCTCAACCTGCAAATTGACCCCGCCATCCAGCGGGTGCGGGCCGAGGAGCGTGAGCAGATCAAG ACCCTCAACAACAAGTTTGCCTCCTTCATCGACAAGGTGCGGTTCCTAGAGCAGCAGAACAAGGTTCTGGACACCAAGTGGACC CTGCTGCAGGAGCAGGGCACCAAGACTGTGAGGCAGAACCTGGAGCCGTTGTTCGAGCAGTACATCAACAACCTCAGGAGGCAG CTGGACAGCATCGTGGGGGAACGGGGTCGTCTGGACTCGGAGCTGAGAAACATGCAGGACCTGGTGGAGGACCTCAAGAACAAA TATGAGGATGAAATCAACAAGCGCACAGCAGCAGAGAATGAATTTGTGACTCTGAAGAAGGATGTGGATGCTGCCTACATGAAC AAGGTTGAACTGCAAGCCAAGGCAGACACTCTTACAGATGAGATCAACTTCCTGAGAGCCTTGTATGATGCAGAGCTGTCCCAG ATGCAGACCCACATCTCAGACACATCCGTGGTGCTATCCATGGACAACAACCGCAACCTGGACCTGGACAGCATCATCGCTGAG GTCAAGGCCCAATATGAGGAGATTGCTCAGAGGAGCAGGGCTGAGGCTGAGTCCTGGTACCAGACAAAGTACGAGGAGCTGCAG GTCACAGCAGGCAGACATGGGGACGACCTGCGCAACACCAAGCAGGAGATTGCTGAGATCAACCGCATGATCCAGAGGCTGAGA TCTGAGATCGACCACGTCAAGAAGCAGTGTGCCAACCTACAGGCTGCCATTGCTGATGCTGAGCAGCGTGGGGAGATGGCCCTC AAGGATGCTAAGAACAAGCTGGAAGGGCTGGAGGATGCCCTGCAGAAGGCCAAGCAGGACCTGGCCCGGCTGCTGAAGGAGTAC CAGGAGCTGATGAACGTCAAGCTGGCCCTGGACGTGGAGATCGCCACCTACCGCAAGCTGCTGGAGGGCGAGGAGTGCAGGCTG AATGGCGAAGGCGTTGGACAAGTCAACATCTCTGTAGTGCAGTCCACCGTCTCCAGTGGCTATGGCGGTGCCAGCGGTGTCGGC AGTGGCTTAGGCCTGGGTGGAGGAAGCAGCTACTCCTATGGCAGTGGTCTTGGCGTTGGAGGCGGCTTTAGTTCCAGCAGCGGC AGAGCCACTGGGGGTGGCCTCAGCTCTGTTGGAGGCGGCAGTTCCACCATCAAGTACACCACCACCTCCTCCTCCAGCAGGAAG AGCTACAAGCACTGA 423
MNGPALQPSSPSSAPSASPAAAPRGWSEFCELHAVAAARE ARQYWLFAREHPQHAPLRAELVSLQFTDLFQRYFCREVRDGRA PGRDYRDTGRGPPAKAEASPEPGPGPAAPGLPKARSSEELAPPRPPGPCSFQHFRRSLRHIFRRRSAGELPAAHTAAAPGTPGE AAETPARPGLAKKF PWS AREPPPEA KEAV RYSLADEASMDSGAR QRGRLALRRAPGPDGPDR¥LELFDPPKSSRPKLQA ACSSIQEVRWCTRLEMPDNLYTF¥ KVKDRTDIIFE¥GDEQQ NSMAELSECTGRG ESTEAEMHIPSALEPSTSSSPRGSTD SLNQGASPGGLLDPACQKTDHFLSCYPWFHGPISRVKAAQLVQLQGPDAHGVFLVRQSETRRGEYVLTFNFQGIAKHLRLSLTE RGQCRVQHLHFPSWDMLHHFQRSPIPLECGAACDVRLSSYWWSQPPGSCNTVLFPFS PH DSESLPH GSELGLPHLSSS • GCPRGLSPEG PGRSSPPEQIFHLVPSPEELANSLQHLEHEPVNRARDSDYEMDSSSRSHLRAIDNQYTPL
424
CCCGGGCCACCGCCTCCGCCCGGCTGCCCGCCCGGACTGTCGCGGCCCGCGGTGGCGACGGCGGCCGCTGCAAAGTTTCCCCGG CGGCGGCGGCCCGGGGGCGCATCCTCCCGCAACTGTCAAGCGCTGGCGGCGGAAATGATGAGGCGCTGGCCATTTTCCGAGCCC GGGTTTCCTGCCTGAGCCCCGCTCGAGCGAGCCGCGAGCGAGGAGCCGGCGGGCGGGAGAGGACGCGCCCAGGGCGGGGGCCCG CCCGCCCCCTCGGGATTTCGAGGGCCCGGGGGCGCGCGACGCCATGGGCCGGCCGGGCCCAGAGCTCCTGTCTCTCAGCCCGGC CGCACCACCTGGGTCTCCGCCATGAACGGGCCTGCCCTGCAGCCCTCCTCGCCCTCTTCCGCGCCCTCAGCCTCCCCGGCGGCG GCCCCGCGGGGCTGGAGCGAGTTCTGTGAGTTGCACGCCGTAGCGGCGGCCCGGGAGCTGGCCCGCCAGTACTGGCTGTTCGCC CGGGAGCATCCGCAGCACGCGCCGCTGCGCGCCGAGCTGGTGTCGCTGCAGTTCACCGACCTCTTCCAGCGCTACTTCTGCCGC GAGGTGCGCGACGGACGGGCGCCGGGCCGCGACTACCGGGACACAGGCCGTGGGCCCCCAGCCAAGGCCGAGGCGTCCCCGGAG CCAGGCCCCGGCCCCGCCGCCCCTGGCCTGCCCAAGGCCCGCAGCTCTGAGGAGCTGGCCCCGCCGCGGCCGCCCGGGCCCTGC TCCTTCCAGCACTTTCGCCGCAGCCTCCGCCACATCTTCCGCCGCCGCTCGGCCGGGGAGCTGCCAGCGGCCCACACCGCTGCC GCCCCCGGGACCCCCGGAGAGGCTGCTGAGACCCCCGCCCGGCCTGGCCTGGCCAAGAAGTTCCTGCCCTGGAGCCTGGCCCGG GAGCCGCCACCCGAGGCGCTGAAGGAGGCGGTGCTGCGCTACAGCCTGGCCGACGAGGCCTCCATGGACAGCGGGGCACGCTGG CAGCGCGGGAGGCTGGCGCTGCGCCGGGCCCCGGGCCCCGATGGCCCCGACCGCGTGCTGGAGCTCTTCGACCCACCCAAGAGT TCAAGGCCCAAGCTACAAGCAGCTTGCTCCAGCATCCAGGAGGTCCGGTGGTGCACACGGCTTGAGATGCCTGACAACCTTTAC ACCTTTGTGCTGAAGGTGAAGGACCGGACAGACATCATCTTTGAGGTGGGAGACGAGCAGCAGCTGAATTCATGGATGGCTGAG CTCTCGGAGTGCACAGGCCGAGGGCTGGAGAGCACAGAAGCAGAGATGCATATTCCCTCAGCCCTAGAGCCTAGCACGTCCAGC TCCCCAAGGGGCAGCACAGATTCCCTTAACCAAGGTGCTTCTCCTGGGGGGCTGCTGGACCCGGCCTGCCAGAAGACGGACCAT
* TTCCTGTCCTGCTACCCCTGGTTCCACGGCCCCATCTCCAGAGTGAAAGCAGCTCAGCTGGTTCAGCTGCAGGGCCCTGATGCT
CATGGAGTGTTCCTGGTGCGGCAGAGCGAGACGCGGCGTGGGGAATACGTGCTCACTTTCAACTTTCAGGGGATAGCCAAGCAC
CTGCGCCTGTCGCTGACAGAGCGGGGCCAGTGCCGTGTGCAGCACCTCCACTTTCCCTCGGTCGTGGACATGCTCCACCACTTC
CAGCGCTCGCCCATCCCACTCGAGTGCGGCGCCGCCTGTGATGTCCGGCTCTCCAGCTACGTGGTAGTCGTCTCCCAACCACCA GGTTCCTGCAACACGGTCCTCTTCCCTTTCTCCCTTCCTCACTGGGATTCAGAGTCCCTTCCTCACTGGGGTTCAGAGTTGGGC CTTCCCCACCTTAGTTCTTCTGGCTGTCCCCGGGGGCTCAGCCCAGAGGGTCTCCCAGGGCGATCCTCACCCCCCGAGCAGATC TTCCACCTGGTGCCTTCGCCCGAAGAACTGGCCAACAGCCTGCAGCACCTGGAGCATGAGCCTGTGAATCGAGCCCGGGACTCG GACTACGAAATGGACTCATCCTCCCGGAGCCACCTGCGGGCCATAGACAATCAGTACACACCTCTCTGACCAGTGAGGAATTCC AGGCCTCAACAGCTGCCCTTGAGGAGCACAGGCAGAAGTGTGAACTTGTGAATGTAATTGATCTTTCCTTCCTTCCAGAGAAAG ATTTAAGGGACACTGTTAACTGCTCGTGCCAGTTTGGAAGTGACCCTTCTATTAGGCCTGTTGAAGGGCCCTCCTGTAGGTTTC ATCTATCCACCTGGCTTTCTCCTTATTGTTTACAGATGTAGTTCTTGTTAGAGGATGCCGCTAGCTCCTGCCCGGGGTCCCTAT GCCCAGTCCCCGTTACTCTTAGAGAAAGGAGTTGGGGTGAGGGCCAGAGCTGGCAGTGGAAACTTGTTCTCTTTTTCACTGACA CTGTCACAGCGGATGACAGACTTTCTACGGGGAGGAGGGGGGGATCATCAGGAAGCCCAGAACACTAACAAGCGGTTCTCCCAT CTACCGTCAGTCCACATGGCAGGTCTGCTGTGTCCACACCACAGATGACCACATCTAATCCTGCTTCTACTCTCAGCTTTAGGA CAAAAGCTCTGTCAGAGGCAC.AAGCTGAAGGTCAAAAATGATTTAAAACATTTTACCTCAGACTAATTTCTTTAAAGGATTCAG GTTCAAAACTTAACCACTGCTTATTTCAGTGCACTGTTTCAACTAACACCCATGCTATTTTTGTAGTCAGAAACAGCTATGCAA ACCCTACCTAATTTACAGTCTGAGCCAGCATGCTGGCTTGTCTACTGCATCCTCGGGACAGTCACCTGCCACTGAGTGGCCACT .GTCCTTCCTAAATGTCAAGAAGTGAAGTATGTCACCCTTTCAGGGAAATTCAGGCAATTACTGAAATAGGAAGGTGGCAAGAAC' AGTTCTATCCTGGTGCCTTACGAATAAAAAACTGGATTCTGGTTTACAGCAGCTTTACAGTGATAGTTAAATTAACTGGGGCTA GGGGAAAAGCAACCAAAAAGGGAAAAAGGACTCCTAGGCCCTTTCTATTAAATCCTTCAGCAACAAGGCTGGCTTGGTGCCCTC CAAGCATCTAATGGCTTATTAAATTATCCCACAATTGGGTTTTAGGCTCCTTTTTTGACCCAAAATGGAAGCTGGGAATCTGGT GCCATAACTAATGAGAAACTCCTTTAATACCCCACAATCAGTGTTCTGTTCTACCTGGCTACTGCTTCACTGGATTGAAAATCT ATCTATCTCCTTGCACACATGGGCACACACAATCTCCACCATCCAGGGAGGTCCTGAATTCAAATCTCTATCTATCCAAGTGAT ACAATTCATAGGGGGCTGGCTCCTCCCAGAACCTGTCTGGAGGCTCAGAAACGGGGGCAGTGACAGTGGAGTCAGCTGCTCTTG GGTGCCAGCAGAGCCATTCAGTACAACCCCCAGGCTCACAGCAGTGGCTTCTAGGAAACTGGGAGTTTAGATCAGCTTTACAGA TACATCGATCAGAGGCTAAAATGAAACCTCAGCCTAAAACTCATAGGACTGACTGCCTGGGAGGAGGGTTAGGTCTGCTTCTTC CACTTATACTTAGTCTCTGTGCTCCAAGAGGTCAAATTTTTGCTTCTAGAATTTCCTTGGGGTCTTTCAGAGGGTGGGGGAACA AACCCCTATGCACTTTTCTTTTTTTTTTTTGAGATGGAGTTTCTCTTGTCAACCGGGCTGGAGTGCAGTGGTGCAATCTTGGCT CACTGCAACCTCCACCTTCCTGGTTCAAGCGATTCTGCCTCGACCTCTCAAGTAGCTGGGATTACAAGCACCAGCCACCATGCC TGGCTAATTTTGTATTTTTAGTAGAGACAGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAATGTCTGACCTCAGGTGATCCAC CCGCCTTGGCCTCCCAAAGTGCTGGGATTACAGGCGCGAGCCACCGCGCCCAGCCTACACCACTTTTAGTACCAACACTCTTGG GTGATTTCATGGACCCTAAAGCAGACCTGACACTGATCCAGATTTGCAGTCCATTTTTAAGGACACCTGTCTTTATTTCCTCAA AGTCAAGCAGCTTTCTCTGGAAAATGAATGCTAATTAGTGTGAACCAAAAGAGTAAGTAAGAGTCTGAAGTTTTTTTAAAGGAG AAAGCTTATTATGGAAAGTCACTGGTCCTCCCCTCCGCACAGGAAAGGTACCCAGTAGATAATGAACCAAATTAAGTTCCCTCC CTCCAGCCAGAAGTTAAACATCTGGGATATGACGTCTTCATGCCAGGGGCACTCATTTCTTAGCAGCCTCTCTACATACATCTC TCAGGTGGTGCCAAGAGGCACACCAGGTAGAGCAAACTTAGCAGCTCTGACTAACAGGCTGCAAAGTGCAAGTTCAGATTCTGT GGCAGAGATTTGGAGGGCACCCACGTCCAGACTGCTTCCCGTCCAAGTTACCAGGACAGCTCAAAAACATGCTGACAGAAAACT CCCATGGCTCTAGGAAAAAGTGACACTAAGCCAACACCTTTCTTTATGTGGGAGCAAAATCAGCTGATGAAGGGGTGGGCACCA TTGTGGGGCAGGCACCCCACTGGCTGCAGCTAGCCCACCATAGGCACAGCACATCCCACCACTCTCCTTCCAGTCCTGACCAGG CCCCAGCCGGCAACTTCTACCGAGAGCCATGGCTCAACACCAAACTGGACAGTAGACATCATGATCCCTCCAGTTAGCTCTAAT TACAGACCCCACCAGTACAGCTTGACAGCTCCCGGCACCATCCCTTCCTTCATCTGACTTATTGAACTTTTACAAACTAACAGT CACCAGCACCAAAGAATTAAGTCAACTAACCTGCCTTGAATTTTAAACCAGCAATCCATATGGCTTTATCTGGTATAAATCTTC TGCCTTTGATCATTTCTGGACCGTAGGAAAAAGGAATAGCAATCATTAAAATCTTGGGCCAGAGAACACTATTTTTACATAACA GTTTCTTAACCTAAAGTCAAGGCCTTGGACTCTTCCCTGAGGGTTGCCTGAAATTCCTTCATGCTTTCTATTCAGGACTAATTC CCTTACTGCAAATGTGTTAGCTCTAACATCTCCCACAAGCTAAAGGAACTTGCAAGTATATTAACAAGGACACATCTGACATCC TGTGTTTGGTTAAAATATACAGCACATTGTGATAACATAAAGTGGATCCATCTTGTATCATTATAGGCAAAAGGTATTTGGCAA ATTTTTATGTATGGTTTTATGTACTGTACAAGTAACTTATTCTTGAATAATGCAAATTTTGCTATAATGTACAAATTGCTATAT GTGAATTAAAAAGTTTCCAAAATCTTGAAAAAAAAAAAAAAAAAAAA
425 MMAAAPIQQNGTHTGVPIDLDPPDSRKRPLEAPPEAGSTKRTNTGEDGQYFLKVLIPSYAAGSIIGKGGQTIVQLQKETGATIK LSKLSKSKDFYPGTTERVCLIQGTVEALNA¥HGFIAEKIREMPQNVAKTEPVSILQPQTTVNPDRIKQTLPSSPTTTKSSPSDP MTTSRANQVKI1VPNSTAGLIIGKGGATVKAVMEQSGA VQLSQKPDGIN QERVVTVSGEPEQNRKAVELIIQKIQEDPQSGS C NISYANVTGPVMSNPTGSPYATAEV PTAAAAAGLLGHA AG¥AAFPAVLSGFTGNDLVAITSANTLASYGYNLNTLG LG SQAAATGALAAAAASANPAAAAAN LATYASEASASGSTAGGTAGTFALGSLAAATAATNGYFGAASPLAASAI GTEKST DGSKDWEIA¥PENLVGAILGKGGKTVEYQELTGARIQISKKGEFVPGTRNRKVTITGTPAATQAAQY ITQRITYEQGVRAA NPQKVG
426
GAATTCCGACAAAACAAAAGGGAGAACCTTCTCCCGGTAGCAGCGGCAGGAACTGCAAACATGATGGCGGCAGCTCCCATCCAG CAGAACGGGACCCACACTGGGGTTCCCATAGACCTGGACCCGCCGGACTCGCGGAAAAGGCCGCTGGAAGCCCCCCCTGAAGCC GGCAGCACCAAGAGGACCAATACGGGCGAAGACGGCCAGTATTTTCTAAAGGTTCTCATACCTAGTTATGCTGCTGGATCTATA ATTGGGAAGGGAGGACAGACAATTGTTCAGTTGCAAAAAGAAACTGGAGCCACCATCAAGCTGTCTAAGCTGTCTAAGTCCAAA GATTTTTACCCAGGTACTACTGAGCGAGTGTGCTTGATCCAGGGAACGGTTGAAGCACTGAATGCAGTTCATGGATTCATTGCA GAAAAAATTCGAGAAATGCCCCAAAATGTGGCCAAGACAGAACCAGTCAGCATTCTACAACCCCAGACCACCGTTAATCCAGAT CGCATCAAACAAACATTGCCATCTTCCCCAACTACCACCAAGTCCTCTCCATCTGATCCCATGACCACCTCCAGAGCTAATCAG GTAAAGATTATAGTTCCCAACAGCACAGCAGGTCTGATAATAGGGAAGGGAGGTGCTACTGTGAAGGCTGTAATGGAGCAGTCA GGGGCTTGGGTGCAGCTTTCCCAGAAACCTGATGGGATCAACTTGCAAGAGAGGGTTGTCACTGTGAGTGGAGAACCTGAACAA AACCGAAAAGCTGTTGAACTTATCATCCAGAAGATACAAGAGGATCCACAAAGTGGCAGCTGTCTCAATATCAGTTATGCCAAT GTGACAGGTCCAGTGGCAAATTCCAATCCAACCGGATCTCCTTATGCAAACACTGCTGAAGTGTTACCAACTGCTGCAGCAGCT GCAGGGCTATTAGGACATGCTAACCTTGCTGGCGTTGCAGCCTTTCCAGCAGTTTTATCTGGCTTCACAGGCAATGACCTGGTG GCCATCACCTCTGCACTTAATACATTAGCCAGCTATGGATATAATCTCAACACTTTAGGTTTAGGTCTCAGTCAAGCAGCAGCA ACAGGGGCTTTGGCTGCAGCAGCTGCCAGTGCCAACCCAGCAGCAGCAGCAGCCAATTTATTGGCCACCTATGCCAGTGAAGCC TCAGCCAGTGGCAGCACAGCTGGTGGTACGGCGGGGACATTTGCATTAGGTAGCCTGGCTGCTGCTACTGCTGCAACCAATGGA TATTTTGGAGCTGCTTCTCCCCTAGCTGCCAGTGCCATTCTAGGAACAGAAAAGTCCACAGATGGATCCAAGGATGTAGTTGAA ATAGCAGTGCCAGAAAACTTAGTTGGTGCAATACTTGGCAAAGGAGGGAAAACATTAGTGGAATACCAGGAGTTGACTGGTGCA AGGATACAGATCTCCAAAAAAGGAGAATTCGTACCTGGCACAAGGAATCGGAAGGTAACCATTACTGGAACACCAGCTGCAACA CAGGCTGCTCAATATTTAATTACACAAAGGATCACATATGAGCAAGGAGTTCGGGCTGCCAATCCTCAGAAAGTGGGTTGAGTG CCCCAGTTACACATCAGATTGTTTTAACCCCTCCTTTACCCCATTTTCAAGAAGGATGTACTGTACTTTGCAGAAGTGAAGTTT TTCTGTTATTAATATATAATTATGCAAATGAATGCGACTATGTTGACAATGTGTATATGTAAATAATATGTGTTTTACCAGATG TTTCATAGAAAGAATTTTTTCTTGATCTGTTTTGTTCTCTATACTTTGCTTGTGTATATTTGTCAGAGGTGTTTCTAGTGTAAG ATTTAAGCCTGCCATTTTACCAGCATTATTGTAGTTTAATGATTGAATGTAGACAGGGATATGCGTATAGTTTTCAGTATTAGT TCTAGATAACACTAAATTAACTACTGTTAGGTTGAGTATGGTGGGGTCAGTGACCTAAAATGGAGTGAGGCCAAAGCACTGTCC TGTAAGTCTTACTTCCTGCTTAGGGCACAGTGAAGTAGGAAACAATATTTTGAAAATAAGTTTTAAATTTAAAATGATCAAAAA GCAATATAGTTGCATAAAAGCACTGTAAAATATTTAAAAGGTTAAAACTGTGGAAAATTATATTGGTAAGTTTACAGATCAATA AAAGCACCTGTTCTCCATCTGAACTAGACAATGGAAATAATGCTGCATGCTGCCATGGCCCATTCTTCATCATTTGTAAGTTCA ACAAAAGTTCTCACATGGAGTCCCACCTCTTCAGAGGTTGCACATTTGTTTTTAAGACTGAATTCACTACTGATCCCATCGCCT GGCCGAGACAGTCATTACTCCATTAACATCCTCACTGTTTAGACACATAACTGTGGTACAGGATTGGAAATTATAAACAAAAGT GAAAGTGCCAACAAATTATTGATAGCTGATAATGTTTCATATCTGCAACTGCTTGATAAGTATGTTGCATTTTAAGAGCTTATA ATTGTGTATAATTTGTTAACACTAGAAACCTATTAGTATTGTGAATGTAGATTTTACTGTGAAGCTATCTGTGATTTAGCTGTT TGCTCCCATGATGGAGTCTTTGCAGCATGGCGCTAGCAGCCAATGCAGTTTCTAATACTCGGTAATTTGCATGTTTTGTGGAGC ATTTTTATGTCACCAACCAGACAGTATTTCCTGCATGCTTATTTAGAAGAGGCAGCTTATCTTGAGAGGTAGTGTTATCTACCT TTGTCAGGCTTTTTGACAGGTCATTTCAGAGTAAGCCTTTGTTCCCAAGACCCAACAACTGTCACCCTCTTCTGTACCTCTCCT GAGTGCCAACTGTCCAGGCCATTTGACACACCATCTGTTAACCTCTGAGTTTGCCCACTCAAGGCCACTCATAGGGGCATCCTA GCCCTGTGCACTCAGCACTCATAGGATCATCCAGACTCTCATGCGGCATGCAGTCTAATCATGACAAATAATGCTGCTACTCTG ATATCTGGCTGAGCAACTGAATTACAAAAGAGAATTACTTCCATCTCAACTTCAACCCATTGATTACGTCCATCCTAGCAAGCT AAATGGCATCCCAGCTGCTCCTTTCTGTGCAACCAATTAAAGAACAATGAGTGTGATGCTCCATGTCTGAATTTCGTCCAGCCT CTCTCTGAACTGTGATCTTTGTCCTCATGAACTTTCCCTTTTGTTCATTGAACTATATGGACTCTTCATTTCATATTGATTTAC TGTGCAATTTACTTTTGGACATTGAGAACTTGAAATTATTTCCTGATCCCTTCCCCTTCCACTATTAATAATTCATTTCTGTCA AACTGTAAGAGTAGACTCATTTTTTTTTTTTTTAGTTTTTAACATTGGACTGTTATTTCATTTAGAGTTCTCTATCTCTAAATA TTTATTTAGAGAATGATTTTAAAAGGGAATGATATGCTTGTTTAAATGAAAGAGAAAAGCTGTAGTAAACTGTGTTAATTGGTA ATGACTATTTATCGTCGATACTCTGTAGCTGTGTAAGTTTTGACAAATAGTGTATCTCGTGGAATCAGTGGTTAGCATTGCCGC, TATTATATTTACTCATTTTATCATTATAAATGTGTTTAGTTCATCATGTAGCATCAAAA
427
MAFIRKKQQEQQLQLYSKERFSLLL N EEYYFEQHRA HILHKGSHHERKIRGS KICSKS¥IFEPDSISQPIIKIP RDCIK IGKHGENGA RHFTKAKSGGIS IFSQVYFIKEHNWAPYKIERGK--EYVFELDVPGKVEDVVETLLQLHRASCLDK GDQTAM ITAILQSRLARTSFDKNRFQNISEKLHMECKAEMVTPLVTNPGHVCITDTN YFQP NGYPKP QITLQDVRRIYKRRHGLMP LGLEVFCTEDD CSDIY KFYEPQDRDDLYFYIATYLEHHVAEHTAESYMLQ QRGHLSNYQY HLM ADRSCNDLSQYPVF PWIIHDYSSSELDLSNPGTFRDLSKPVGA NKERLERLLTRYQE PEPKFMYGSHYSSPGYVLFYLVRIAPEYM CLQNGRFDN ADRMFNSIAET KNCLDGATDFKELIPEFYGDDVSFLV SLKLDLGKRQGGQMVDDVELPPWASSPEDFLQKSKDA ESNYVSE HLHE IDLIFGYKQKGSDAVGAHNVFHP TYEGGVDLNSIQDPDEKVAM TQILEFGQTPKQLFVTPHPRRITPKFKSLSQTSS YNAS DSPGEESFEDLTEESKT A rølTKLQLHEHYKIHKEAVTGITVSRNGSSVFTTSQDSTLKMFSKESKMLQRSISFSN LSSCLLLPGDATVITSSWDIM/YFYSIAFGRRQDTLMGHDDAVSKIC HDNRLYSASWDSTVKV SGVPAEMPGTKRHHFD LAELEHD¥SVDTISLNAASTLL¥SGTKEGTVNIWDLTTATLMHQIPCHSGIVCDTAFSPDSRHVLSTGTDGC NVIDVQTGM I SSMTSDEPQTCFVWDGNSV SGSQSGE LV DLLGAKISERIQGHTGAVTCI MNEQCSSIITGGEDRQIIFWKLQY
428 GAATTCGCCTCGATGGCGTTTATCCGGAAGAAGCAGCAGGAGCAGCAGCTGCAGCTCTACTCCAAGGAGAGATTTTCCTTGCTG CTGCTTAACTTGGAGGAGTACTACTTTGAACAGCATAGAGCCAATCACATTTTGCACAAGGGCAGTCACCATGAAAGGAAAATC AGAGGCTCCTTAAAAATATGTTCAAAATCGGTGATTTTTGAACCAGATTCAATATCCCAGCCCATCATCAAGATTCCTTTGAGA GACTGTATAAAAATAGGAAAGCATGGAGAAAATGGAGCCAATAGACACTTCACAAAGGCAAAATCTGGGGGTATTTCACTCATT TTCAGTCAGGTATATTTCATTAAAGAACATAATGTTGTTGCACCATATAAAATAGAAAGGGGCAAAATGGAATATGTTTTTGAA TTGGATGTTCCCGGGAAAGTGGAAGATGTTGTGGAGACGTTGCTTCAGCTTCACAGAGCATCCTGCCTTGACAAATTGGGTGAC CAAACCGCCATGATAACAGCTATTTTGCAGTCTCGTTTAGCTAGAACATCATTTGACAAAAACAGGTTCCAAAACATTTCTGAA AAGCTGCACATGGAATGCAAAGCAGAAATGGTGACGCCTCTGGTGACTAATCCTGGACACGTGTGCATCACGGACACAAACCTG TATTTTCAGCCCCTCAACGGCTACCCGAAACCTGTGGTCCAGATAACACTCCAAGATGTCCGCCGCATCTACAAAAGGAGGCAC GGCCTCATGCCTCTGGGCTTGGAAGTATTTTGCACAGAAGATGATCTGTGTTCCGACATCTACCTAAAGTTCTATGAACCTCAA GATAGAGATGATCTCTATTTTTACATTGCCACATACCTAGAGCACCATGTGGCGGAGCACACTGCTGAGAGCTACATGCTGCAG TGGCAGCGTGGACACCTTTCCAACTATCAGTACCTCCTTCACCTCAACAACCTGGCCGACCGCAGCTGCAACGACCTCTCCCAG TACCCTGTGTTTCCATGGATAATACATGATTATTCCAGCTCAGAACTAGATTTGTCAAATCCAGGAACCTTCCGGGATCTCAGT AAGCCAGTAGGGGCCCTAAATAAGGAACGGCTGGAGAGACTACTGACACGCTACCAGGAAATGCCTGAACCAAAGTTCATGTAT GGGAGTCACTACTCTTCCCCGGGTTATGTACTTTTTTATCTTGTTAGGATTGCACCAGAGTATATGCTGTGCCTGCAGAATGGA AGATTTGATAATGCAGATAGAATGTTCAACAGTATTGCAGAAACTTGGAAAAACTGTGTGGATGGTGCAACGGATTTTAAAGAG TTAATTCCAGAATTCTATGGTGATGATGTGAGCTTTCTAGTCAATAGCCTGAAGTTGGATTTGGGAAAGAGACAAGGAGGACAG ATGGTTGACGACGTGGAGCTTCCCCCTTGGGCTTCCAGTCCCGAGGACTTTCTCCAGAAGAGCAAAGATGCATTGGAAAGCAAT TATGTGTCTGAACACCTTCACGAGTGGATTGATCTAATATTTGGCTACAAACAAAAAGGGAGTGATGCAGTTGGGGCCCATAAT GTATTTCATCCCCTGACCTATGAAGGAGGTGTAGACTTGAACAGCATCCAGGATCCTGATGAGAAGGTAGCCATGCTTACGCAA ATCTTGGAATTTGGGCAGACACCAAAACAACTATTTGTGACACCACATCCTCGAAGGATCACCCCAAAGTTTAAAAGTTTGTCC CAGACCTCCAGTTATAATGCTTCTATGGCAGATTCCCCAGGTGAAGAGTCTTTTGAAGACCTGACCGAAGAAAGCAAAACACTG GCCTGGAATAACATCACCAAACTGCAGTTACACGAGCACTATAAAATCCACAAAGAAGCAGTTACTGGAATCACGGTCTCTCGC AATGGATCTTCAGTATTCACAACATCCCAAGATTCCACCTTGAAGATGTTTTCTAAAGAATCAAAAATGCTACAAAGAAGTATA TCATTTTCAAATATGGCTTTATCGTCTTGTTTACTTTTACCAGGAGATGCCACTGTCATAACTTCTTCATGGGATAATAATGTC TATTTTTATTCCATAGCATTTGGAAGACGCCAGGACACGTTAATGGGACATGATGATGCTGTTAGTAAGATCTGTTGGCATGAC AACAGGCTATATTCTGCATCGTGGGACTCTACAGTGAAGGTGTGGTCTGGTGTTCCTGCAGAGATGCCAGGCACCAAAAGACAC CACTTTGACTTGCTGGCCGAGCTGGAACATGATGTCAGTGTAGATACAATCAGTTTAAATGCTGCAAGCACACTGTTAGTTTCC GGCACCAAAGAAGGCACAGTGAATATTTGGGACCTCACAACGGCCACCTTAATGCACCAGATTCCATGCCATTCAGGGATTGTA TGTGACACTGCTTTTAGCCCAGATAGTCGCCATGTCCTCAGCACAGGAACAGATGGCTGTCTTAATGTCATTGATGTGCAGACA GGAATGCTCATCTCCTCCATGACATCAGATGAGCCCCAGACGTGCTTTGTCTGGGATGGAAATTCCGTTTTATCTGGCAGTCAG TCTGGTGAACTGCTCGTTTGGGAGCTCCTTGGAGCAAAAATCAGTGAGAGAATACAGGGCCACACAGGTGCTGTGACATGTATA TGGATGAATGAACAGTGTAGCAGTATCATCACAGGAGGGGAAGACAGACAAATTATATTCTGGAAATTGCAGTATTAAGTGCCT TTTCCTCTCCTGAATATTAAATTGAACTCTATTTAATGCATTTTTAAACCAAACTTTTAAACGGACTGGTGAATGTGCAATGTT AGTAATTAGAAGTTTTACCACATGGAAAATTTGTGGTTTTAAACTTTCTAAATCATGGTGACTTCATTGAAAGCCATTAGTTGC CATTCTCTTAGGGCAGATAAAATGCGGCTGTGTTAGGAAAAACATGTTACACTGTAAGGCAGATGATCGTCCCCGTATGATGAT TGTCAGAAGACAGGACTAAGTAGCAGAGAATAGCTAAGAGATAAATTGGGCTGGGGAAACTTGTCAGAAAGCACTGAACAATTA AGAAATTTTCCAAGAAAATGTGCAGTATTCTCTGCTACTTCTGAATCTGTTTTGTCTTCCTAATCTATCACAATTGCCACCCAT CGGGTTTTGGGTGTGTGTTTTCATAGCGTGGTTACTTTCTATAATGCTGTACCCAGATTCTAAGAACCTGGAGAAGGATTAGCA GTTCTTAGTAAGTTTACTGTGTATAGGAACGGTTTGTATTTCATTACAGCTATTCATCTTTTCTACATTAAAAATAT.TTTTCTC TAAAAAAAAAAAAAAAAAAA
429
M ALRCGSR LGLLSVPRSVPLR PAARACSKGSGDPSSSSSSGNPL¥YLDVDANGKPLGRWLELKADWPKTAENFRA CTG EKGFGYKGSTFHRVIPSFMCQAGDFTNHNGTGGKSIYGSRFPDENFTLKHVGPGV SMANAGPNTNGSQFFICTIKTDWLDGKH WFGHVKEGMDWKKIESFGSKSGRTSKKIVITDCGQLS 430
GAATTCCGGAGTTCCGGGCGCGCGCGACGTCAGTTTGAGTTCTGTGTTCTCCCCGCCCGTGTCCCGCCCGACCCGCGCCCGCGA TGCTGGCGCTGCGCTGCGGCTCCCGCTGGCTCGGCCTGCTCTCCGTCCCGCGCTCCGTGCCGCTGCGCCTCCCCGCGGCCCGCG CCTGCAGCAAGGGCTCCGGCGACCCGTCCTCTTCCTCCTCCTCCGGGAACCCGCTCGTGTACCTGGACGTGGACGCCAACGGGA AGCCGCTCGGCCGCGTGGTGCTGGAGCTGAAGGCAGATGTCGTCCCAAAGACAGCTGAGAACTTCAGAGCCCTGTGCACTGGTG AGAAGGGCTTCGGCTACAAAGGCTCCACCTTCCACAGGGTGATCCCTTCCTTCATGTGCCAGGCGGGCGACTTCACCAACCACA ATGGCACAGGCGGGAAGTCCATCTACGGAAGCCGCTTTCCTGACGAGAACTTTACACTGAAGCACGTGGGGCCAGGTGTCCTGT CCATGGCTAATGCTGGTCCTAACACCAACGGCTCCCAGTTCTTCATCTGCACCATAAAGACAGACTGGTTGGATGGCAAGCATG TTGTGTTCGGTCACGTCAAAGAGGGCATGGACGTCGTGAAGAAAATAGAATCTTTCGGCTCTAAGAGTGGGAGGACATCCAAGA AGATTGTCATCACAGACTGTGGCCAGTTGAGCTAATCTGTGGCCAGGGTGCTGGCATGGTGGCAGCTGCAAATGTCCATGCACC CAGGTGGCCGCGTTGGGCTGTCAGCCAAGGTGCCTGAAACGATACGTGTGCCCACTCCACTGTCACAGTGTGCCTGAGGAAGGC TGCTAGGGATGTTAGACGGAATTCC
431
MEPKRIREGYLWKGSVFNT KPM L EDGIEFYKKKSDNSPKGMIPLKGSTLTSPCQDFGKRMFVFKITTTKQQDHFFQAA FLEERDA VRDINKAIKCIEGGQKFARKSTRRSIR PETIDLGA Y SMKDTEKGIKELNLEKDKKIFNHCFTGNCVID LVSN QSVRNRQEGLMIASSL NEGYLQPAGDMSKSAVDGTAENPFLDNPDAFYYFPDSGFFCEENSSDDDVILKEEFRGVIIKQGCLL KQGHRRKWKVRKFI REDPAYLHYYDPAGAEDPLGAIHLRGCVVTSVESNSNGRKSEEENLFEIITADEVHYFLQAATPKERT E IKAIQMASRTGK
432 GGCCCAGCTGCTGAGAGGAGTTGCCTGAGAGTGACCTTTGCATCTGCCTGTCCAGCCAGCATGGAACCAAAGCGGATCAGAGAG GGCTACCTTGTGAAGAAGGGGAGCGTGTTCAATACGTGGAAACCCATGTGGGTTGTATTGTTAGAAGATGGAATTGAATTCTAT AAGAAGAAAAGTGACAACAGCCCCAAAGGAATGATCCCGCTGAAAGGGAGCACTCTGACTAGCCCTTGTCAAGACTTTGGCAAA AGGATGTTTGTGTTTAAGATCACTACGACCAAACAGCAGGACCACTTCTTCCAGGCAGCCTTCCTGGAGGAGAGAGATGCCTGG GTTCGGGATATCAATAAGGCCATTAAATGCATTGAAGGAGGCCAGAAATTTGCCAGGAAATCTACCAGGAGGTCCATTCGACTG CCAGAAACCATTGACTTAGGTGCCTTATATTTGTCCATGAAAGACACTGAAAAAGGAATAAAAGAACTGAATCTAGAGAAGGAC AAGAAGATTTTTAATCACTGCTTCACAGGTAACTGCGTCATTGATTGGCTGGTATCCAACCAGTCTGTTAGGAATCGCCAGGAA GGCCTCATGATTGCTTCATCGCTGCTCAATGAGGGGTATCTGCAGCCTGCTGGAGACATGTCCAAGAGTGCAGTGGATGGAACT- GCTGAAAACCCTTTCCTGGACAACCCTGATGCCTTCTACTACTTTCCAGACAGTGGGTTCTTCTGTGAAGAGAATTCCAGTGAT GATGATGTGATTCTGAAAGAAGAAT.TCAGAGGGGTCATTATCAAGCAGGGATGTTTACTGAAGCAGGGGCATAGAAGGAAAAAC TGGAAAGTGAGGAAGTTCATCTTGAGAGAAGACCCTGCCTACCTGCACTACTATGACCCTGCTGGGGCAGAAGATCCCCTGGGA GCAATTCACTTGAGAGGCTGTGTGGTGACTTCAGTGGAGAGCAACTCAAATGGCAGGAAGAGTGAGGAAGAGAACCTTTTTGAG ATCATCACAGCAGATGAAGTGCACTATTTCTTGCAAGCAGCCACCCCCAAGGAGCGCACAGAGTGGATCAAAGCCATCCAGATG GCCTCCCGAACTGGGAAGTAAAGAGACTCCTGCATTCCTCCTCCCCTCCTGAGGGAAGCCCATGGACAAGCTCAGTCCAGGACC TGTCCACTTCTGTGACAAATCAACGGGAAACAGCCCAGGGGTGGGAAGTTTTCATTTGCAGGGGGGTCTGAATGTAACTCACCA TGTGGTGTGCAAGGTTCCCCTGCATTGTATTGCTCACTGCAGCCCCTCTGCCCCTATCCATGACCCCCAAGCAGATATAACAAG CTGTGCAGCCTCAGTAGGCTGCTTGCCCTCTCCAGCCTCAGGGCCTCTTCTGGAAAATGAAGAAATTCAACTAGTAGATTCCTG AGGTCCCCCTAGCTTAAAAAAAAAAAAATCTGCCCCATGATTCTAACACTCGCAGTAGTGATAGTGTATCTAGTTGTTCTGCTG GTGTCCTTCCTTGGCTAAGTCTTGGCCTTCAGTTATCTTCAAATGTACCAGAACCTGAGCCAACGCCTCCCTGTGAAACTGTTG CTGATCTGTAGTACAGTACCAGGAAGAAACCTCTTTTGTTCTCTTTAGACATCTTCTACTTGCTCTTGGCCTTGAGATCGTGTA ACAAAATGAAGGAGGGCTCTCTTCTTTCTTCCTCATCCTACTCAAAAACTTCCCGAGAGCAGTGGTGGTTTTGAGGGTTTTGAC TTCTATTACTTTTGGCAGCCTGGAAAGTTGTGTCTTCTGGGAAAGAGACCCGGGGAGGCCAGGAGTAGCTGAGGGTCCTTTCTG TGCCCTTAAACCGCCCAGAGGAGCCCTATTCCACTCTGGTTTTAGGCTGATCTGAGAGGGTCTCCCTTTGTTCCTTTCTGGAGC ATTTCTCTAACGTTTATTACAATTAGGAGGGGGACCCCACATCTGTGAGATTCTGTTTCATTTGAGGTTTACAGAAAAAAAAAA GTGGCCAGATGTGTTCCCCCCATGGGTGAGAGGCCTGGGCAACTGCCTGGTGAATGTGTCTTGCGGCAGCTGCAGCAAGTGGAG GGGCTGAACTACTGGCCAGCTCACTGGATGATGGGTTAATACAACAACTGCACTGTAAGGACTCAGAGCCACACAGAACTTCTG AGAGGGGCTGTTAGCATTGCGCAGCATCTTCAGTTCTCCAGTAAATGATATTGCGTTCGTGCCTCAGCTTTAAGCACAAGTAGC AGCAGCTCCTGCTTGAGTTCTGAGGGCATCATGGCCCTATGATTAACCAGAGTGATCTAACCTAGACTAAAATTGGGAACTTAT TTGCAATTTTTGACCCTGACCACTAACTAGTGATTCTTCTCCAAAATTGAGAAAGACAGCACCCATTGAAACAGATATGTGTGT GAAAGTATATTTTTCAATTCCAGATTTTTAATTTTAAGGCTCCAGGAAAGAAAGGAGAGTAGAACATTTTTCCTCATTTTATCA AATCCTCTCTTGCCCTCCCTCAATTCCCCTGTAACATTCCTGAAGCTGTTCCCACTCCCAGATGGTTTTATCAATAGCCTAGAG GTAAAGAACTGTCTTTTTCTCTGATTCTTTAATAAATTATCTTTATAGAATATGCACAAGTTTTTCTACACTCAGTGTTAAAGT ATTTATTAATGGGAAGTCAACTTAATGTTTTGAAATAAATATATGACTCTGTTTAAT
433
ML QSQTMGVSHSFTPKGITIPQREKPGHMYQNEDYLQNG PTETTVLGTVQILCCLLISSLGAILVFAPYPSHFNPAISTTLM SGYPFLGALCFGITGSLSIISGKQSTKPFDIJSSLTSNAVSSVTAGAGLF LADSMVALRTASQHCGSEMDYLSS PYSEYYYPI YEIKDCLLTS¥SLTGV VVMLIFTVLE LLAAYSSVF KQLYSMPGSSFSSTQSQDHIQQVKKSSSRSWI
434 AAGTCTCAGAGGCTGGAGAGCAGAGCACCAAGATCGTTCTGGCAGGAACAGCCAGTGGGAGGTTCCAGCTGAGCGCTCCCCAGA GGTGAGCTGATCCCCAGCCACAGCACACAGGACCAGGCTGCGAGAACAGCATCATCAGCATCATGCTATTACAATCCCAAACCA TGGGGGTTTCTCACAGCTTTACACCAAAGGGCATCACTATCCCTCAAAGAGAGAAACCTGGACACATGTACCAAAACGAAGATT ACCTGCAGAACGGGCTGCCAACAGAAACCACCGTTCTTGGGACAGTCCAGATCCTGTGTTGCCTGTTGATTTCAAGTCTGGGGG CCATCTTGGTTTTTGCTCCCTACCCCTCCCACTTCAATCCAGCAATTTCCACCACTTTGATGTCTGGGTACCCATTTTTAGGAG CTCTGTGTTTTGGCATTACTGGATCCCTCTCAATTATCTCTGGAAAACAATCAACTAAGCCCTTTGACCTGAGCAGCTTGACCT CAAATGCAGTGAGTTCTGTTACTGCAGGAGCAGGCCTCTTCCTCCTTGCTGACAGCATGGTAGCCCTGAGGACTGCCTCTCAAC ATTGTGGCTCAGAAATGGATTATCTATCCTCATTGCCTTATTCGGAGTACTATTATCCAATATATGAAATCAAAGATTGTCTCC TGACCAGTGTCAGTTTAACAGGTGTCCTAGTGGTGATGCTCATCTTCACTGTGCTGGAGCTCTTATTAGCTGCATACAGTTCTG TCTTTTGGTGGAAACAGCTCTACTCCAACAACCCTGGGAGTTCATTTTCCTCGACCCAGTCACAAGATCATATCCAACAGGTCA AAAAGAGTTCTTCACGGTCTTGGATATAAGTAACTCTTGGCCTCAGAGGAAGGAAAAGCAACTCAACACTCATGGTCAAGTGTG ATTAGACTTTCCTGAAATCTCTGCCATTTTAGATACTGTGAAACAAACTAAAAAAAAAAAAGCTTTTGTTTTGTATTTGTTTAC TATGAGTCGTTATTTAATTTCTCTTGAAAATAATTTCCTCAAAGCCCAAGTCAATAAA
435 MVNVPKTRRTFCKKCGKHQPHKVTQYKKGKDSLYAQGRRRYDRKQSGYGGQTKPIFRKKAKTTKKIVLRLECVEPNCRSKRM A
IKRCKHFELGGDKKRKGQVIQF
436
GGCGAGAGCTGCGAAAGGCGAGAGCTGCGAAGGGCCAGGTGTCGGGCGCTGTTTCTCGTTTTCATCATATAGACAAAACAGCCC GCTGCAAAGATGGTCAACGTACCTAAAACCCGAAGAACCTTCTGTAAGAAGTGTGGCAAGCATCAGCCTCACAAAGTGACACA GTATAAGAAGGGCAAGGATTCTTTGTATGCCCAGGGAAGGAGGCGCTATGATCGGAAGCAGAGTGGCTATGGTGGGCAGACAAA GCCAATTTTCCGGAAGAAGGCTAAGACCACAAAGAAGATTGTGCTAAGGCTGGAATGTGTTGAGCCTAACTGCAGATCCAAGAG GATGCTGGCCATTAAGAGATGCAAGCATTTTGAACTGGGAGGAGATAAGAAGAGAAAGGGCCAAGTGATCCAGTTCTAAACTTT GGGATATTTTTCTTCAATTTTGAAGAGAAAATGGTGAAGCCATAGAAAAGTTACCCGAGGGAAAATAAATACAGTGATATTCTT ACGCAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 437
MATNGSKVADGQISTEVSEAP¥ANDKPKTLVVK¥QKKAADLPDRDTWKGRFDFLMSCVGYAIGLG VWRFPY CGKNGGGAF I PYFLTLIFAGVPLFL ECSLGQYTSIGGLGV KLAPMFKGVGLAAAV SF LNIYYIVIISWAIYYLYNSFTTT PWKQCDNPW NTDRCFSOTSMVNTTMTSAWEF ERMHQMTDGLDKPGQIRWP AITLAIAWILWFCIWKGVGWTGKWYFSATYPYIMLI ILFFRGVTLPGAKEGILFYITPNFRKLSDSEVWLDAATQIFFSYGLGLGSLIALGSYNSFHN VYRDSIIVCCINSCTSMFAGF VIFSIVGFMAHVTKRSIADVAASGPGLAFLAYPEAVTQLPISP AILFFSMLLMLGIDSQFCTVEGFITALVDEYPRLLRNRR ELFI VCIISYLIGLSNITQGGIWFKLFDYYSASGMSLLFLVFFECVSISWFYGV RFYDNIQEMVGSRPCIWWK CWSFFT PII¥AGVFIFSAVQMTPLTMGNWFPKWGQGVGWLMALSSMVLIPGYMAYMFLALKGS KQRIQVMVQPSEDTVRPENGPEHAQ AGSSTSKEAYI
438 GAATTCCGCTCCGGCCGCAGGATCTCCCCAAGGTGGCAGAAGGAGGCCTTCTGGAGCTGACCCACCCCCGACGACCATCAGGGT GAGGCAACTCCAAGGTCCTACTCTCTTTCTGTGCCTGTTACCCACCCCGTCCTCCTAGGGTGCCCTTGAGCCGCAAAACTGCTG TCCACGTGGACCGGGGGTGACATCGCACGTCCATCTGCCAGGACCCCTGCGTCCAAATTCCGAGACATGGCGACCAACGGCAGC AAGGTGGCCGACGGGCAGATCTCCACCGAGGTCAGCGAGGCCCCTGTGGCCAATGACAAGCCCAAAACCTTGGTGGTCAAGGTG CAGAAGAAGGCGGCAGACCTCCCCGACCGGGACACGTGGAAGGGCCGCTTCGACTTCCTCATGTCCTGTGTGGGCTATGCCATC GGCCTGGGCAACGTCTGGAGGTTCCCCTATCTCTGCGGGAAAAATGGTGGGGGAGCCTTCCTGATCCCCTATTTCCTGACACTC ATCTTTGCGGGGGTCCCACTCTTCCTGCTGGAGTGCTCCCTGGGCCAGTACACCTCCATCGGGGGGCTAGGGGTATGGAAGCTG GCTCCTATGTTCAAGGGCGTGGGCCTTGCGGCTGCTGTGCTATCATTCTGGCTGAACATCTACTACATCGTCATCATCTCCTGG GCCATTTACTACCTGTACAACTCCTTCACCACGACACTGCCGTGGAAACAGTGCGACAACCCCTGGAACACAGACCGCTGCTTC TCCAACTACAGCATGGTCAACACTACCAACATGACCAGCGCTGTGGTGGAGTTCTGGGAGCGCAACATGCATCAGATGACGGAC GGGCTGGATAAGCCAGGTCAGATCCGCTGGCCACTGGCCATCACGCTGGCCATCGCCTGGATCCTTGTGTATTTCTGTATCTGG AAGGGTGTTGGCTGGACTGGAAAGGTGGTCTACTTTTCAGCCACATACCCCTACATCATGCTGATCATCCTGTTCTTCCGTGGA GTGACGCTGCCCGGGGCCAAGGAGGGCATCCTCTTCTACATCACACCCAACTTCCGCAAGCTGTCTGACTCCGAGGTGTGGCTG GATGCGGCAACCCAGATCTTCTTCTCATACGGGCTGGGCCTGGGGTCCCTGATCGCTCTCGGGAGCTACAACTCTTTCCACAAC AATGTCTACAGGGACTCCATCATCGTCTGCTGCATCAATTCGTGCACCAGCATGTTCGCAGGATTCGTCATCTTCTCCATCGTG GGCTTCATGGCCCATGTCACCAAGAGGTCCATTGCTGATGTGGCCGCCTCAGGCCCCGGGCTGGCGTTCCTGGCATACCCAGAG GCGGTGACCCAGCTGCCTATCTCCCCACTCTGGGCCATCCTCTTCTTCTCCATGCTGTTGATGCTGGGCATTGACAGCCAGTTC TGCACTGTGGAGGGCTTCATCACAGCCCTGGTGGATGAGTACCCCAGGCTCCTCCGCAACCGCAGAGAGCTCTTCATTGCTGCT GTCTGCATCATCTCCTACCTGATCGGTCTCTCTAACATCACTCAGGGGGGTATTTATGTCTTCAAACTCTTTGACTACTACTCT GCCAGTGGCATGAGCCTGCTGTTCCTCGTGTTCTTTGAATGTGTCTCTATTTCCTGGTTTTACGGTGTCAACCGATTCTATGAC AATATCCAAGAGATGGTTGGATCCAGGCCCTGCATCTGGTGGAAACTCTGCTGGTCTTTCTTCACACCAATCATTGTGGCGGGC GTGTTCATTTTCAGTGCTGTGCAGATGACGCCACTCACCATGGGAAACTATGTTTTCCCCAAGTGGGGCCAGGGTGTGGGCTGG CTGATGGCTCTGTCTTCCATGGTCCTCATCCCCGGGTACATGGCCTACATGTTCCTCGCCCTAAAGGGCTCCCTGAAGCAGCGC ATCCAAGTCATGGTCCAGCCCAGCGAAGACACTGTTCGCCCAGAGAATGGTCCTGAGCACGCCCAGGCGGGCAGCTCCACCAGC AAGGAGGCCTACATCTAGGGTGGGGGCCACTCACCGACCCGACACTCTCACCCCCCGACCTGGCTGAGTGCGACCACCACTTGA TGTCTGAGGATACCTTCCATCTCAACCTACCTCGAGTGGTGATCCAGACACCATCACCACGCAGAGAGGGGAGGTGGGAGGACA GTTAGACCCCTGGGTGGGCCCTGCCGTGGGCAAGGATACCCGGTGGCTTCTGGCACTGGCGGGCTGGTGACCTTTTTAATCCAG GCCCCATCAGCATCCCACTCCTGGCGGGAT
439
MEGYSEEAS LRHLEKVASEEEEVPLVVYLKENAALLTANGLHLSQNREAQQSSPAPPPAEVHSPAADV QNLASPSATLTTPT SNSSHNPPATDVNQNPPATVVPQSLPLSSIQQNSSEAQLPSNGTGPASKPSTLCADGQPQAPAEEVRCSTLLIDKVSTPATTTS TFSREATLIPSSRPPASDFMSSSLLIDIQPNTLWSADQEMSGRAAATTPTKVYSEVHFTLAKPPSVVNRTARPFGIQAPGGTS QMERSPM ERRHFGEKAPAPQPPSLPDRSPRPQRHIMSRSPWERRMMGQRSPASERRPLGNFTAPPTYTETLSTAPLASWVRS PPSYSVLYPSSDPKSSH KGQAVPASKTGILEESMARRGSRKSMFTFVEKPKVTPNPDLLDLVQTADEKRRQRDQGEVGVEEEP FALGAEASNFQQEPAPRDRASPAAAEEVVPEWASCLKSPRIQAKPKPKPNQN SEASGKGAELYARRQSRMEKYVIESSSHTPE LARCPSPTMSLPSSWKYPTNAPGAFRVASRSPARTPPASLYHGYLPENGVLRPEPTKQPPYQLRPSLFVSPIKEPAKVSPRAA SPAKPSS DVPNLPKGALPPSPA PRPSRSSPGLYTSPGQDSLQPTAVSPPYGGDISPVSPSRAWSPRAKQAPRPSFSTRNAG IEAQDRRESLPTSPPWTPGASRPPSSLDGWVSPGPWEPGRGSSMSSPPPLPPPPPMSPSWSERSVSPLRPETEARPPSRQLQA LARNIINAARRKSASPRSAGAENPRPFSPPRAPPPPPPPPPPPPRMRSPQPARPGSAAVPGAAFAPIPRSPLPAGPSSCTSPRS PLPAPPRPFLYRRSPTDSDVSLDSEDSGAKSPGILGYNICPRGW1.GSLR KRGSLPAEASCTT
440
GAGAAAAGTCACATCCAGCTCCTTCATGTTGCTGCCGATGTGGGATTTTCCTGGCTTCGTCAGCCAAGCAATTGGCTGCCTTTG CCGGAGGCTTTGAGAACCAAGGCTTGAAGGCCGGCAGGAGCATCCAGGGGGAAGCTTGGCTTCAGGGAGGACCTAGCAGACGTT GGGCCGGAGCACTAGCCTCACGGAGAAGGATCTGAAAGAAGCCAAGGCGCGGAGCCAGCAGATTGCAGCCCAGCTGACCACCCC TCCCAGCTCCAATTCCCGTGGCGTCCAGCTCTTCAACAGGCGCCGGCAGAGGGTGAACGAGTTCACCTTGGAGAGCCACGGCCA GAGGGGACAGAAGCCCAGCCAGGAGTCCCTCAGAGTGCTCCCTTCAAGCCTCCCAGGCCATGCACCGGGGCTCAGCCTGAGTTC CACCTCGCTGCCGGAGCCAGGCCCTCCACGGCACCCCAGTCCCCAGAGCCCCGACAGAGGGGTCCCTGGCCACAGCATGGAGGG GTACTCAGAGGAGGCTAGCTTGCTGCGGCACCTGGAGAAGGTGGCCAGTGAGGAGGAAGAGGTACCACTGGTGGTTTATCTAAA GGAGAATGCAGCACTGCTGACAGCCAATGGGCTGCACCTGTCCCAAAACCGAGAGGCCCAGCAGTCCTCACCGGCCCCACCTCC AGCTGAGGTCCACAGCCCAGCTGCAGATGTCAACCAAAACCTTGCCTCGCCCAGTGCCACGCTCACCACACCAACTTCTAACAG CAGCCACAATCCGCCAGCCACCGATGTCAATCAGAACCCACCGGCAACTGTTGTCCCACAGAGCCTGCCACTTTCTAGCATCCA ACAGAATTCCTCAGAGGCCCAACTCCCATCTAATGGCACAGGGCCTGCTTCCAAACCCAGCACCCTGTGTGCTGATGGGCAACC CCAGGCACCGGCTGAGGAGGTGAGATGCAGCACACTCCTAATTGACAAGGTATCAACTCCAGCTACCACCACCAGCACCTTCTC CAGAGAAGCTACGCTCATCCCCAGCTCCAGGCCCCCAGCCTCAGATTTCATGTCCAGCTCCCTGCTCATTGACATCCAGCCCAA CACCCTAGTGGTGTCAGCAGATCAAGAGATGTCTGGGCGAGCAGCTGCCACCACGCCCACCAAGGTCTACAGTGAGGTCCACTT CACACTGGCCAAGCCCCCATCAGTGGTCAACAGGACGGCCAGGCCTTTTGGGATCCAGGCGCCAGGGGGCACCAGCCAGATGGA GAGGAGCCCCATGCTAGAGAGACGACATTTTGGGGAGAAGGCCCCGGCTCCCCAGCCCCCCAGTTTGCCAGACAGGAGCCCCCG GCCACAGAGACACATAATGTCCCGCAGCCCCATGGTGGAAAGGAGGATGATGGGGCAGCGAAGCCCGGCCTCAGAGAGACGCCC CTTGGGGAACTTCACTGCACCCCCCACCTACACTGAGACCTTGTCCACAGCCCCTCTGGCTTCCTGGGTGAGGTCTCCTCCCTC ATATTCTGTCCTGTATCCCAGCTCCGACCCCAAGTCTTCTCATCTGAAGGGCCAGGCGGTTCCTGCCAGCAAGACGGGCATTCT GGAGGAGTCGATGGCCCGCCGGGGCAGCCGCAAATCCATGTTTACTTTCGTGGAGAAGCCCAAGGTGACCCCGAATCCAGACTT GCTGGATCTGGTACAGACAGCGGATGAGAAGCGGCGGCAGAGGGACCAGGGGGAGGTAGGCGTGGAGGAGGAGCCCTTCGCACT GGGGGCCGAGGCCTCCAACTTCCAGCAGGAGCCAGCACCTCGTGACAGGGCCAGCCCCGCGGCGGCGGAGGAGGTGGTACCAGA GTGGGCCTCCTGCCTCAAGTCACCCCGCATCCAGGCCAAGCCGAAGCCCAAACCCAACCAGAACCTCTCCGAGGCCTCTGGGAA GGGAGCTGAGCTCTACGCCCGCCGCCAGTCACGGATGGAGAAATATGTCATCGAGTCTTCAAGCCACACGCCAGAGCTGGCCCG CTGCCCATCACCTACCATGTCCCTGCCTTCCTCCTGGAAATACCCCACTAACGCCCCCGGGGCCTTCCGAGTGGCATCCCGAAG CCCAGCCCGGACCCCGCCTGCCTCCCTCTACCATGGCTACCTGCCTGAGAACGGGGTCCTGCGCCCAGAGCCCACCAAGCAGCC GCCATACCAGCTGCGCCCCTCGCTCTTTGTCCTCTCACCTATCAAGGAGCCTGCCAAGGTCTCACCAAGAGCTGCCTCGCCCGC CAAGCCCAGCTCCTTGGACCTGGTGCCCAACCTGCCCAAGGGGGCTCTCCCTCCATCTCCTGCCCTGCCTCGGCCCTCGCGCTC CTCACCGGGCCTCTACACCTCCCCCGGCCAGGACAGCCTGCAGCCCACTGCCGTGAGCCCTCCTTACGGCGGTGACATCTCCCC CGTGTCTCCCTCCAGGGCGTGGTCTCCCCGAGCCAAGCAGGCCCCCAGGCCCTCCTTCTCTACCCGGAACGCCGGGATCGAGGC TCAGGACCGCCGGGAGAGCCTGCCCACCTCCCCACCCTGGACGCCGGGCGCGTCCCGGCCCCCCAGCAGCCTAGACGGCTGGGT GAGCCCGGGCCCGTGGGAGCCAGGTCGCGGGAGCAGCATGAGCAGCCCCCCGCCGCTGCCGCCGCCACCGCCCATGTCTCCCTC GTGGAGCGAGCGCTCGGTGTCCCCGCTGCGACCTGAGACCGAGGCGCGGCCCCCCAGCCGCCAGCTGCAGGCGCTTCTGGCGCG AAACATCATCAATGCGGCCCGGCGCAAGAGCGCCTCCCCGCGGTCGGCGGGCGCCGAGAACCCGCGGCCCTTCTCCCCGCCGAG GGCGCCACCGCCCCCGCCCCCGCCCCCGCCCCCGCCCCCGCGCATGCGCTCGCCACAGCCCGCCCGCCCCGGCTCGGCTGCTGT GCCGGGGGCAGCCTTCGCGCCCATCCCGCGGAGCCCGTTGCCCGCCGGTCCTTCGTCCTGCACCAGTCCCCGGAGCCCGCTGCC CGCGCCTCCCAGGCCCTTCCTCTACCGCCGCTCGCCCACGGACTCCGACGTGTCCCTCGACTCCGAGGACTCCGGGGCTAAGTC TCCAGGCATCCTGGGCTACAATATCTGTCCCCGCGGGTGGAATGGCAGCCTTCGGCTCAAGCGTGGCAGCCTCCCCGCCGAGGC CTCCTGCACCACCTAGAGCCCCACCCCCGACCCCACCCCGGGAGGGCAGAGCCAGAAGAAGGCTCATTAGACCTGGGGGACCCA AAGGGTCTGGCCTCTTTGGGCAGCCCCAGAGATGAGGGGTCAGCAGAGGAGAGCTCTGGGGTTGGGGATGGGTTAGGGACGCAA GCTTGAGTTCTAGCCCTTGCTCTCATTCAGCTGTTGTGTGACCCTGGGTAAGACCCTTCCTTGTTTGACCCTCAGCTTTCCCAT CTGTTTAATGGTGGCTTTGGCCAAGGCAATCCACAAACGTCAAAATTCCCCTTCCCATCAGTACACACACCGATGCACACACAC TCTCTCTTTCTCTCTCTCTCTCTCTCACACACACACACACACACACACACACACACACACACACACACACACACTAGTTAGTGC CTTGGATGAGGCGGGGCAGTGTGTATATGGACCCCTGGACTTGCTACCTTCAGGGTT'CCATACTCGTCCCTCCCCTCCTGGCTC TGCTGTCTGGAGTCTGGCAAGCGGGGTGTGTTCAGAAGGTCCTAGGCCTGTGTCGCATGTCCAGGCACTGGCCTGACCATCCGG CTCCCTGGCACCAAGTCCCAGGCAGGAGCAGCTGTTTTCCATCCCTTCCCAGACAAGCTCTATTTTTATCACAATGACCTTTAG AGAGGTCTCCCAGGCCAGCTCAAGGTGTCCCACTATCCCCTCTGGAGGGAAGAGGCAGGAAAATTCTCCCCGGGTCCCTGTCAT GCTACTTTCTCCATCCCAGTTCAGACTGTCCAGGACATCTTATCTGCAGCCATAAGAGAATTATAAGGCAGTGATTTCCCTTAG GCCGAGGACTTGGGCCTCCAGCTCATCTGTTCCTTCTGGGCCCATTCATGGCAGGTTCTGGGCTCAAAGCTGAACTGGGGAGAG AAGAGATACAGAGCTACCATGTGACTTTACCTGATTGCCCTCAGTTTGGGGTTGCTTATTGGGAAAGAGAGAGACAAAGAGTTA CTTGTTACGGGAAATATGAAAAGCATGGCCAGGATGCATAGAGGAGATTCTAGCAGGGGACAGGATTGGCTCAGATGACCCCTG AGGGCTCTTCCAGTCTTGAAATGCATTCCATGATATtAGGAAGTCGGGGGTGGGTGGTGGTGGTGGGCTAGTTGGGCTTGAATT TAGGGGCCGATGAGCTTGGGTACGTGAGCAGGGTGTTAAGTTAGGGTCTGCCTGTATTTCTGGTCCCCTTGGAAATGTCCCCTT CTTCAGTGTCAGACCTCAGTCCCAGTGTCCATATCGTGCCCAGAAAAGTAGACATTATCCTGCCCCATCCCTTCCCCAGTGCAC TCTGACCTAGCTAGTGCCTGGTGCCCAGTGACCTGGGGGAGCCTGGCTGCAGGCCCTCACTGGTTCCCTAAACCTTGGTGGCTG TGATTCAGGTCCCCAGGGGGGACTCAGGGAGGAATATGGCTGAGTTCTGTAGTTTCCAGAGTTGGCTGGTAGAGCCTTCTAGAG GTTCAGAATATTAGCTTCAGGATCAGCTGGGGGTATGGAATTGGCTGAGGATCAAACGTATGTAGGTGAAAGGATACCAGGATG TTGCTAAAGGTGAGGGACAGTTTGGGTTTGGGACTTACCGGGGTGATGTTAGATCTGGAACCCCCAAGTGAGGCTGGAGGGAGT TAAGGTCAGTATGGAAGATAGGGTTGGGACAGGGTGCTTTGGAATGAAAGAGTGACCTTAGAGGGCTCCTTGGGCCTCAGGAAT GCTCCTGCTGCTGTGAAGATGAGAAGGTGCTCTTACTCAGTTAATGATGAGTGACTATATTTACCAAAGCCCCTACCTGCTGCT GGGTCCCTTGTAGCACAGGAGACTGGGGCTAAGGGCCCCTCCCAGGGAAGGGACACCATCAGGCCTCTGGCTGAGGCAGTAGCA TAGAGGATCCATTTCTACCTGCATTTCCCAGAGGACTAGCAGGAGGCAGCCTTGAGAAACCGGCAGTTCCCAAGCCAGCGCCTG GCTGTTCTCTCATTGTCACTGCCCTCTCCCCAACCTCTCCTCTAACCCACTAGAGATTGCCTGTGTCCTGCCTCTTGCCTCTTG TAGAATGCAGCTCTGGCCCTCAATAAATGCTTCCTGCATT
441
MFGFHKPKMYRSIEGCClCRAKSSSSRFTDSKRYEKDFQSCFGLHETRSGDICNAC LVKR KKLPAGSKKNTOHWDARAGP S KTTLKPKKVKTLSGNRIKSNQISKLQKEFKRHNSDAHSTTSSASPAQSPCYSNQSDDGSDTEMASGSNRTPVFSF DLTY K RQKICCGIIYKGRFGEVLIDTHLFKPCCSNKKAAAEKPEEQGPEP PISTQE
442
AGACTATCTTTCTAGACAAGGCAGTTGAGGAGGAGGGAGCGCTTGAGGGGGACTGGCCTGGCGTGCACTCCGCACCTCGGGGAC
ATTATTGCGCGTGGAACGGCTGCTTTTGGAAGGCACAACTTCCTGAATGGACCATGACTCCCACCAAAGATCCCTGTCTCTGAT TCACCAAACAGCTTCAACCCTGAAACCAGGACGAGAAGTTGACAACATCTGAGTGGACAGCTAATTGACCTAAGACTTCAGACC AGACTATTGCCCAGAAGAAAAGATGTTTGGTTTTCACAAGCCAAAGATGTACCGAAGTATAGAGGGCTGCTGTATTTGCAGAGC TAAGTCCTCCAGTTCTCGATTCACTGACAGTAAACGCTATGAAAAGGACTTCCAGAGCTGTTTTGGATTGCATGAGACTCGTTC AGGAGACATCTGCAATGCCTGTGTCCTGCTTGTGAAAAGATGGAAGAAGTTGCCAGCAGGATCAAAAAAAAACTGGAATCATGT GGTAGATGCAAGGGCTGGACCCAGTCTAAAGACTACATTGAAACCAAAGAAAGTGAAAACTCTATCTGGGAACAGGATAAAAAG CAACCAGATCAGTAAACTGCAGAAGGAATTTAAACGTCATAATTCTGATGCTCACAGTACCACCTCAAGTGCCTCCCCAGCTCA ATCTCCTTGTTACAGTAACCAGTCAGATGACGGCTCAGATACAGAGATGGCTTCTGGTTCTAACAGAACACCAGTTTTTTCCTT TTTAGATCTCACTTACTGGAAAAGACAGAAGATATGTTGTGGGATCATCTATAAAGGCCGTTTTGGGGAAGTCCTCATTGACAC ACATCTCTTCAAGCCTTGCTGCAGCAATAAGAAAGCAGCTGCTGAGAAGCCAGAGGAGCAGGGGCCAGAGCCTCTGCCCATCTC CACTCAGGAGTGGTGACTGAGGTTTTTATGTAGAAGGGGAACAAAAAAAAAAATCTGAATTTTGAAAAACCACAAAGCTACAAA CTGACCCTCTTTTTTTTTTTTTTTTTTTGAGACGGAGTTTTGCTCTTGTTACCCAGGCTGGAGTGCAGTGGCGTGATCTTGGCT CACTGCAACTTCCGTCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGTTTATAGGTGCCCGCCACCAG ACCCGGCTAATTTTTTAGTTTTAGTAGAGACGGGGTTTCACCACGTTGGCCAGGCTGGTCTTAAATGACCCTCTTATTTTTAAC TTGGATACCTGCTATTCTGCCAAAAGACAATTTCTAGAGTAGTTTTGAATGGGTTGATTTCCCCCACTCCCACAAACTCTGAAG CCAGTGTCTAGCTTACTAAAAAAAGAGTTGTATATAATATTTAAGATGCTGAGTATTTCATAGGAAAGCTGAATGCTGCTGTAA AGTGCTCTTTAAGTCTTTTTTTTTTTAATCCCCTTCTAATGAATGAAACTAGGGGAAT'TTCAGGGGACAGAGATGGGATTTGTT GTATGATAAACTGTATGTAGTTTTTAGTCTTTCTGTTTTGAGAAGCAGTGGTTGGGGCATTTTTAAGATGGCTGGCTACTCTTG TTTTCCCTCATGATAATAAATTTGTCATAACTCAGTAACATGAACTTGCCCCTAGAGGTAGTTGTTAATAATTTTGAAATATTA AGGTCTTGCCAAGCTTCTGATGATTCACACCTGTACTACTGATTATTAAGCAGGACAGACTGAGCTTTCTGTTGCAAATACCTT GGAGGAGAAAGTAATTTCTAAATATACAGAGAGGTAACTTGACTATATATGTTGCATCCTGTGCCTCCCTTCATATTAATATTT GATAAAGATTTTAATTTATGTAAAACTTCTAAAGCAGAATCAAAGCTCCTCTTGGGGAAATGGCAAGTCTTTAGGATAGGCAAG ACCCTGTATGAATAGTACCAAAGCATTACCGCATGGTAGAGAACACACTCGATTAAAAATGTTAAGCTATCTGAAAAATAAAAT GTGCAAGTCTTCAGGATGGCACAAAACAAAGGTTAATGCTTCTTGGGGCACATTTCTTAGAGGGCTTGCTGAGTGTGTAAATAT AATCGACTTTTGTTTGTGTTACATGACTTCTGTGACTTCATTGAAAATCTGCACAATTCAGTTTCAGCTCTGGATTACTTCAGT TGACCTTTGTGAAGGTTTTTATCTGTGTAGAATGGGTGTTTGACTTGTTTTAGCCTATTAAATTTTTATTTTCTTTCACTCTGT ATTAAAAGTAAAACTTACTAAAAGAAAAGAGGTTTGTGTTCACATTAAATGGTTTTGGTTTGGCTTCTTTTAGTCAGGCTTTCT GAACATTGAGATATCCTGAACTTAGAGCTCTTCAATCCTAAGATTTTCATGAAAAGCCTCTCACTTGAACCCAAACCAGAGTAC TCTTACTGCCTCTTTTCTAAATGTTCAGGAAAAGCATTGCCAGTTCAGTCTTTTCAAAATGAGGGAGAAACATTTGCCTGCCTT GTAATAACAAGACTCAGTGCTTATTTTTTAAACTGCATTTTAAAAATTGGATAGTATAATAACAATAAGGAGTAAGCCACCTTT TATAGGCACCCTGTAGTTTTATAGTTCTTAATCTAAACATTTTATATTTCCTTCTTTTGGAAAAAACCTACATGCTACAAGCCA CCATATGCACAGACTATACAGTGAGTTGAGTTGGCTCTCCCACAGTCTTTGAGGTGAATTACAAAAGTCCAGCCATTATCATCC TCCTGAGTTATTTGAAATGATTTTTTTTGTACATTTTGGCTGCAGTATTGGTGGTAGAATATACTATAATATGGATCATCTCTA CTTCTGTATTTATTTATTTATTACTAGACCTCAACCACAGTCTTCTTTTTCCCCTTCCACCTCTCTTTGCCTGTAGGATGTACT GTATGTAGTCATGCACTTTGTATTAATATATTAGAAATCTACAGATCTGTTTTGTACTTTTTATACTGTTGGATACTTATAATC AAAACTTTTACTAGGGTATTGAATAAATCTAGTCTTACTAGAAAAAAAAAAAAAAGAAAAAAAAAAAAAAAAA 443
MKSQWCRP¥AMD GVYQLRHFSISFLSSLLGTENASVRLDNSSSGASVVAIDNKIEQAMDLVKSH MYAVREEVEVLKEQIKEL IEKNSQLEQEN L KTLASPEQLAQFQAQLQTGSPPATTQPQGTTQPPAQPASQGSGPTA
444
CGCCTCTTCACGGCACTGGGATCCGCATCTGCCTGGGATCATCAAGCCCTAGAAGCTGGGTTTCTTTAAATTAGGGCTGCCGTT TTCTGTTTCTCCCTGGGCTGCGGAAAGCCAGAAGATTTTATCTAGCTTATACAAGGCTGCTGGTGTTCCCTCTTTTTTTCCACG
AGGGTGTTTTTGGCTGCAATTGCATGAAATCCCAATGGTGTAGACCAGTGGCGATGGATCTAGGAGTTTACCAACTGAGACATT
TTTCAATTTCTTTCTTGTCATCCTTGCTGGGGACTGAAAACGCTTCTGTGAGACTTGATAATAGCTCCTCTGGTGCAAGTGTGG
TAGCTATTGACAACAAAATCGAGCAAGCTATGGATCTAGTGAAAAGCCATTTGATGTATGCGGTCAGAGAAGAAGTGGAGGTCC
TCAAAGAGCAAATCAAAGAACTAATAGAGAAAAATTCCCAGCTGGAGCAGGAGAACAATCT'GCTGAAGACACTGGCCAGTCCTG AGCAGCTTGCCCAGTTTCAGGCCCAGGTGCAGACTGGCTCCCCCCCTGCCACCACCCAGCCACAGGGCACCACACAGCCCCCCG
CCCAGCCAGCATCGCAGGGCTCAGGACCAACCGCATAGCTGCCTATGCCCCCGCAGAACTGGCTGCTGCGTGTGAACTGAACAG
ACGGAGAAGATGTGCTAGGGAGAATCTGCCTCCACAGTCACCCATTTCATTGCTCGCTGCGAAAGAGACGTGAGACTGACATAT
GCCATTATCTCTTTTCCAGTATTAAACACTCATATGCTTATGGCTTGGAGAAATTTCTTAGTTGGGTGAATTAAAGGTTAATCC
GAGAATTAGCATGGATATACCGGGACCTCATGCAGCTTGGCAGATATCTGAGAAATGGTTTAATTCATGCTCAGGAGCTGTGTG CCTTTCCATCCCTTCCGGCTCCCTACCCCTCACTTCCAAGGGTTCTCTCTCCTGCTTGCGCTTAGTGTCCTACATGGGGTTGTG AAGCGATGGAGCTCCTCACTGGACTCGCCTCTCTCCTCTCCTCCCCCCAGGAGGAACTTGAAAGGAGGGTAAAAAGACTAAAAT GAGGGGGAACAGAGTTCACTGTACAAATTTGACAACTGTCACCAAAATTCATAAAAAACAATAGTACTGTGCCTCTTTCTTCTC AAACAATGGATGACACAAAACTATGAGAGTGACAAAATGGTGACAGGTAGCTGGGACCTAGGCTATCTTACCATGAAGGTTGTT TTGCTTATTGTATATTTGTGTATGTAGTGTAACTATTTTGTACAATAGAGGACTGTAACTACTATTTAGGTTGTACAGATTGAA ATTTAGTTGTTTCATTGGCTGTCTGAGGAGGTGTGGACTTTTATATATAGATCTACATAAAAACTGCTACATGACAAAAACCAC ACCTAAACCCCTTTTAAGAATTTGGCACAGTTACTCACTTTGTGTAATCTGAAATCTAGCTGCTGAATACGCTGAAGTAAATCC TTGTTCACTGAAGTCTTTCAATTGAGCTGGTTGAATACTTTGAAAAATGCTCAGTTCTAACTAATGAAATGGATTTCCCAGTAG GGGTTTCTGCATATCACCTGTATAGTAGTTATATGCATATGTTTCTGTGCATGTTCTCTACACAATTGTAAGGTGTCACTGTAT TTAACTGTTGCACTTGTCAACTTTCAATAAAGCATATAAATGTTG 446
TTTTTTTTTTTTTTTTTTTCACTATGAAAATGCTTTAATGGTGGTGTCTGTACAGCATGGATGTGGACAGGGAAAACAGCAAGT GCACACAGTGGGACAGGCCACAGGACAGGCTGGGAGTGAATAAAGAGTTCACACTGCTTCCCTGCTTTCCCCAGTGACTGAA'GG CTCTAGGCCACCTCCTCCTCAGCCTCCTGCTCGAACTCGCCCTCCTCCTCGGCTGTGGCATCCTGGTACTGCTGGTACTCGGAC ACCAGGTCATTCATGTTGCTCTCGGCCTCGGTGAACTCCATCTCGTCCATGCCCTCGCCCGTGTACCAGTGCAGGAAGGCCTTG CGCGGNAACATGGCCGTGAACTGCTCGGAGATGCGCTTGAACAGCTCCTGGATGGCCGTGCTGTTGCCAATGAAGGTGGCGGAC ATTTTTAACCCCGAGGTGGGATGTCACGACAGCCGTTTTCACATTGTTGGGGGATCACTCAACAAAATAGC
447
MLTELEKALNSIIDVYHKYSLIKGNFHAVYRDDLKKLLETECPQYIRKKGADVWFKELDINTDGAVNFQEFLILVIKMGWQPTK KAMKKATKSS 448
ATGTCTCTTGTCAGCTGTCTTTCAGAAGACCTGGTGGGGNAAGTCCGTGGGCATCATGTTGACCGAGCTGGAGAAAGCCTTGAA CTCTATCATCGACGTCTACCACAAGTACTCCCTGATAAAGGGGAATTTCCATGCCGTCTACAGGGATGACCTGAAGAAATTGCT AGAGACCGAGTGTCCTCAGTATATCAGGAAAAAGGGTGCAGACGTCTGGTTCAAAGAGTTGGATATCAACACTGATGGTGCAGT TAACTTCCAGGAGTTCCTCATTCTGGTGATAAAGATGGGCTGGCAGCCCACAAAAAAAGCCATGAAGAAAGCCACAAAGAGTAG CTGAGTTACTGCCCAGAGGCTGGGCCCCTGACATGTACCTGCAGAATAATAAAGTCATCAATACCTCAAAAAAAAAAAAAAAAA AAAA
449
MDIRKFFGVIPSGKKLVSETVKKNEKTKSDEETLKAKKGIKEIKVNSSRKEDDFKQKQPSKKKRIIYDSDSESEET QVKNAKK PPEKLPVSSKPGKISRQDP¥TYISETDEEDDFMCKKAASKSKENGRSTNSHLGTSNMKK EENTKTKNKPLSPIK TPTSV DY FGTGSVQRSNKKMVASKRKELSQNTDESGLNDEAIAKQ QLDEDAE ERQLHEDEEFARTLAMLDEEPKTKKARKDTEAGETFS SVQANLSKAEKHKYPHK¥KTAQVSDERKSYSPRKQSKYESSKESQQHSKSSADKIGEVSSPKASSKLAIMKRKEESS.YKEIEPV ASKRKENAIKLKGETKTPKKTKSSPAKKESVSPEDSEKKRTNYQAYRSYLNREGPKALGSKEIPKGAENC EGLIFVITGVLES IERDEAKSLIERYGGKVTGNVSKKTNYLVMGRDSGQSKSDKAAALGTKIIDEDGLLNLIRTMPGKKSKYEIAVETEMKKESK E RTPQK¥QGKRKISPSKKESESKKSRPTSKRDS AKTIKKETDVFWKS DFKEQVAEETSGDSKARNLADDSSENKVENLLW¥D KYKPTSLKTIIGQQGDQSCMKLLRWRNWQKSSSED5KHAAKFGKFSGKDDGSSFKAAL SGPPGVGKTTTAS VCQELGYSY VELNASDTRSKSSLKAI¥AESLmTSIKGFYSNGAASSVSTKHALIMDEVDGMAGNEDRGGIQELIG IKHTKIPIICMCNDRN HPKIRSLVHYCFDLRFQRPRVEQIKGAMMSIAFKEGLKIPPPAM EIILGANQDIRQVLHN SM CARSKA TYDQAKADSHRA KKDIKMGPFD¥ARKVFAAGEETAHMSL¥DKSD FFHDYSIAPLFVQENYIHVKPVAAGGDMKKHLML SRAADSICDGDLVDSQ IRSKQMSLLPAQAIYASVLPGELMRGYMTQFPTFPSWLGKHSSTGKHDRIVQDLALHMSLRTYSSKRTVMDYLSLLRDAVQ PLTSQGVDGVQDWALMDTYYLMKEDFENIMEISS GGKPSPFSKLDPKVKAAFTRAYNKEAHLTPYSLQAIKASRHSTSPS D SEYNEELNEDDSQSDEKDQDAIETDAMIKKKTKSSKPSKPEKDKEPRKGKGKSSKK
450
GTCCTTGCTTCTTTTTTCATTGATGTAAATTTTTTTAACTTAATATGAAAACTCTCCAAGTCTTGATCATCAGCCAGGATTTTG CCACAGCAATTTCATTCTCTTATCGGAGCTTGTATGTGTCAAAGTATACTTCAGAGTGCAAACATTAAGCAAGTAATATATTTT ACCTACAGATACTTATGAAGACATTCTTTCGCTATCGTGAGTAAAAGTATATAAAGCTGTTTCTAACTGAAAATGCTTGAAATA AGCCTGTAATAGAAATATTTTTTCATTTTTTAAAAAAGGGCGGAATTCCCAGACTGTCTTCGCCTTCTTGCACTTCGCGGGAGA AGTTGTTGGCGCGAATGGATCCTGAGCeTCGATAACAGATTCCTCAACCGGCCCACCCGCCAGCCAGCCAGCGCCTTCATCCTG GGGCTGCGATGGACATTCGGAAATTCTTTGGAGTAATACCAAGTGGAAAGAAACTTGTAAGTGAAACAGTAAAGAAGAATGAGA AAACAAAGTCTGATGAAGAAACTTTAAAAGCAAAGAAAGGAATAAAGGAAATCAAGGTAAATAGCTCCCGTAAAGAGGATGACT TCAAACAAAAGCAACCAAGCAAGAAAAAGAGGATCATCTATGATTCAGATTCAGAGTCAGAGGAGACGTTGCAGGTAAAAAATG CCAAAAAGCCACCAGAAAAACTGCCAGTATCTTCTAAACCTGGTAAAATTTCACGGCAGGATCCTGTTACATACATTTCAGAAA CAGATGAAGAAGATGACTTTATGTGTAAGAAGGCGGCCTCTAAATCAAAAGAGAATGGAAGATCTACAAATAGTCATCTTGGAA CATCAAACATGAAAAAGAATGAAGAAAACACTAAGACCAAGAATAAGCCTTTATCACCAATAAAACTTACACCCACATCAGTAC TTGATTATTTTGGAACTGGAAGTGTCCAAAGATCTAATAAGAAGATGGTGGCAAGCAAAAGAAAAGAGCTTTCACAAAATACAG ATGAGTCTGGATTAAATGATGAAGCCATCGCCAAGCAATTACAGCTTGATGAAGATGCGGAGCTGGAGAGGCAGTTGCATGAAG ATGAAGAGTTTGCCAGAACATTAGCCATGTTGGATGAAGAACCCAAGACCAAAAAGGCTCGAAAGGACACAGAAGCGGGAGAAA CGTTTTCATCTGTCCAAGCCAATTTAAGTAAAGCAGAAAAACATAAATATCCTCATAAAGTAAAAACAGCACAAGTTTCAGATG AAAGAAAGAGCTACAGTCCTAGGAAGCAAAGTAAATATGAAAGTTCAAAAGAATCTCAGCAACATTCCAAGTCATCAGCTGACA AAATAGGAGAAGTCTCTTCTCCCAAGGCCAGTTCTAAGCTGGCAATTATGAAAAGAAAAGAAGAGAGCTCTTATAAAGAAATAG AGCCTGTGGCCTCAAA GAAAAGAAAATGCCATTAAATTGAAAGGAGAGACAAAAACTCCTAAGAAAACCAAAAGTTCTCCAG CTAAAAAAGAGTCTGTAAGTCCTGAAGATTCTGAAAAGAAACGCACTAATTATCAAGCTTATCGAAGCTACTTAAATCGAGAAG GTCCCAAGGCTCTGGGCTCCAAAGAAATACCAAAGGGAGCTGAAAATTGCTTGGAAGGCCTTATATTTGTAATCACAGGCGTGC TGGAGTCTATTGAACGAGATGAGGCCAAGTCTCTAATTGAACGTTATGGGGGAAAAGTAACAGGAAATGTCAGCAAGAAAACAA ATTATCTTGTCATGGGTCGTGATAGTGGACAGTCCAAGAGTGATAAGGCCGCAGCCTTGGGGACAAAAATTATTGATGAAGATG GCCTGTTGAATCTGATTCGGACTATGCCAGGCAAGAAATCCAAGTATGAAATAGCAGTTGAAACTGAGATGAAGAAAGAGTCCA AACTGGAGAGAACACCCCAAAAAAATGTCCAAGGAAAAAGAAAAATTAGTCCATCTAAAAAGGAATCAGAATCTAAAAAGAGCA GGCCGACTTCCAAAAGGGACAGTTTGGCAAAGACAATAAAAAAGGAAACAGATGTGTTTTGGAAAAGCCTGGATTTCAAGGAGC AGGTGGCTGAGGAGACAAGTGGTGACAGCAAGGCTAGGAATTTGGCTGATGACAGCAGTGAAAACAAAGTGGAAAATTTGCTCT GGGTGGATAAATATAAGCCAACCTCGCTCAAGACCATAATTGGACAGCAAGGTGACCAGAGCTGTGCCAACAAACTCCTACGCT GGCTCCGAAACTGGCAAAAGAGTTCTTCCGAAGATAAAAAACACGCAGCAAAGTTTGGTAAATTTTCCGGCAAAGATGATGGCT CTAGTTTTAAAGCAGCGTTGCTGTCAGGCCCTCCTGGTGTTGGCAAAACCACCACAGCTTCCCTGGTGTGTCAGGAGTTGGGAT ACAGCTACGTGGAACTGAATGCAAGTGACACCCGGAGTAAGAGCAGTTTGAAGGCGATTGTTGCTGAGTCACTGAACAATACCA GCATCAAAGGCTTTTATTCAAATGGAGCAGCCTCTTCAGTAAGCACGAAACATGCTCTCATCATGGATGAAGTAGATGGCATGG CAGGCAATGAGGATAGGGGAGGAATTCAGGAATTAATTGGCCTGATAAAACATACTAAAATTCCCATTATTTGTATGTGCAATG ATAGAAATCATCCCAAGATTCGCTCTCTGGTTCATTATTGTTTTGATCTTCGTTTTCAAAGACCTCGGGTTGAACAGATTAAGG GTGCTATGATGTCTATTGCATTTAAAGAAGGTTTAAAGATTCCCCCTCCAGCTATGAATGAAATAATTTTGGGAGCCAATCAAG ATATCAGACAGGTTTTACATAATCTGAGTATGTGGTGTGCACGAAGTAAAGCATTAACCTATGACCAGGCCAAAGCTGATTCTC ACAGAGCCAAAAAGGATATCAAAATGGGCCCATTTGATGTTGCCCGGAAAGTGTTTGCAGCTGGAGAGGAGACTGCTCACATGT CACTTGTGGACAAGTCAGATCTCTTTTTTCATGATTATTCAATAGCACCCCTCTTCGTCCAGGAAAATTACATACACGTGAAGC CTGTAGCAGCAGGGGGTGACATGAAAAAGCACCTGATGCTTTTAAGCAGAGCAGCAGACAGCATATGCGATGGTGACCTAGTGG ACAGCCAGATCCGGAGTAAGCAAAACTGGAGTCTTCTGCCTGCGCAGGCCATTTATGCCAGTGTTCTTCCTGGAGAGTTGATGA GGGGGTACATGACCCAGTTTCCCACCTTCCCAAGCTGGCTGGGGAAGCACTCGTCTACAGGCAAACATGATCGTATTGTTCAGG ACCTGGCCTTGCATATGAGTCTCAGAACTTACTCCAGCAAAAGGACTGTAAACATGGATTATCTGTCGCTTCTAAGGGATGCAC TTGTACAGCCCTTGACCTCACAAGGAGTAGACGGAGTACAGGATGTTGTTGCACTTATGGACACATATTATTTGATGAAAGAAG ACTTTGAGAATATCATGGAAATCAGCAGCTGGGGTGGCAAACCTAGTCCCTTTTCAAAGCTGGATCCCAAGGTGAAAGCAGCCT TCACAAGAGCTTACAATAAGGAAGCCCACCTTACTCCATACTCACTTCAAGCTATAAAGGCATCTAGACACAGCACAAGCCCAT CCCTGGATTCGGAATACAATGAAGAATTAAATGAAGATGACTCTCAATCTGATGAGAAAGACCAAGATGCTATAGAAACTGATG CCATGATCAAGAAAAAGACAAAATCTTCAAAGCCTTCAAAACCAGAAAAAGATAAGGAGCCCAGAAAAGGAAAAGGAAAAAGTT CGAAGAAATGAAACCATTTTTCACTAGCGACAGCCACTTTTTACTCTCCCTCCTGACCAGTCCAGCTGGTCTAGAGAAAGCCTT GTTTTTTCCCAGAGCAACCATGTTTTAGCATAATGGGATGACCTGGTGTCCCATTATAAATAAAGGGTGGTATGGCTAGAAGGG TATGAGCAGTAGGCTTATGTACACCTCTTATAGAGGTTGATAGGACTGCTTGGGTCCTCCACTGTCCTCTGTCAATCTAGTTAG ACGTGCTTCTGAATGACTGTAGAATTGGAACTAGAAACTACACCTGGGCTTTGGAGTCAGATTTTAGTTAACAATAATGAGCCT GGAGCAGTAGTACTAAGGCGTCTTTTGTAGGCTTAAGAATTTATCCTAATGGCCTTTATAGGACCAATGCTGATTTTTTTTAAA GGCAGTTCCTATTATGTGGTGAAATTTTGTAAATAAATGATTATACAAAACAGTCACCACCTAGAACTGGGTATTCTTTGTACA TTGTCAGATATCTTTCAAAGTATAAATTAGGAATAAAAATGTTCCACATGATATGTGTACAAATTCTTTTTAAGATTGTCATCT TGTACAGCAAAATATTATGTTGGTATATTACTTCCTTATTAATTTGCAAATGATTGGATTAAAAAAGCTCACTGTATTCCTTAC TAACCTGTTGTGTGAAACATAACATTGGCAGTCGAGGAGTCAGAACTCGGATTCCCAGCCTCACTCCCTCTGTGTGTGTTGACC ACGTCTCTGCTGTGAATAGGATTTCATGCAGTGGTCTGTTATGGGGCTTTGCAGCGTGGGGGGCTGCAGAAGATTCTCAGACAT TCTTATCCTTCTGGAGTCTCAACCCATCAGGTTCAGACCAGTAGGAACCAGGCTGGGTCAGGCTCTTAATTTCACTACGGTGGG GGACAAAATGAACACTGGCTTTTGTTCACTTTGCCCCTGAGAGATCTAGTCCTGTCCTGTGATGGCTTCCACAAACCCTGTTGG AAGTTTGGGTTATTCCTATAACTGTATGTGTTGAGTGGCCGTGACGTATGGACCTAGCCTGGAATTTAGATGTCTAGCTATTTT TTAATCTTGTTGGTAAATGCTCAGAGGTCTGTGCTACCTCTGTGAGGTATATACTAAAATGAATGTAAAATAAGGATCGTATTC CCTGCTTTAAGGAACTGGTAGTCTTGTTTGGGTGATGAGACAAAGTTCTTGAGACATTTAAACTGTATTTACCAGTGTGAAAAA TGTCATTTATGGAGATTAATTCATTATGGAAATAAAACATTGCCTAAGCCCTTGCCTGCTG
451 CA RSPADQDRFICIYPAYLMKKTIAEGRRIPISKAVENPTATEIQDVCSAVGLWFLEKNKMYSREWNRDVQYRGRVRV QLKQEDGS CLVQFPSRKSVMLYAAEMIPKLKTRTQKTGGADQSLQQGEGSKKGKGKKKK
452 CGGAAACTCAGAGCCGGGTTCCTCCCGGGTTTCTGCCGGGTTTCTCCCTGCGGCTCCTGGGTTGTTGAGACTCTTGTGAAGATG GCTTGCGCTGCCGCGCGGTCCCCGGCCGACCAGGACAGGTTTATTTGTATCTATCCTGCTTATTTAAATAATAAGAAGACCATC GCAGAGGGAAGGCGAATCCCCATAAGTAAGGCTGTTGAAAATCCTACAGCTACAGAGATTCAAGATGTATGTTCAGCAGTTGGA CTTAACGTATTTCTTGAGAAAAATAAAATGTACTCTAGAGAATGGAATCGTGATGTCCAATACAGAGGCAGAGTCCGGGTCCAG CTCAAACAGGAAGATGGGAGCCTCTGCCTTGTACAGTTCCCATCACGTAAGTCAGTAATGTTGTATGCAGCAGAAATGATACCT AAACTAAAAACAAGGACACAAAAAACAGGAGGTGCTGACCAAAGTCTTCAACAAGGAGAGGGAAGTAAAAAAGGGAAAGGAAAG AAAAAGAAGTAACCTAGTATCAGCATCAAGTATGTGGTACTACTGTAAGAGACATGAATGGAGACTTCTAATTTGTATCGGAGG GAAACAGAAGCTTTTTGTTTGCATCATTTAACTGAACTGTGAACCCTTGTGCCTCTCATCTTTATCATCGGAGTTGACAGTGAA ACAAATTTACATCAGAAGTTTGCATCTCGCGTATATGCCGTATAAAAGAATTTTTTTGTCTTTCAATGCAGTTTTTTGGAAGAA AATATTTTTAAATGGACAATGGACTGTACAATAAGTTACTTGAAATAAGTTGTTTCAGATAAATTTCAATTAGATTTAAAATAA ACATTATGTCCACCTTTTAAGTTAATGAAATAAAATTTGAAACTGAAAAAAAAA
454
CAAATTCCCTCTGGCACAGTGGGGATGTGTGGAAAAAAACTGAAGTCAAAGACCTCCTGCGTCGTCTAACTGGTCAGGCTGAAG GCAAGCTAATCTCTGTAGAATATGGAACAGAGGAAAAAATAAAAATACCAGTAATATCTGTTTATTCAGGTCCACTCAGAAGTG GTAGGAACATAGAAAGAGTGTCTTTCTACCTAGGATTTTCCATTGAAGGCCCTCTGGCATATGATATAGAAGTAATTTAAGACA ATACATCACCTGTAGTTCAAATATGTTTATTTATATCTTTATGATTTTATTCTCTCTCTCCATTCTCATGGCACTTTCATAACA TTATGGCTAACCTCTAATTAGAGATTTTGCTTTTGCCTCCCTGAATGAATTACAAGCCTTTTTAAGATATGAAATATGCCTACC CGCAGAGCTTGGCACAAAGTGGAGTCAATCTTTTAATGTTTTAAATATGCATTTTCAGACTCAAATAATTAAGAAGTTTCATTG ATATCCACTGGTCACATCATAACTGTCTATAGGGCAATAAAATCTGTGTTAAACTCAAAAAAAACAAAAAAAAA
455 MSRRYDSRTTIFSPEGRLYQVEYAMEAIGHAGTCLGILANDGVLLAAERR IHKLLDE¥FFSEKIYKLNEDMACSVAGITSDAN VLTNELR IAQRYLLQYQEPIPCEQLVTALCDIKQAYTQFGGKRPFGVS LYIGWDKHYGFQLYQSDPSGNYGGWKATCIG S AAAVSMLKQDYKEGEMT KSALALAIKVLNKTMDVSKLSAEKVEIAT TRENGKTVIRVLKQKEVEQLIKKHEEEEAKAEREKK EKEQKEKDK
456 CCGTGGACATCTCAGGTCTTCAGGGTCTTCCATCTGGAACTATATAAAGTTCAGAAAACATGTCTCGAAGATATGACTCCAGGA CCACTATATTTTCTCCAGAAGGTCGCTTATACCAAGTTGAATATGCCATGGAAGCTATTGGACATGCAGGCACCTGTTTGGGAA TTTTAGCAAATGATGGTGTTTTGCTTGCAGCAGAGAGACGCAACATCCACAAGCTTCTTGATGAAGTCTTTTTTTCTGAAAAAA TTTATAAACTCAATGAGGACATGGCTTGCAGTGTGGCAGGCATAACTTCTGATGCTAATGTTCTGACTAATGAACTAAGGCTCA TTGCTCAAAGGTATTTATTACAGTATCAGGAGCCAATACCTTGTGAGCAGTTGGTTACAGCACTGTGTGATATCAAACAAGCTT ATACACAATTTGGAGGAAAACGTCCCTTTGGTGTTTCATTGCTGTACATTGGCTGGGATAAGCACTATGGCTTTCAGCTCTATC
AGAGTGACCCTAGTGGAAATTACGGGGGATGGAAGGCCACATGCATTGGAAATAATAGCGCTGCAGCTGTGTCAATGTTGAAAC
AAGACTATAAAGAAGGAGAAATGACCTTGAAGTCAGCACTTGCTTTAGCTATCAAAGTACTAAATAAGACCATGGATGTTAGTA
AACTCTCTGCTGAAAAAGTGGAAATTGCAACACTAACAAGAGAGAATGGAAAGACAGTAATCAGAGTTCTCAAACAAAAAGAAG
• ■TGGAGCAGTTGATCAAAAAACATGAGGAAGAAGAAGCCAAAGCTGAGCGTGAGAAGAAAGAAAAAGAACAGAAAGAAAAGGATA AATAGAATCAGAGATTTTATTACTCATTTGGGGCACCATTTCAGTGTAAAAGCAGTCCTACTCTTCCACACTAGGAAGGCTTTA CTTTTTTTAAGTGGTGCAGTGGGAAAATAGGACATTACATACTGAATTGGGTCCTTGTCATTTCTGTCCAATTGAATACTTTAT TGTAACGATGATGGTTACCCTTCATGGACGTCTTAATCTTCCACACACATCCCCTTTTTTTGGAATAAAA 457
MAAELSMGPELPTSPLAMEYVNDFDL KFDVKKEP GRAERPGRPCTRLQPVGSVSSTPLSTPCSS¥PSSPSFSPTEQKTHLED LYMASNYQQMNPEALNLTPEDAVEALIGSHPVPQPLQSFDSFRGAHHHHHHHHPHPHHAYPGAGVAHDELGPHAHPHHHHHHQ ASPPPSSAASPAQQLPTSHPGPGPHATASATAAGGNGSVEDRFSDDQLVSMSVRELNRHLRGFTKDEVIRLKHKRRT K RGYA QSCRYKRVQQKHHLENEKTQLIQQVEQLKQE¥SRARERDAYKVKCEKLANSGFREAGSTSDSPSSPEFFL
458
CGCTTGGCTCGGCGCGCTCCGGCCGGCCGCAAAGTTTCCCGGGCGGCAGCGGCGGCTGCGCCTCGCTTCAGCGATGGCCGCGGA GCTGAGCATGGGGCCAGAGCTGCCCACCAGCCCGCTGGCCATGGAGTATGTCAACGACTTCGACCTGCTCAAGTTCGACGTGAA GAAGGAGCCACTGGGGCGCGCGGAGCGTCCGGGCAGGCCCTGCACACGCCTGCAGCCAGTCGGCTCGGTGTCCTCCACACCGCT CAGCACTCCGTGTAGCTCCGTGCCCTCGTCGCCCAGCTTCAGCCCGACCGAACAGAAGACACACCTCGAGGATCTGTACTGGAT GGCGAGCAACTACCAGCAGATGAACCCCGAGGCGCTCAACCTGACGCCCGAGGACGCGGTGGAAGCGCTCATCGGCTCGCACCC AGTGCCACAGCCGCTGCAAAGCTTCGACAGCTTTCGCGGCGCTCACCACCACCACCATCACCACCACCCTCACCCGCACCACGC GTACCCGGGCGCCGGCGTGGCCCACGACGAGCTGGGCCCGCACGCTCACCCGCACCATCACCATCATCACCAAGCGTCGCCGCC GCCGTCCAGCGCCGCTAGCCCGGCGCAACAGCTGCCCACTAGCCACCCCGGGCCCGGGCCGCACGCGACGGCCTCGGCGACGGC GGCGGGCGGCAACGGCAGCGTGGAGGACCGCTTCTCCGACGACCAGCTCGTGTCCATGTCCGTGCGCGAGCTGAACCGCCACCT GCGGGGCTTCACCAAGGACGAGGTGATCCGCCTGAAGCACAAGCGGCGGACCCTGAAGAACCGGGGCTACGCCCAGTCTTGCAG GTATAAACGCGTCCAGCAGAAGCACCACCTGGAGAATGAGAAGACGCAGCTCATTCAGCAGGTGGAGCAGCTTAAGCAGGAGGT GTCCCGGCTGGCCCGCGAGAGAGACGCCTACAAGGTCAAGTGCGAGAAACTCGCCAACTCCGGCTTCAGGGAGGCGGGCTCCAC CAGCGACAGCCCCTCCTCTCCCGAGTTCTTTCTGTGAGTCGTGGCCGGTCCTGGCCCCCGCCCTTGCCCCGGCCCGGACTCCCT GTCCCACGTCCCTAGTCCCAGACTACCCCGGACCCTGTCCCTGCCGCGGCCCCAGCCTTGACCTGTTTGACTTGAGCGAGAGGG AGGAAGGGCGCGCGGGCCGCGGGCGACGGGCGGGTGCGCGGGCGGGCAGGGGACCTTGGCTAAGGCGAGAGTAGCGCACGCCAG CGCCGCCTCCTAGACTCGAGCAGAGCCGGAGAGAGAGACGAGAGGGTGGGAGGTCCCGGAGTAACTTCTCTCCAGGCTGAAGGG CGGCGAGGCATACTCCCGATAAGTCACCAAGGCCATCTGGAGACTCCTGGCTTTCTGAACTTTGCGCGTTAAGCCGGGACAGCT GCTTTGCTGCCCGGAGAGTAGTCCGCGCCAGGAAGAGAGCAACGAGGAAAGGAGAGGGACTCTGGCGTCCCGGCAGGCGAGAGG CGAGGCTGAGCGAAAGAAGGAAGGACCAGACGGACCCTGTCTGTCAGAGTTCGGAGAAACACTGGCTCCTCAGCCCTGAGACAC AGGCCCTCAGTTAGGGACGCTCGGGGCACGAGGCTCATCAGTTTTATTGCCTGCTCGATTATATAGAAAAATACAAAAAATCTG CATTAAAAATATTAATCCTGCATGCTGGACATGTATGGTAATAATTTCTATTTTGTACCATTTTCTTGTTTAACTTTAGCATGT TGTTGATCATGGATCATACTCCCCTTGTTTCTTTGGGTGAGAAGGGATCGCAGTTTGGAAACTCCGGCGGCTGCGTGCGGGGTT TCAGTCCCAGCTGTAGGCTTGTAAATACCCGCCCCGCCAAACCGCATAGAGAACGTGGCAGCAAGCTGAGGGTCTTTGTTTGGG TTTATTATTACGGTATTTTTGTTTGTAAGTTAAAAAGAAAAAAAAAAAGAAAAAGTTCCGGGCATTTTGCATCAGAAAACAACT TTGTCTTGGGGCACACTTGGAAGTTGCATGTTTTCTTTCCTTCCCTTATCCCCATTCGGTCCTCTTTTTCCTCTCTCGCTTTAG TTTTCAACCTTGTTGGTGCTGAGAGAGAGAACCGAGAGGTCCCAGTACAAGGGCAGGGCAGGGCAGGGAAGCTGCCAAGCTCCG CACCCCAGAGGAGTGTTCTGGACTACAGCCTTGTCTTATGGTCAAATTGATACCCTTAATAAGAAAGGAAAGGAAAGGAAAACA GATCCTCCCCTCTGCTTTTTATTGTAACCAGAATCACCCTGAGGTCCCTTCTGAACCCTCTGGGCCTGCGCTAATTGTAGGAGC CACAGCGCTCCTAGGGTGAGAGGCTTAGCCATCCCTGACCCTGGCAGTGCACTGGTAAGCAGACACTGCACTGAACCAACTGCT ATGCTCAGAATGTACCAGAAACCCAAACATTGGCAAGTAATTTTGCAACTTTCAAGTGCGTTCTTTAGACCAATGCATTGCGTT TCTTTCCCTGCTTTTGAGATAGTAGGAAGAGTTCTTGGTGGTGTCCCCCCCCTTCAATTCTTCAGTTGTATAGTAGTTATAGGG AAGATATGGGTGTTTTTCTTTATTATTACTTTTTTTTTTCTGCAGGTCAGTAAAAGGATTTAAGTTGCACTGACAAAAATACCA AAATAAAAGTGTATTTTTAAGTTCCCATTTGAAATTGCTGGCGCTGCTGGCCGGATGCATTTTTGAGTTTGTATTAGTTGATAA ATTAACAGTAATAACAAGATTGTATGAACCGCATGGTGCTTGCAGTTTTAAATATTGTGGATATTTGTCCTGCATCAGAAACGA GCTTTGGTTTTTACAGATTCAACTGTGTTGAAATCAAACCTGCCGCAACAGAAATTGTTTTTATTTCATGTAAAATAAGGGATC AATTTCAAACCCTGCTTATGATATGAAAATATTAAAACCTAGTCTATTGTAGTTTTATTCAGACTGGTTTCTGTTTTTTGGTTA TTAAAATGGTTTCCTATTTTGCTTATTAAAAAAAAAAAAAAAAAAAA
459
MAPVGVEKKLLLGPNGPAVAAAGDLTSEEEEGQSLWSSILSEVSTRARSKLPSGKNI VFGEDGSGKTTLMTKLQGAEHGKKGR GLEYLYLSVHDEDRDDHTRCNVWILDGDLYHKGLLKFAVSAESLPETLVIFVADMSRP TVMESLQKASVLREHIDKMKIPPE KMRELERKF¥KDFQDYMEPEEGCQGSPQRRGP TSGSDEEVALPLGDVLTHNLGIPVLWCTKCDAVSVLEKEHDYRDEHLD FIQSHLRRFCLQYGAALIYTSVKEEKNLD YKYIVHKTYGFHFTTPALWEKDAVFIPAGDNEKKIAI HENFTTVKPEDAY EDFIVKPPVRKLVHDKELAAEDEQVF MKQQSLLAKQPATPTRASESPARGPSGSPRTQGRGGPASVPSSSPGTSVKKPDPNIK IrøAASEGVLASFFNSLLSKKTGSPGSPGAGGVQSTAKKSGQKTVLSNVQEELDRMTRKPDSMVTNSSTENEA
460
GGCAAGATGGCGCCGGTGGGGGTGGAGAAGAAGCTGCTGCTAGGTCCCAACGGGCCCGCGGTGGCGGCCGCCGGCGACCTGACC AGTGAGGAGGAGGAAGGCCAGAGCCTATGGTCCTCCATTCTGAGCGAAGTGTCCACCCGCGCCAGGTCCAAGCTGCCGTCCGGC AAGAACATCCTGGTCTTCGGTGAAGATGGTTCTGGTAAAACAACCCTCATGACTAAACTACAAGGAGCTGAGCATGGCAAAAAA GGAAGAGGCCTAGAATATCTCTACCTCAGTGTCCATGATGAGGACCGAGATGATCACACGCGCTGCAACGTGTGGATTCTGGAT GGAGACTTGTACCACAAAGGCCTGCTGAAATTTGCAGTTTCTGCTGAATCCTTGCCAGAGACCCTCGTCATTTTTGTTGCAGAC ' ATGTCTAGACCTTGGACTGTGATGGAATCTCTGCAGAAATGGGCTAGTGTTTTACGTGAGCACATTGATAAAATGAAAATTCCA CCAGAAAAAATGAGGGAGCTGGAACGGAAGTTTGTGAAAGATTTTCAAGACTATATGGAACCTGAAGAAGGTTGTCAAGGTTCC CCACAGAGAAGAGGCCCTCTGACCTCAGGCTCCGATGAAGAAAATGTTGCCCTGCCTCTGGGTGACAATGTGCTGACTCATAAC CTGGGGATCCCGGTGTTGGTGGTGTGCACAAAGTGTGATGCGGTGAGTGTCCTGGAGAAGGAGCACGATTACAGGGATGAGCAT TTGGACTTTATCCAGTCACACCTGCGGAGGTTCTGCCTTCAGTATGGAGCTGCCTTGATTTACACATCAGTGAAAGAAGAGAAA AACCTCGACTTGTTGTATAAGTATATTGTTCATAAAACATACGGTTTCCACTTCACCACACCTGCCTTAGTTGTGGAAAAGGAT GCCGTTTTTATACCTGCAGGCTGGGACAATGAAAAGAAAATAGCTATTTTACATGAAAATTTTACAACCGTGAAGCCGGAAGAT GCATATGAAGACTTTATTGTGAAACCTCCCGTGAGAAAGCTGGTCCACGACAAAGAGTTGGCAGCAGAAGATGAGCAGGTGTTC CTAATGAAGCAACAGTCACTCCTTGCCAAGCAACCAGCCACTCCCACGAGAGCTTCTGAATCTCCTGCAAGAGGACCCTCTGGC TCTCCAAGGACCCAGGGTCGGGGAGGGCCAGCCAGTGTGCCTAGCTCCTCCCCAGGCACGTCAGTAAAAAAGCCGGACCCAAAC ATCAAAAATAATGCAGCAAGTGAAGGGGTGTTGGCCAGCTTCTTCAACAGTCTGTTGAGTAAAAAGACAGGCTCTCCTGGAAGT CCTGGTGCTGGTGGGGTGCAGAGCACAGCCAAGAAGTCAGGACAAAAGACTGTGTTGTCAAATGTTCAGGAAGAACTGGATAGA • ATGACTCGAAAGCCAGACTCTATGGTAACAAACTCTTCAACAGAAAATGAAGCCTGAACCTCCTTAAAAAGTGCATATGTCGAA TGACCAAATAACTATGTATATTGATCTGCTAAGACCAGGATTTTTCTGATATGGCACATGCTATCAGTTTTTTGGGGCAGGGGA GATGAACTTTAAAAAAAAAAAAAAAA
461 MASNKTTLQKMGKKQNGKSKK¥EEAEPEEFWEKVLDRRVVNGKVEYFLK KGFTDADNTWEPEENLDCPELIEAFLNSQKAGK EKDGTKRKSLSDSESDDSKSKKKRDAVDKPRGFARGLDPERIIGATDSSGELMF MKWKDSDEADLVLAKEANI-KGPQI¥IAFY EERLTWHSCPEDEAQ
' 462
GGAGACGCTGCAGACCCGCGACCCGGAGCAGCTCGGAGGCGGTGAATAATAGCTCTTCAAGTCTGCAATAAAAAATGGCCTCCA ACAAAACTACATTGCAAAAAATGGGAAAAAAACAGAATGGAAAGAGTAAAAAAGTTGAAGAGGCAGAGCCTGAAGAATTTGTCG TGGAAAAAGTACTAGATCGACGTGTAGTGAATGGGAAAGTAGAATATTTCCTGAAGTGGAAGGGATTTACAGATGCTGACAATA CTTGGGAACCTGAAGAAAATTTAGATTGTCCAGAATTGATTGAAGCGTTTCTTAACTCTCAGAAAGCTGGCAAAGAAAAAGATG GTACAAAAAGAAAATCTTTATCTGACAGTGAATCTGATGACAGCAAATCAAAGAAGAAAAGAGATGCTGTTGACAAACCAAGAG GATTTGCCAGAGGTCTTGATCCTGAAAGAATAATTGGTGCCACAGACAGCAGTGGAGAATTGATGTTTCTCATGAAATGGAAAG ATTCAGATGAGGCAGACTTGGTGCTGGCGAAAGAGGCAAATATGAAGTGTCCTCAAATTGTAATTGCTTTTTATGAAGAGAGAC TAACTTGGCATTCTTGTCCAGAAGATGAAGCTCAATAATTGTTCACATTGTTCTTTTATATATATTTATATATATATATAAAAA TTGGGTCTTAGATTTTGATTTACTAGTGTGACAAAATAACTACATCCTAATGAAAATCAAGTTTGATATGTTTGTTTTGAAAGT AGCGTTGGAAGAGTTGTTGGGGTTTTTTTGCATCCATAGCACTGGTTACTTTGAACAAATAAATAAAAGCTTTCTGTAGTTGCT TCCTTTATCAGAAAAGAACATTTGATACCATGGTATATCATTTCCTCTTCATTAAAGAACAGCTTTTCTAAATGTTGGGGGAAA TGTCCATAGTCATTACTCAGTCAAAACTTGTGTTCTCATGAGCCTAAGGACCATTCTAGATTTATTACGTGTTTTTTGTGTGTG* TGTGTGTGTGTGTGTGTGTGTATCCATAAAATGCATATGTAAATTTTTTTTTGTTTTTAAGCATTCACCCAAACAAAAAAATCA CAGGTAAACCCATGTTTCTGAGATGCCATTATTCCAAGCAAAATAAGAGATAATCCCTTCAAGTTAAATTGAAAATTTTCCTGA AACCATACATTTCAAGTGAAATAAGTAATTCTAGATAGGACAATTTAAATTGGATAATTTTAAAGTGTCTATAATTGCAGTGGT TTATTTGCAAAATTCCTAAAAGGAAAAATTTTATCACTGCCATCACAGCAGGTTTCCTCATCCAGATGAGGAAACTAGACAAAT GCTAGTGTGTTTTAACTAGCTAAACAAAACTAAGTTAAATGAACATTTAAAAGTTTCCCTAGCGGGCCATTCCTTAGCAAAATG TTGGAATCCCTGTTGCTACATTGACTAAAAGGTCATGATGAATGGAATATGTAAGACTTGGCTCATAGAAACCTAATCAGATGG TTAGAGGTGTTGGCAGTTTAGGACCTGCTGTCATAAATGTGTGAACAACCTTTTGTAACCTAACCTATTGACCTGCATGTTTTT TCTTTACCCCAATTCATTACATGGAGGCTCAATCTTGAGTTTGCTTTACTGGTTCAGCAAAAGCCAGGAAGAACAACTTTGTAG TAATCAAAATGTTATCCAACTGTATATTGTTTACTTTATTGTAAATACTGGTGAACAGTGGTTAATAAATAGTTTTATATTCCA AAAAAAAAAAAAAAAAAAAAAAAAAA
463
MKASAALLC LLTAAAFSPQGLAQPVGINTSTTCCYRFINKKIPKQR ESYRRTTSSHCPREAVIFKTKLDKEICADPTQKWVQ DFMKHLDKKTQTPKL
464
AGCAGAGGGGCTGAGACCAAACCAGAAACCTCCAATTCTCATGTGGAAGCCCATGCCCTCACCCTCCAACATGAAAGCCTCTGC AGCACTTCTGTGTCTGCTGCTCACAGCAGCTGCTTTCAGCCCCCAGGGGCTTGCTCAGCCAGTTGGGATTAATACTTCAACTAC CTGCTGCTACAGATTTATCAATAAGAAAATCCCTAAGCAGAGGCTGGAGAGCTACAGAAGGACCACCAGTAGCCACTGTCCCCG GGAAGCTGTAATCTTCAAGACCAAACTGGACAAGGAGATCTGTGCTGACCCCACACAGAAGTGGGTCCAGGACTTTATGAAGCA
CCTGGACAAGAAAACCCAAACTCCAAAGCTTTGAACATTCATGACTGAACTAAAAACAAGCCATGACTTGAGAAACAAATAATT
TGTATACCCTGTCCTTTCTCAGAGTGGTTCTGAGATTATTTTAATCTAATTCTAAGGAATATGAGCTTTATGTAATAATGTGAA
TCATGGTTTTTCTTAGTAGATTTTAAAAGTTATTAATATTTTAATTTAATCTTCCATGGATTTTGGTGGGTTTTGAACATAAAG
• CCTTGGATGTATATGTCATCTCAGTGCTGTAAAAACTGTGGGATGCTCCTCCCTTCTCTACCTCATGGGGGTATTGTATAAGTC CTTGCAAGAATCAGTGCAAAGATTTGCTTTAATTGTTAAGATATGATGTCCCTATGGAAGCATATTGTTATTATATAATTACAT ATTTGCATATGTATGACTCCCAAATTTTCACATAAAATAGATTTTTGTAAAAAA
465
MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAA TTF YATRPKPLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVY FYDDVTTLYEGFQRGIQVS GPC GSRKPDQPYE LSYKQVAELSECIGSA IQKGFKTAPDQFIGIFAQNRPEWVIIEQGCF AYSMVIVP YDT GNEAITYIWKAELSLVFVDKPEKAKL LEGVENKLIPG KII¥VMDAYGSELVERGQRCG¥EVTSMKAME DLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPAHMFERWECVMLC HGAKIGFFQGDIRL MDDLKVQPTVFPWPRLLNRMFDRIFGQANTT KRWLLDFASKRKEAELRSGIIRN SLWDRLIFHK¥ QSS GGRVRMVTG PVSATVLTFLR GCQFYEGYGQTECTAGCC TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEG EGEVCVKGPVFQGYLKDPAKTAEALDKDGWLHTGDIGKWLPNGT KIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFV HGESLQAFLIAIWPD¥ETLCSWAQKRGFEGSFEELCRKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTP TMKAKRPELR YFRSQIDDLYSTIKV .
466
TCAACACAGGACAATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCCGACAGTACGTGCGTAC TCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACCTTCTGGTACGCCACGAGACCCAAACCCCTGAA GCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGTGGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGA GCCCTTGGTGTATTTCTATGATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTG TTTAGGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTGCATAGGCTCAGC ACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTCAAAATAGACCTGAGTGGGTGATTATTGA ACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTTTATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAA AGCTGAACTCTCTCTGGTTTTTGTTGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGTTAATACCAGG CCTTAAAATCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTCACCAGCAT GAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGAAGATCTTGCAGTAATTTGTTTCAC AAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACCGAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAAC AGAGAATACAGTCAATCCTTGCCCAGATGATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTG TGTAATGCTGTGTCATGGAGCTAAAATCGGATTTTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTCAACC CACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCAAACACCACGCTGAAGCGATG GCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGGCATCATCAGAAACAACAGCCTGTGGGACCGGCTGAT CTTCCACAAAGTACAGTCGAGCCTGGGCGGAAGAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGAC GTTCCTCAGAGCAGCCCTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTAACCATGCC TGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGGAAGAAATGAATTACAT GGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAGGGCTACTTGAAGGACCCAGCGAAAACAGCAGA AGCTTTGGACAAAGACGGCTGGTTACACACAGGGGACATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAA AAAGCACATATTTAAGCTGGCACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGC TCAGGTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATTATGTTCCTGGGC CCAAAAGAGAGGATTTGAAGGGTCGTTTGAGG ACTGTGCAGAAATAAGGATGTCAAAAAAGCTATCCTCGAAGATATGGTGAG ACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTCAAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGG CCTTCTGACTCCAACAATGAAGGCGAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTAT CAAGGTTTAGTGTGAAGAAGAAAGCTCAGAGGAAATGGCACAGTTCCACAATCTCTTCTCCTGCTGATGGCCTTCATGTTGTTA ATTTTGAATACAGCAAGTGTAGGGAAGGAAGCGTTCGTGTTTGACTTGTCCATTCGGGGTTCTTCTCATAGGAATGCTAGAGGA AACAGAACACCGCCTTACAGTCACCTCATGTTGCAGACCATGTTTATGGTAATACACACTTTCCAAAATGAGCCTTAAAAATTG TAAAGGGGATACTATAAATGTGCTAAGTTATTTGAGACTTCCTCAGTTTAAAAAGTGGGTTTTAAATCTTCTGTCTCCCTGCTT TTCTAATCAAGGGGTTAGGACTTTGCTATCTCTGAGATGTCTGCTACTTGCTGCAAATTCTGCAGCTGTCTGCTGCTCTAAAGA GTACAGTGCACTAGAGGGAAGTGTTCCCTTTAAAAATAAGAACAACTGTCCTGGCTGGAGAATCTCACAAGCGGACCAGAGATC
TTTTTAAATCCCTGCTACTGTCCCTTCTCACAGGCATTCACAGAACCCTTCTGATTCGTAAGGGTTACGAAACTCATGTTCTTC
TCCAGTCCCCTGTGGTTTCTGTTGGAGCATAAGGTTTCCAGTAAGCGGGAGGGCAGATCCAACTCAGAACCATGCAGATAAGGA
GCCTCTGGCAAATGGGTGCTCATCAGAACGCGTGGATTCTCTTTCATGGCAGAATGCTCTTGGACTCGGTTCTCCAGGCCTGAT
■ TCCCCGACTCCATCCTTTTTCAGGGGTTATTTAAAAATCTGCCTTAGATTCTATAGTGAAGACAAGCATTTCAAGAAAGAGTTA CCTGGATCAGCCATGCTCAGCTGTGACGCCTGAATAACTGTCTACTTTATCTTCACTGAACCACTCACTCTGTGTAAAGGCCAA CAGATTTTTAATGTGGTTTTCATATCAAAAGATCATGTTGGGATTAACTTGCCTTTTTCCCCAAAAAATAAACTCTCAGGCAAG CATTTCTTTAAAGCTATTAAGGGAGTATATACTTGAGTACTTATTGAAATGGACAGTAATAAGCAAATGTTCTTATAATGCTAC CTGATTTCTATGAAATGTGTTTGACAAGCCAAAATTCTAGGATGTAGAAATCTGGAAAGTTCATTTCCTGGGATTCACTTCTCC AGGGATTTTTTAAAGTTAATTTGGGAAATTAACAGCAGTTCACTTTATTGTGAGTCTTTGCCACATTTGACTGAATTGAGCTGT CATTTGTACATTTA AGCAGCTGTTTTGGGGTCTGTGAGAGTACATGTATTATATACAAGCACAACAGGGCTTGCACTAAAGAA TTGTCATTGTAATAACACTACTTGGTAGCCTAACTTCATATATGTATTCTTAATTGCACAAAAAGTCAATAATTTGTCACCTTG GGGTTTTGAATGTTTGCTTTAAGTGTTGGCTATTTCTATGTTTTATAAACCAAAACAAAATTTCCAAAAACAATGAAGGAAACC AAAATAAATATTTCTGCATTTCG
467 MADEELEALRRQRLAE QAKHGDPGDAAQQEAKHREAEMRNSI AQVLDQSARARLSNLA VKPΞKTKAVENYLIQMARYGQLS EKVSEQG IEILKKVSQQTEKTTTWFNRRKVMDSDEDDDY
468
CTGCTCCAGCGCTGACGCCGAGCCATGGCGGACGAGGAGCTTGAGGCGCTGAGGAGACAGAGGCTGGCCGAGCTGCAGGCCAAA CACGGGGATCCTGGTGATGCGGCCCAACAGGAAGCAAAGCACAGGGAAGCAGAAATGAGAAACAGTATCTTAGCCCAAGTTCTG GATCAGTCGGCCCGGGCCAGGTTAAGTAACTTAGCACTTGTAAAGCCTGAAAAAACTAAAGCAGTAGAGAATTACCTTATACAG' ATGGCAAGATATGGACAACTAAGTGAGAAGGTATCAGAACAAGGTTTAATAGAAATCCTTAAAAAAGTAAGCCAACAAACAGAA AAGACAACAACAGTGAAATTCAACAGAAGAAAAGTAATGGACTCTGATGAAGATGACGATTATTGAACTACAAGTGCTCACAGA CTAGAACTTAACGGAACMGTCTAGGACAGAAGTTAAGATCTGATTATTTACTTTGTTTATTGTCTATATGCCTTTTAAAAAAA TA CTTGTTATGCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 469
MQVSTAALAVL CTMALCNQV SAPLAADTPTACCFSYTSRQIPQNFIADYFETSSQCSKPSVIFLTKRGRQVCADPSEEWQK •YVSD E SA
470
CGCAAAGAGTAGTCAGTCCCTTCTTGGCTCTGCTGACACTCGAGCCCACATTCCATCACCTGCTCCCAATCATGCAGGTCTCCA CTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCTGCACCACGTGAGTCCATGTTGTTGTTGT GGGTATCACCACTCTCTGGCCATGGTTAGACCACATCAGTCTTTTTTTGCGGCCTGAGAGCCCCGAAGAGAAAAGAAGGAAGTT CTTAAAGCGCTGCCAAACACCTTGGTCTTTTTCTTCACAACTTTTATTTTTATCTCTAGAAGGGGTCTTAGCCCTCCTAGTCTC CAGTTGCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGAGGAGT GGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCCTGAGGGGTCCAGAAGCTTCGAGGCCCAGCGACCTCAGTGGGCCCAG TGGGGAGGAGCAGGAGCCTGAGCCTTGGGAACATGCGTGTGACCTCTACAGCTACCTCTTCTATGGACTGGTTATTGCCAAACA GCCACACTGTGGGACTCTTCTTAACTTAAATTTTAATTTATTTATACTATTTAGTTTTTATMTTTATTTTTGATTTCACAGTG TGTTTGTGATTGTTTGCTCTGAGAGTTCCCCCTGTCCCCTCCACCTTCCCTCACAGTGTGTCTGGTGACAACCGAGTGGCTGTC ATCGGCCTGTGTAGGCAGTGATGGCACCAAAGCCACCAGACTGACAAATGTGTGATCAGATGCTTTTGTTCAGGGCTGTGATCG GCCTGGGGAAATAATAAAGATGTTCTTTTAAACGGT
471
MELRPWL WVVAATGTLVLAADAQGQKVFTNTAVRIPGGPAVANSVARKHGFLNLGQIFGDYYHF HRGVTKRSLSPHRPRH SRLQREPQVQWLEQQVAKRRTKRDVYQEPTDPKFPQQWYLSGVTQRDL VKAAWAQGYTGHGIWSILDDGIEK HPDLAGNYD PGASFDVNDQDPDPQPRYTQ DNRHGTRCAGEVAAVANGVCGVGVAYNARIGGVRMLDGE¥TDAVEARSLGLNPNHIHIYSA SWGPEDDGKTVDGPARLAEEAFFRGVSQGRGG GSIFVWASGNGGREHDSCNCDGYTNSIYTLSISSATQFGVPWYSEACSST LATTYSSGNQNEKQIVTTDLRQKCTESHTGTSASAP AAGIIALTLEAK-.LTWRDMQH WQTSKPAHLNA DWATNGVGRKV SHSYGYGLLDAGAMVALAQNWTT¥APQRKCIIDILTEPKDIGKRLEVRKTVTACLGEPNHITRLEHAQARLTLSY RRGDLAIH LVSPMGTRST LAARPHDYSADGFNDWAFMTTHSWDEDPSGE VLEIENTSEA YGTLTKFTLVLYGTAPEGLPVPPESSGCK TLTSSQACVVCEEGFSLHQKSCVQHCPPGFAPQ¥LDTHYSTEND¥ETIRASVCAPCHASCATCQGPALTDCLSCPSHASLDPVE QTCSRQSQSSRESPPQQQPPRLPPEVEAGQRLRAGLLPSHLPEV¥AGLSCAFIVLVFVTVFL¥LQLRSGFSFRGVKVYTMDRGL ISYKG PPEA QEECPSDSEEDEGRGERTAFIKDQSAL
472 GCGGGGAAGCAGCAGCGGCCAGGATGAATCCCAGGTGCTCTGGAGCTGGATGGTGAAGGTCGGCACTCTTCACCCTCCCGAGCC CTGCCCGTCTCGGCCCCATGCCCCCACCAGTCAGCCCCGGGCCACAGGCAGTGAGCAGGCACCTGGGAGCCGAGGCCCTATGAC CAGGCCAAGGAGACGGGCGCTCCAGGGTCCCAGCCACCTGTCCCCCCCATGGAGCTGAGGCCCTGGTTGCTATGGGTGGTAGCA GCAACAGGAACCTTGGTCCTGCTAGCAGCTGATGCTCAGGGCCAGAAGGTCTTCACCAACACGTGGGCTGTGCGCATCCCTGGA GGCCCAGCGGTGGCCAACAGTGTGGCACGGAAGCATGGGTTCCTCAACCTGGGCCAGATCTTCGGGGACTATTACCACTTCTGG CATCGAGGAGTGACGAAGCGGTCCCTGTCGCCTCACCGCCCGCGGCACAGCCGGCTGCAGAGGGAGCCTCAAGTACAGTGGCTG GAACAGCAGGTGGCAAAGCGACGGACTAAACGGGACGTGTACCAGGAGCCCACAGACCCCAAGTTTCCTCAGCAGTGGTACCTG TCTGGTGTCACTCAGCGGGACCTGAATGTGAAGGCGGCCTGGGCGCAGGGCTACACAGGGCACGGCATTGTGGTCTCCATTCTG GACGATGGCATCGAGAAGAACCACCCGGACTTGGCAGGCAATTATGATCCTGGGGCCAGTTTTGATGTCAATGACCAGGACCCT GACCCCCAGCCTCGGTACACACAGATGAATGACAACAGGCACGGCACACGGTGTGCGGGGGAAGTGGCTGCGGTGGCCAACAAC GGTGTCTGTGGTGTAGGTGTGGCCTACAACGCCCGCATTGGAGGGGTGCGCATGCTGGATGGCGAGGTGACAGATGCAGTGGAG GCACGCTCGCTGGGCCTGAACCCCAACCACATCCACATCTACAGTGCCAGCTGGGGCCCCGAGGATGACGGCAAGACAGTGGAT GGGCCAGCCCGCCTCGCCGAGGAGGCCTTCTTCCGTGGGGTTAGCCAGGGCCGAGGGGGGCTGGGCTCCATCTTTGTCTGGGCC TCGGGGAACGGGGGCCGGGAACATGACAGCTGCAACTGCGACGGCTACACCAACAGTATCTACACGCTGTCCATCAGCAGCGCC ACGCAGTTTGGCAACGTGCCGTGGTACAGCGAGGCCTGCTCGTCCACACTGGCCACGACCTACAGCAGTGGCAACCAGAATGAG AAGCAGATCGTGACGACTGACTTGCGGCAGAAGTGCACGGAGTCTCACACGGGCACCTCAGCCTCTGCCCCCTTAGCAGCCGGC ATCATTGCTCTCACCCTGGAGGCCAATAAGAACCTCACATGGCGGGACATGCAACACCTGGTGGTACAGACCTCGAAGCCAGCC CACCTCAATGCCAACGACTGGGCCACCAATGGTGTGGGCCGGAAAGTGAGCCACTCATATGGCTACGGGCTTTTGGACGCAGGC GCCATGGTGGCCCTGGCCCAGAATTGGACCACAGTGGCCCCCCAGCGGAAGTGCATCATCGACATCCTCACCGAGCCCAAAGAC ATCGGGAAACGGCTCGAGGTGCGGAAGACCGTGACCGCGTGCCTGGGCGAGCCCAACCACATCACTCGGCTGGAGCACGCTCAG GCGCGGCTCACCCTGTCCTATAATCGCCGTGGCGACCTGGCCATCCACCTGGTCAGCCCCATGGGCACCCGCTCCACCCTGCTG GCAGCCAGGCCACATGACTACTCCGCAGATGGGTTTAATGACTGGGCCTTCATGACAACTCATTCCTGGGATGAGGATCCCTCT GGCGAGTGGGTCCTAGAGATTGAAAACACCAGCGAAGCCAACAACTATGGGACGCTGACCAAGTTCACCCTCGTACTCTATGGC ACCGCCCCTGAGGGGCTGCCCGTACCTCCAGAAAGCAGTGGCTGCAAGACCCTCACGTCCAGTCAGGCCTGTGTGGTGTGCGAG GAAGGCTTCTCCCTGCACCAGAAGAGCTGTGTCCAGCACTGCCCTCCAGGCTTCGCCCCCCAAGTCCTCGATACGCACTATAGC ACCGAGAATGACGTGGAGACCATCCGGGCCAGCGTCTGCGCCCCCTGCCACGCCTCATGTGCCACATGCCAGGGGCCGGCCCTG ACAGACTGCCTCAGCTGCCCCAGCCACGCCTCCTTGGACCCTGTGGAGCAGACTTGCTCCCGGCAAAGCCAGAGCAGCCGAGAG TCCCCGCCACAGCAGCAGCCACCTCGGCTGCCCCCGGAGGTGGAGGCGGGGCAACGGCTGCGGGCAGGGCTGCTGCCCTCACAC CTGCCTGAGGTGGTGGCCGGCCTCAGCTGCGCCTTCATCGTGCTGGTCTTCGTCACTGTCTTCCTGGTCCTGCAGCTGCGCTCT GGCTTTAGTTTTCGGGGGGTGAAGGTGTACACCATGGACCGTGGCCTCATCTCCTACAAGGGGCTGCCCCCTGAAGCCTGGCAG GAGGAGTGCCCGTCTGACTCAGAAGAGGACGAGGGCCGGGGCGAGAGGACCGCCTTTATCAAAGACCAGAGCGCCCTCTGATGA GCCCACTGCCCACCCCCTCAAGCCAATCCCCTCCTTGGGCACTTTTTAATTCACCAAAGTATTTTTTTATCTTGGGACTGGGTT TGGACCCCAGCTGGGAGGCAAGAGGGGTGGAGACTGTTTCCCATCCTACCCTCGGGCCCACCTGGCCACCTGAGGTGGGCCCAG GACCAGCTGGGGCGTGGGGAGGGCCGTACCCCACCCTCAGCACCCCTTCCATGTGGAGAAAGGAGTGAAACCTTTAGGGCAGCT TGCCCCGGCCCCGGCCCCAGCCAGAGTTCCTGCGGAGTGAAGAGGGGCAGCCCTTGCTTGTTGGGATTCCTGACCCAGGCCGCA GCTCTTGCCCTTCCCTGTCCCTCTAAAGCAATAATGGTCCCATCCAGGCAGTCGGGGGCTGGCCTAGGAGATATCTGAGGGAGG AGGCCACCTCTCCAAGGGCTTCTGCACCCTCCACCCTGTCCCCCAGCTCTGGTGAGTCTTGGCGGCAGCAGCCATCATAGGAAG GGACCAAGGCAAGGCAGGTGCCTCCAGGTGTGCACGTGGCATGTGGCCTGTGGCCTGTGTCCCATGACCCACCCCTGTGCTCCG TGCCTCCACCACCACTGGCCACCAGGCTGGCGCAGCCAAGGCCGAAGCTCTGGCTGAACCCTGTGCTGGTGTCCTGACCACCCT CCCCTCTCTTGCACCCGCCTCTCCCGTCAGGGCCCAAGTCCCTGTTTTCTGAGCCCGGGCTGCCTGGGCTGTTGGCACTCACAG ACCTGGAGCCCCTGGGTGGGTGGTGGGGAGGGGCGCTGGCCCAGCCGGCCTCTCTGGCCTCCCACCCGATGCTGCTTTCCCCTG TGGGGATCTCAGGGGCTGTTTGAGGATATATTTTCACTTTGTGATTATTTCACTTTAGATGCTGATGATTTGTTTTTGTATTTT TAATGGGGGTAGCAGCTGGACTACCCACGTTCTCACACCCACCGTCCGCCCTGCTCCTCCCTGGCTGCCCTGGCCCTGAGGTGT GGGGGCTGCAGCATGTTGCTGAGGAGTGAGGAATAGTTGAGCCCCAAGTCCTGAAGAGGCGGGCCAGCCAGGCGGGCTCAAGGA AAGGGGGTCCCAGTGGGAGGGGCAGGCTGACATCTGTGTTTCAAGTGGGGCTCGCCATGCCGGGGGTTCATAGGTCACTGGCTC TCCAAGTGCCAGAGGTGGGCAGGTGGTGGCACTGAGCCCCCCCAACACTGTGCCCTGGTGGAGAAAGCACTGACCTGTCATGCC CCCCTCAAACCTCCTCTTCTGACGTGCCTTTTGCACCCCTCCCATTAGGACAATCAGTCCCCTCCCATCTGGGAGTCCCCTTTT CTTTTCTACCCTAGCCATTCCTGGTACCCAGCCATCTGCCCAGGGGTGCCCCCTCCTCTCCCATCCCCCTGCCCTCGTGGCCAG CCCGGCTGGTTTTGTAAGATACTGGGTTGGTGCACAGTGATTTTTTTCTTGTAATTTAAACAGGCCCAGCATTGCTGGTTCTAT TTAATGGACATGAGATAATGTTAGAGGTTTTAAAGTGATTAAACGTGCAGACTATGCAAACCAG 473
MAMESTATAAVAADWSADKIEDVPAPSTSADKVESLD¥DSEAKKL GLGQKHLVMGDIPAAVNAFQEAAS GKKYGETANEC GEAFFFYGKSL ELARMENGVLGNALEGVHVEEEEGEKTEDESLVENNDNIDEEAREE REQVYDAMGEKEEAKKTEDKSLAKP ETDKEQDSEMEKGGREDMDISKSAEEPQEK¥DLTLDWLTETSEEAKGGAAPEGPNEAEVTSGKPEQEVPDAEEEKSVSGTDVQE ECREKGGQEKQGEVIVSIEEKPKEVSEEQPWTLEKQGTAVEVEAESLDPTVKPVDVGGDEPEEKVVTSENEAGKAVLEQLVGQ EVPPAEESPEVQTE EASAVEAGSEVSEKPGQEAPVLPKDGAWGPSWGDQTPIEPQTSIERLTETKDGSGLEEKVRAKLVP
SQEETKLSVEESEAAGDGVDTKVAQGATEKSPEDKVQIAANEETQEREEQMKEGEETEGSEEDDKENDKTEEMPNDSVLENKSL
•QENEEEEIGNLELAWDMLDLAKIIFKRQETKEAQ YAAQAHLKLGEVSVESE YVQA¥EEFQSCLN QEQYLEAHDRLLAETHY
QLGLAYGYNSQYDEA¥AQFSKSIE¥IENRMAVLNEQVKEAEGSSEYKKEIEELKELLPEIREKIEDAKESQRSGN¥AELALKAT
L¥ESSTSGFTPGGGGSSVSMIASRKPTDGASSSNCVTDISHLVRKKRKPEEESPRKDDAKKAKQEPEWGGSGDA¥PSGNEVSE MEEEAENQ KRGAAVEGTLEAGATVESTAC
474
GCCTGAGTGAGTCTCTGGCGTCCCAAATTGCCTGTTTTTCTCGCAGGCTCTATTCCGTTCGCTGGTTCGCCACCTCAGGGGAAC GATGGCCATGGAGTCCACAGCCACTGCCGCCGTCGCCGCGGACGTGGTTTCTGCCGACAAAATTGAAGATGTCCCTGCTCCTTC TACATCTGCAGATAAAGTGGAGAGTCTGGATGTGGATAGTGAAGCTAAGAAACTATTGGGTTTAGGACAGAAACATCTGGTGAT GGGGGATATTCCAGCAGCTGTCAATGCATTCCAGGAAGCAGCTAGTCTTTTAGGTAAGAAGTATGGAGAGACAGCTAATGAGTG TGGAGAAGCCTTCTTTTTCTATGGGAAATCACTTCTGGAGTTGGCAAGAATGGAGAATGGTGTGTTGGGAAACGCCTTGGAAGG TGTGCATGTGGAAGAGGAAGAAGGAGAAAAAACAGAAGATGAATCTCTGGTAGAAAATAATGATAACATAGATGAGGAAGCAAG GGAAGAGTTGAGAGAACAGGTTTATGACGCCATGGGAGAAAAAGAAGAAGCCAAAAAAACAGAAGACAAGTCTTTGGCAAAGCC TGAAACTGATAAAGAACAGGACAGTGAAATGGAGAAGGGTGGAAGAGAAGATATGGATATAAGTAAATCTGCAGAGGAGCCACA GGAAAAAGTTGACTTGACTCTAGATTGGTTAACTGAAACCTCTGAAGAGGCAAAAGGAGGAGCAGCACCAGAAGGACCGAATGA AGCTGAGGTCACTTCTGGGAAGCCAGAACAGGAAGTACCAGATGCTGAGGAAGAAAAATCAGTTTCTGGAACTGATGTCCAAGA
AGAGTGCAGAGAAAAAGGAGGTCAGGAGAAGCAGGGAGAGGTAATTGTGAGCATAGAGGAGAAGCCAAAAGAAGTTTCAGAAGA
GCAGCCTGTGGTGACTCTAGAAAAGCAGGGCACTGCAGTGGAGGTAGAAGCAGAGTCTTTAGACCCGACAGTCAAGCCAGTGGA
TGTGGGTGGGGACGAGCCAGAGGAGAAGGTAGTTACCTCTGAAAACGAGGCAGGAAAGGCGGTTCTTGAACAACTGGTAGGTCA AGAAGTACCACCTGCTGAAGAGTCACCAGAGGTGCAAACAGAGGCTGCAGAGGCCTCAGCTGTAGAGGCTGGATCAGAAGTCTC TGAAAAGCCTGGGCAGGAGGCTCCAGTTCTCCCTAAGGATGGTGCAGTCAATGGACCGTCAGTTGTAGGAGATCAGACTCCTAT TGAACCACAGACTTCTATAGAAAGACTGACAGAAACAAAAGATGGCTCAGGACTAGAGGAGAAGGTCAGGGCAAAGCTGGTTCC TAGTCAGGAGGAGACTAAGCTGTCTGTAGAAGAGTCTGAGGCAGCTGGAGATGGGGTTGATACCAAGGTAGCCCAGGGAGCTAC TGAGAAATCACCTGAAGACAAAGTTCAGATAGCTGCTAATGAAGAGACACAAGAGAGAGAAGAACAGATGAAAGAGGGTGAAGA AACTGAAGGCTCGGAAGAGGATGATAAAGAAAATGATAAGACTGAAGAAATGCCAAATGATTCAGTCCTTGAAAACAAGTCTCT TCAAGAAAATGAGGAGGAGGAGATTGGGAACCTAGAGCTTGCCTGGGATATGCTGGATTTAGCAAAGATCATTTTTAAAAGGCA AGAAACAAAAGAAGCACAGCTTTATGCTGCCCAGGCACATCTTAAACTCGGAGAAGTTAGTGTTGAATCTGAAAACTATGTGCA AGCTGTGGAGGAGTTCCAGTCCTGCCTTAACCTGCAGGAACAGTACCTGGAAGCCCACGACCGTCTGCTTGCAGAGACCCACTA CCAGCTGGGCTTGGCTTATGGGTACAACTCTCAGTATGATGAGGCAGTGGCACAGTTCAGCAAATCTATTGAAGTCATTGAGAA CAGAATGGCTGTACTAAACGAGCAGGTGAAGGAGGCTGAAGGATCGTCTGAATACAAGAAAGAAATTGAGGAACTAAAGGAACT GCTACCCGAAATTAGAGAGAAGATAGAAGATGCAAAGGAGTCTCAGCGTAGTGGGAATGTAGCTGAACTGGCTCTGAAAGCTAC TCTGGTGGAGAGTTCTACTTCAGGTTTCACTCCTGGTGGAGGAGGCTCTTCAGTCTCCATGATTGCCAGTAGAAAGCCAACAGA CGGTGCTTCCTCATCAAATTGTGTGACTGATATTTCCCACCTTGTCAGAAAGAAGAGGAAACCAGAGGAAGAGAGTCCCCGGAA AGATGATGCAAAGAAAGCCAAACAAGAGCCGGAGGTGAACGGAGGCAGTGGGGATGCTGTCCCGAGTGGAAATGAAGTTTCGGA AAACATGGAGGAGGAGGCTGAGAATCAGCTGAAACGCGGAGCAGCAGTGGAGGGGACACTGGAGGCTGGAGCTACAGTTGAAAG CACTGCATGTTAAGAGGGGGCACAGCCTCCTCCCAAGGGAAAGTGTTTTTGTATATAATGTATTTTTTCACTTTTGGAGGATTC TTTTTGTATAACTTCAATAAAGATTGTAAGCAAAAAAAAAA
475
MEHTGHY HLAFL TTVFSLSPGTKMYTR WANSTSSWDSVIQNKTGRNQNENINTNPITPEVDYKGNSTNMPETSHIVALTS KSEQELYIPS SNSPSTVQSIENTSKSHGEIFKKDVCAEN WMAMLIC IIIAV FLICTF F STW ANKVSSLRRSKQV GKRQPRSNGDF ASGLWPAESDTWKRTKQLTGPN VMQSTGVLTATRERKDEEGTEKLTNKQIG
476
AGTTGCAGTGGAAAGAAATGTGTCATCTGTGGTTTGGTTTTTAAAAGTGGAAAACTAGCTGCACATATCCTTTTTTACTGCAGA TTTACTTTAAGGCTCATATTCTCCAAGTCTATTCTGCTTTAAAAAGAAGACAAGAAAAGAAGTGGTTTATCAAAATCACGTTAT AATCAGATTTTGACCAAGCATTTTGTAAGATTGCCAAGTATGCCCACGGACATGGAACACACAGGACATTACCTACATCTTGCC TTTCTGATGACAACAGTTTTTTCTTTGTCTCCTGGAACAAAAGCAAACTATACCCGTCTGTGGGCTAACAGTACTTCTTCCTGG GATTCAGTTATTCAAAACAAGACAGGCAGAAACCAAAATGAAAACATTAACACAAACCCTATAACTCCTGAAGTAGATTATAAA GGTAATTCTACAAACATGCCTGAAACATCTCACATCGTAGCTTTAACTTCTAAATCTGAACAGGAGCTTTATATACCTTCTGTC GTCAGCAACAGTCCTTCAACAGTACAGAGCATTGAAAACACAAGCAAAAGTCATGGTGAAATTTTCAAAAAGGATGTCTGTGCG GAAAACAACAACAACATGGCTATGCTAATTTGCTTAATTATAATTGCAGTGCTTTTTCTTATCTGTACCTTTCTATTTCTATCA ACTGTGGTTTTGGCAAACAAAGTCTCTTCTCTCAGACGATCAAAACAAGTAGGCAAGCGTCAGCCTAGAAGCAATGGCGATTTT CTGGCAAGCGGTCTATGGCCCGCTGAATCAGACACTTGGAAAAGAACAAAACAGCTCACAGGACCCAACCTAGTGATGCAATCT ACTGGAGTGCTCACAGCTACAAGGGAAAGAAAAGATGAAGAAGGAACTGAAAAACTTACTAACAAACAGATAGGTTAGTGAAGA AAAATGCAAAGTAGCAATGAGAAGGCTTATGGAGTAAAAATGAAGTCAGTTGGTATTTAATCCCAAAGTGTTGTTCTGATTATC TAAAATTTGACATGGTAGACCTTGCAATTTAGAATCAAGCAGGTGAGACAGGGAGAAGTATGCCTGCTTAATTATTTAAACTGT GTACTTTTGTTTTGACACTGAATATTTTAAAAAGCAAATAATAAAATAACTAAGCATTTGAGGAAAATTTTAAGGATAAATTGA GGAAACTGATTAATAGAGATAGCAAGGGATAATTAAATAAATATTCCCTATGTAGCAACAGTGGTTAGATGATCTTTGTCTGAA TGTAATAAAACTTTGAATAGTTTTAGTGTGTCCTTAAAGCCAAGTATATGCTTTAACATCAAATGGAAGTCAAATTCCTAATGC ATAGATAGAGAGAGCTAAACTGTGTAATTTAATGGTATCTTCCTTGCTGGATGTGGCAGAATCCACACCAGCTTATCAACCAAC ACAGCTAATTTTAGAATAGGTCCTTTATCTTTCCATATGGCACACGTAAGAAAGTGTTTTTCTACTATTAATATTAAATTAAAA CCTTTACTTTTGTATAATAAATTAAAACTCAGAATAAACCTGTGACCACGT
477
MAENGDNEKMAALEAKICHQIEYYFGDFNLPRDKF KEQIKDEGWVPLEIMIKFNRLNRLTTDFNVI¥EA SKSKAELMEISE DKTKIRRSPSKPLPEVTDEYKDVKNRSVYIKGFPTDATLDDIKEWLEDKGQVNIQMRRTLHKAFKGSIFVVFDS1ESAKKFV ETPGQKYKETD LILFKDDYFAKKNEERKQNKVEAKLRAKQEQEAKQKLEEDAEMKSLEEKIGC LKFSGDLDDQTCREDLHIL FSNHGE1K IDFVRGAKEGII FKEKAKEALGKAKDAMGNLQLRKEVTWE¥LEGEVEKEAKKIIEDQQES NKWKSKGRRF KGKGKGNKAAQPGSGKGKVQFQGKKTKFASDDEHDEHDENGATGPVKRAREETDKEEPASKQQKTENGAGDQ
478
GGAGTCGTTGTTGTTGCTGTTTGTGAGCCTGTGCGGCGGCTTCTGTGGGCCGGAACCTTAAAGATAGCCGCAATGGCTGAAAAT GGTGATAATGAAAAGATGGCTGCCCTGGAGGCCAAAATCTGTCATCAAATTGAGTATTATTTTGGCGACTTCAATTTGCCACGG GACAAGTTTCTAAAGGAACAGATAAAACTGGATGAAGGCTGGGTACCTTTGGAGATAATGATAAAATTCAACAGGTTGAACCGT CTAACAACAGACTTTAATGTAATTGTGGAAGCATTGAGCAAATCCAAGGCAGAACTCATGGAAATCAGTGAAGATAAAACTAAA ATCAGAAGGTCTCCAAGCAAACCCCTACCTGAAGTGACTGATGAGTATAAAAATGATGTAAAAAACAGATCTGTTTATATTAAA GGCTTCCCAACTGATGCAACTCTTGATGACATAAAAGAATGGTTAGAAGATAAAGGTCAAGTACTAAATATTCAGATGAGAAGA ACATTGCATAAAGCATTTAAGGGATCAATTTTTGTTGTGTTTGATAGCATTGAATCTGCTAAGAAATTTGTAGAGACCCCTGGC CAGAAGTACAAAGAAACAGACCTGCTAATACTTTTCAAGGACGATTACTTTGCCAAAAAAAATGAAGAAAGAAAACAAAATAAA GTGGAAGCTAAATTAAGAGCTAAACAGGAGCAAGAAGCAAAACAAAAGTTAGAAGAAGATGCTGAAATGAAATCTCTAGAAGAA AAGATTGGATGCTTGCTGAAATTTTCGGGTGATTTAGATGATCAGACCTGTAGAGAAGATTTACACATACTTTTCTCAAATCAT GGTGAAATAAAATGGATAGACTTCGTCAGAGGAGCAAAAGAGGGGATAATTCTATTTAAAGAAAAAGCCAAGGAAGCATTGGGT AAAGCCAAAGATGCAAATAATGGTAACCTACAATTAAGGAACAAAGAAGTGACTTGGGAAGTACTAGAAGGAGAGGTGGAAAAA GAAGCACTGAAGAAAATAATAGAAGACCAACAAGAATCCCTAAACAAATGGAAGTCAAAAGGTCGTAGATTTAAAGGAAAAGGA AAGGGTAATAAAGCTGCCCAGCCTGGGTCTGGTAAAGGAAAAGTACAGTTTCAGGGCAAGAAAACGAAATTTGCTAGTGATGAT GAACATGATGAACATGATGAAAATGGTGCAACTGGACCTGTGAAAAGAGCAAGAGAAGAAACAGACAAAGAAGAACCTGCATCC AAACAACAGAAAACAGAAAATGGTGCTGGAGACCAGTAGTTTAGTAAACCAATTTTTTATTCATTTTAAATAGGTTTTAAACGA CTTTTGTTTGCGGGGCTTTTAAAAGGAAAACCGAATTAGGTCCACTTCAATGTCCACCTGTGAGAAAGGAAAAATTTTTTTGTT GTTTAACTTGTCTTTTTGTTATGCAAATGAGATTTCTTTGAATGTATTGTTCTGTTTGTGTTATTTCAGATGATTCAAATATCA AAAGGAAGATTCTTCCATTAAATTGCCTTTGTAATATGAGAATGTATTAGTACAAACTAACTAATAAAATATATACTATATGAA AAGAGCAAAAAAAAAAAAAAAAA
479
M KLTPLPSKMK¥SAALLCL LMAATFSPQGLAQPDSVSIPITCCF VINRKIPIQRLESYTRITNIQCPKEAVIFKTQRGKEV CADPKERVRDSMKHLDQIFQNLKP
480 ATGCTGAAGCTCACACCCTTGCCCTCCAAGATGAAGGTTTCTGCAGCGCTTCTGTGCCTGCTGCTCATGGCAGCCACTTTCAGC CCTCAGGGACTTGCTCAGCCAGATTCAGTTTCCATTCCAATCACCTGCTGCTTTAACGTGATCAATAGGAAAATTCCTATCCAG AGGCTGGAGAGCTACACAAGAATCACCAACATCCAATGTCCCAAGGAAGCTGTGATCTTCAAGACCCAACGGGGCAAGGAGGTC TGTGCTGACCCCAAGGAGAGATGGGTCAGGGATTCCATGAAGCATCTGGACCAAATATTTCAAAATCTGAAGCCATGA
481 MARATLSAAPSNPRLLRVA LLLLL¥AASRRAAGAPLATE RCQC QT QGIHLKNIQSVKVKSPGPHCAQTEVIATLKNGQKA CLNPASPMVKKIIEKMLKNGKSN
482
GACAGAGCCCGGGCCACGGAGCTCCTTGCCAGCTCTCCTCCTCGCACAGCCGCTCGAACCGCCTGCTGAGCCCCATGGCCCGCG CCACGCTCTCCGCCGCCCCCAGCAATCCCCGGCTCCTGCGGGTGGCGCTGCTGCTCCTGCTCCTGGTGGCCGCCAGCCGGCGCG CAGCAGGAGCGCCCCTGGCCACTGAACTGCGCTGCCAGTGCTTGCAGACCCTGCAGGGAATTCACCTCAAGAACATCCAAAGTG TGAAGGTGAAGTCCCCCGGACCCCACTGCGCCCAAACCGAAGTCATAGCCACACTCAAGAATGGGCAGAAAGCTTGTCTCAACC CCGCATCGCCCATGGTTAAGAAAATCATCGAAAAGATGCTGAAAAATGGCAAATCCAACTGACCAGAAGGAAGGAGGAAGCTTA TTGGTGGCTGTTCCTGAAGGAGGCCCTGCCTTACAGGAACAGAAGAGGAAAGAGAGACACAGCTGCAGAGGCCACCTGGCTTGC GCCTAATGTGTTTGAGCATACTTAGGAGAAGTCTTCTATTTATTTATTTATTTATTTATTTGTTTGTTTTAGAAGATTCTATGT TAATATTTTATGTGTAAAATAAGGTTATGATTGAATCTACTTGCACACTCTCCCATTATATTTATTGTTTATTTTAGGTCAAAC CCAAGTTAGTTCAATCCTGATTCATATTTAATTTGAAGATAGAAGGTTTGCAGATATTCTCTAGTCATTTGTTAATATTTCTTC GTGATGACATATCACATGTCAGCCACTGTGATAGAGGCTGAGGAATCCAAGAAAATGGCCAGTAAGATCAATGTGACGGCAGGG AAATGTATGTGTGTCTATTTTGTAACTGTAAAGATGAATGTCAGTTGTTATTTATTGAAATGATTTCACAGTGTGTGGTCAACA TTTCTCATGTTGAAGCTTTAAGAACTAAAATGTTCTAAATATCCCTTGGCATTTTATGTCTTTCTTGTAAGATACTGCCTTGTT TAATGTTAATTATGCAGTGTTTCCCTCTGTGTTAGAGCAGAGAGGTTTCGATATTTATTGATGTTTTCACAAAGAACAGGAAAA TAAAATATTTAAAAATAT
483
MKVRF MKLSHETVTIELKNGTQ¥HGTITGVD¥SM TH KAVKMTLKNREPVQLET SIRGN IRYFI PDSLPLDTLLVDVE PKVKSKKREAVAGRGRGRGRGRGRGRGRGRGGPRR 484
GAATTCCCCCCCCCCCCCCAGTGCTCCGCGCGCTCTTGACGTCCGGAGCCCCTGGAGTAGGCGCTTCCGGCCATTCATACTGCA GTCGGTCAGTGTTCGGTTGAAGGATTCTGTGTGCTGTCGGACCCAGAGGGTGACGGCGCCGCTAGGATGAAGCTCGTGAGATTT TTGATGAAATTGAGTCATGAAACTGTAACCATTGAATTGAAGAACGGAACACAGGTCCATGGAACAATCACAGGTGTGGATGTC AGCATGAATACACATCTTAAAGCTGTGAAAATGACCCTGAAGAACAGAGAACCTGTACAGCTGGAAACGCTGAGTATTCGAGGA AATAACATTCGGTATTTTATTCTACCAGACAGTTTACCTCTGGATACACTACTTGTGGATGTTGAACCTAAGGTGAAATCTAAG AAAAGGGAAGCTGTTGCAGGAAGAGGCAGAGGAAGAGGAAGAGGAAGAGGACGTGGCCGTGGCAGAGGAAGAGGGGGTCCTAGG CGATAATGTCTCTCAAGATTTCAAAGTCATATGAGATTTGGGATATTTTTTGTACAGGTTGTGTTTGTTTATGTCAGTTTTTAA TAAACATAAATGTGGGACAGAGCTGTCTATTTAGTATATCAAAGTTTTAGTAGTTTCCTCCACATTCACGAAATTACCACAGTG AGAGCTAAGCATTTCTACTGGGCAGTTTCATTTTTAGTTGATCAGGTTTTAAGTTTTTGAACTAAAATTTTTCTTTTTCTTTTT ATGATGAATAAGGTTAAAATAAAAGCCTTAGACAAATTAAATTTGGCAGAGTTTAATTGAGCAAAGGACAATTCACAAATCAGG TAGCCCCTGAACCATAATAGGCTCAGAGGCTTCAGCCCAGCTGCATAGTTGAAGATTTATGGACAGAAGGAAAGTGATGTATGG AAAATGGAAGTGAGATACAGCAACAGCCGGATTAGTTACAGTTCAGCGTTTGCCTTATTTGAATATGGTTTGAACAGTTCGCTG TCTTTGGTTGGCTGAAACTTAGTGATTGCCACAAGAGTAGGGTACCGTCTGTTTACACGTCCAGTTAGGCTACAGTTCTATGTA CTGAGAAACCTTTAAGCTGAACTTGAGATATGTAAAGAGACTTTAGGCTAAACTTAACAATATATATAGGAATATATCCCTTCT ACTTCACATGCACTGAATATGCATTTTATTGCTTTACTCTTCATTCTGTGGCACCTACCCACAGGGGAAGTAAGAAGTTTGTTT TGGTATTTCGGAAACTAAAGTCCTTATGGGATGGGGTCTAGAATTGATTCTCCTTTCCTGAGTTTTACTCCACGGAGTCTTAGG TACCTGGTAAAAAGTTGTCTTCTAAATTAAGGGTCATTGCTTTGTTGTCTAGCTGCTAATGTCTTACTTTTGTTTCTTTTGCTT TTTAATCAGTTCTTAATAGGATATAGTTTTATGTTTTCCAAGTTATAACTTGGAGTTAATGGTCACTAGATTATCAGTTATGAG CAGTGTTAAAATCTCCTATTAATGTGTAATGTACCTGTCAGTGCCTCCTTTATTAAGGGGTTCTTTGAGAATAAAAGAGAAAAG ACCTACTTTATTTGACAGCAAAAAAAAAAAGGAATTC 485
MARAALSAAPSNPRLLRVALLLLLL¥AAGRRAAGASVATELRCQCLQTLQGIHPKNIQS¥NVKSPGPHCAQTE¥IATLKNGRKA CLNPASPIVKKIIEKMLNSDKSN
486
CACAGAGCCCGGGCCGCAGGCACCTCCTCGCCAGCTCTTCCGCTCCTCTCACAGCCGCCAGACCCGCCTGCTGAGCCCCATGGC CCGCGCTGCTCTCTCCGCCGCCCCCAGCAATCCCCGGCTCCTGCGAGTGGCACTGCTGCTCCTGCTCCTGGTAGCCGCTGGCCG
GCGCGCAGCAGGAGCGTCCGTGGCCACTGAACTGCGCTGCCAGTGCTTGCAGACCCTGCAGGGAATTCACCCCAAGAACATCCA
AAGTGTGAACGTGAAGTCCCCCGGACCCCACTGCGCCCAAACCGAAGTCATAGCCACACTCAAGAATGGGCGGAAAGCTTGCCT
CAATCCTGCATCCCCCATAGTTAAGAAAATCATCGAAAAGATGCTGAACAGTGACAAATCCAACTGACCAGAAGGGAGGAGGAA
GCTCACTGGTGGCTGTTCCTGAAGGAGGCCCTGCCCTTATAGGAACAGAAGAGGAAAGAGAGACACAGCTGCAGAGGCCACCTG GATTGTGCCTAATGTGTTTGAGCATCGCTTAGGAGAAGTCTTCTATTTATTTATTTATTCATTAGTTTTGAAGATTCTATGTTA
ATATTTTAGGTGTAAAATAATTAAGGGTATGATTAACTCTACCTGCACACTGTCCTATTATATTCATTCTTTTTGAAATGTCAA
CCCCAAGTTAGTTCAATCTGGATTCATATTTAATTTGAAGGTAGAATGTTTTCAAATGTTCTCCAGTCATTATGTTAATATTTC
TGAGGAGCCTGCAACATGCCAGCCACTGTGATAGAGGCTGGCGGATCCAAGCAAATGGCCAATGAGATCATTGTGAAGGCAGGG
GAATGTATGTGCACATCTGTTTTGTAACTGTTTAGATGAATGTCAGTTGTTATTTATTGAAATGATTTCACAGTGTGTGGTCAA CATTTCTCATGTTGAAACTTTAAGAACTAAAATGTTCTAAATATCCCTTGGACATTTTATGTCTTTCTTGTAAGGCATACTGCC
TTGTTTAATGGTAGTTTTACAGTGTTTCTGGCTTAGAACAAAGGGGCTTAATTATTGATGTTTTCATAGAGAATATAAAAATAA
AGCACTTATAG
487
MIFPWKCQSTQRDLMIFKLWGWTMLCCDFLAHHGTDC TYHYSEKPM WQRARRFCRDNYTD VAIQNKAEIEY EKTLPFSR SYYWIGIRKIGGIWTWGTNKSLTEEAE WGDGEP KKNKEDCVEIYIKR KDAGK DDACHKLKAALCYTASCQPWSCSGH GECVEIINNYTCNCDVGYYGPQCQF¥IQCEPLEAPELGTMDCTHPLGNFSFSSQCAFSCSEGTN TGIEETTCGPFGNWSSPEP TCQVIQCEPLSAPDLGIMCSHPLASFSFTSACTFICSEGTELIGKKKTICESSGIWSNPSPICQKLDKSFSMIKEGDYNPLFI PVAV--VTAFSG AFIIW ARRLKKGKKSKRSMNDPY
488 CTCCCTTTGGGCAAGGACCTGAGACCCTTGTGCTAAGTCAAGAGGCTCAATGGGCTGCAGAAGAACTAGAGAAGGACCAAGCAA AGCCATGATATTTCCATGGAAATGTCAGAGCACCCAGAGGGACTTATGGAACATCTTCAAGTTGTGGGGGTGGACAATGCTCTG TTGTGATTTCCTGGCACATCATGGAACCGACTGCTGGACTTACCATTATTCTGAAAAACCCATGAACTGGCAAAGGGCTAGAAG ATTCTGCCGAGACAATTACACAGATTTAGTTGCCATACAAAACAAGGCGGAAATTGAGTATCTGGAGAAGACTCTGCCTTTCAG TCGTTCTTACTACTGGATAGGAATCCGGAAGATAGGAGGAATATGGACGTGGGTGGGAACCAACAAATCTCTTACTGAAGAAGC AGAGAACTGGGGAGATGGTGAGCCCAACAACAAGAAGAACAAGGAGGACTGCGTGGAGATCTATATCAAGAGAAACAAAGATGC AGGCAAATGGAACGATGACGCCTGCCACAAACTAAAGGCAGCCCTCTGTTACACAGCTTCTTGCCAGCCCTGGTCATGCAGTGG CCATGGAGAATGTGTAGAAATCATCAATAATTACACCTGCAACTGTGATGTGGGGTACTATGGGCCCCAGTGTCAGTTTGTGAT TCAGTGTGAGCCTTTGGAGGCCCCAGAGCTGGGTACCATGGACTGTACTCACCCTTTGGGAAACTTCAGCTTCAGCTCACAGTG TGCCTTCAGCTGCTCTGAAGGAACAAACTTAACTGGGATTGAAGAAACCACCTGTGGACCATTTGGAAACTGGTCATCTCCAGA ACCAACCTGTCAAGTGATTCAGTGTGAGCCTCTATCAGCACCAGATTTGGGGATCATGAACTGTAGCCATCCCCTGGCCAGCTT CAGCTTTACCTCTGCATGTACCTTCATCTGCTCAGAAGGAACTGAGTTAATTGGGAAGAAGAAAACCATTTGTGAATCATCTGG AATCTGGTCAAATCCTAGTCCAATATGTCAAAAATTGGACAAAAGTTTCTCAATGATTAAGGAGGGTGATTATAACCCCCTCTT CATTCCAGTGGCAGTCATGGTTACTGCATTCTCTGGGTTGGCATTTATCATTTGGCTGGCAAGGAGATTAAAAAAAGGCAAGAA ATCCAAGAGAAGTATGAATGACCCATATTAAATCGCCCTTGGTGAAAGAAAATTCTTGGAATACTAAAAATCATGAGATCCTTT AAATCCTTCCATGAAACGTTTTGTGTGGTGGCACCTCCTACGTCAAACATGAAGTGTGTTTCCTTCAGTGCATCTGGGAAGATT TCTACCTGACCAACAGTTCCTTCAGCTTCCATTTCGCCCCTCATTTATCCCTCAACCCCCAGCCCACAGGTGTTTATACAGCTC AGCTTTTTGTCTTTTCTGAGGAGAAACAAATAAGACCATAAAGGGAAAGGATTCATGTGGAATATAAAGATGGCTGACTTTGCT CTTTCTTGACTCTTGTTTTCAGTTTCAATTCAGTGCTGTACTTGATGACAGACACTTCTAAATGAAGTGCAAATTTGATACATA TGTGAATATGGACTCAGTTTTCTTGCAGATCAAATTTCACGTCGTCTTCTGTATACTGTGGAGGTACACTCTTATAGAAAGTTC AAAAAGTCTACGCTCTCCTTTCTTTCTAACTCCAGTGAAGTAATGGGGTCCTGCTCAAGTTGAAAGAGTCCTATTTGCACTGTA GCCTCGCCGTCTGTGAATTGGACCATCCTATTTAACTGGCTTCAGCCTCCCCACCTTCTTCAGCCACCTCTCTTTTTCAGTTGG CTGACTTCCACACCTAGCATCTCATGAGTGCCAAGCAAAAGGAGAGAAGAGAGAAATAGCCTGCGCTGTTTTTTAGTTTGGGGG TTTTGCTGTTTCCTTTTATGAGACCCATTCCTATTTCTTATAGTCAATGTTTCTTTTATCACGATATTATTAGTAAGAAAACAT CACTGAAATGCTAGCTGCAAGTGACATCTCTTTGATGTCATATGGAAGAGTTAAAACAGGTGGAGAAATTCCTTGATTCACAAT GAAATGCTCTCCTTTCCCCTGCCCCCAGACCTTTTATCCACTTACCTAGATTCTACATATTCTTTAAATTTCATCTCAGGCCTC CCTCAACCCCACCACTTCTTTTATAACTAGTCCTTTACTAATCCAACCCATGATGAGCTCCTCTTCCTGGCTTCTTACTGAAAG GTTACCCTGTAACATGCAATTTTGCATTTGAATAAAGCCTGCTTTTTAAGTGTTAA

Claims

1. A method for the identification of a gene that is implicated in a specific disease or physiological condition, said method comprising the steps of: a) comparing: i) the transcriptome or proteome of a first specialised cell type that is implicated in the disease or condition under first and second experimental conditions; with ii) the transcriptome or proteome of a second specialised cell type under said first and said second experimental conditions; and b) identifying as a gene implicated in the disease or physiological condition, a gene that is differentially regulated in the two specialised cell types under the first and second experimental conditions.
2. A method according to claim 1 , wherein said specialised cell types are selected from the group consisting of cardiomyocytes, endothelial cells, sensory neurons, motor neurons, CNS neurons, astrocytes, glial cells, schwann cells, mast cells, eosinophils, smooth muscle cells, skeletal muscle cells, pericytes, lymphocytes, tumor cells, monocytes, macrophages, foamy macrophages, granulocytes, synovial cells / synovial fibroblasts and epithelial cells.
3. A method according to claim 1 or claim 2, wherein said first and second experimental conditions differ in respect of the cellular microenvironment, or in respect of exposure to hormones, growth factors, cytokines, chemokines, inflammatory agents, toxins, metabolites, pH, pharmaceutical agents, hypoxia, anoxia, ischemia, imbalance of any plasma-borne nutrient, osmotic stress, temperature, mechanical stress, irradiation, cell-extracellular matrix interactions, cell-cell interactions, accumulations of foreign or pathological extracellular components, intracellular and extracellular pathogens, or a genetic perturbation.
4. A method according to any one of the preceding claims, wherein the first experimental conditions and second experimental conditions differ in that under the second experimental conditions, the cells are exposed to a physiological stimulus.
5. A method according to claim 4, wherein the physiological stimulus is a physiological, mechanical, temperature, chemical, toxic or pharmaceutical stress.
6. A method according to claim 5, wherein said physiological stress is hypoxia.
7. A method according to any one of the preceding claims, wherein said first and second experimental conditions are different genetic conditions.
8. A method according to claim 7, wherein said second experimental conditions differ from said first experimental conditions in that the expression of a genetic element is expressed at a different level in said second experimental conditions relative to the level of expression of the genetic element in said first experimental conditions.
9. A method according to claim 8, wherein said genetic element is heterologous to the specialized cell type.
10. A method according to any one of the preceding claims, wherein the transcriptomes of the specialized cell types are compared by a technique involving hybridization to a nucleic acid array, subtractive mRNA hybridisation, the serial analysis of gene expression (SAGE); the selective amplification via biotin- and restriction-mediated enrichment (SABRE); differential display; representational difference analysis (RDA); differential screening of cDNA libraries; Northern blotting; an RNAse protection assay; an Sl-nuclease protection assays; RT-PCR; real time RT-PCR (Taq-man); EST sequencing; massively parallel signature sequencing (MPSS); or sequencing by hybridisation (SBH).
11. A method according to claim 10, wherein the transcriptomes are compared by hybridization to a nucleic acid array.
12. A substantially purified polypeptide, encoded by a gene implicated in a specific disease or physiological condition by a method according to any one of the preceding claims. 13. A substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11,
13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ
ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or has an amino acid sequence encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
14. A polypeptide according to claim 13, wherein said biological activity is a hypoxia-regulated activity.
15. A polypeptide according to claim 14, wherein the expression of the polypeptide is hypoxia-induced.
16. A polypeptide according to claim 15, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos.: 1,3,5,7,9,11,
1~3, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139 and 141; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ
ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114,
116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142 and 144, or is encoded by a gene identified from an EST recited in any one of these SEQ ID Nos.; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
17. A polypeptide according to claim 14, wherein the expression of the polypeptide is hypoxia-repressed.
18. A polypeptide according to claim 17, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos.: 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205,
207 and 209; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ
ID Nos.: 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or is encoded by a gene identified from an EST recited in any one of these SEQ ID Nos.; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
19. A polypeptide which is a functional equivalent according to part iv) of any one of claims 13-18, is homologous to the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113, 115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153,
157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 or is homologous to the amino acid sequence encoded by a nucleic acid as recited in any one of SEQ ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160,
162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, and has equivalent biological activity to that possessed by the full length polypeptide of i) or ii).
20. A fragment or functional equivalent according to any one of claims 13-19, which has greater than 50% sequence identity with the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11,
13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 63, 67, 69, 73, 75, 77, 85, 87, 89, 91, 93, 95, 99, 103, 113,115, 119, 121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 or with the amino acid sequence that is encoded by a nucleic acid as recited in any one of SEQ ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76,
78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or with fragments thereof, preferably greater than 60%, 70%, 80%, 90%, 95%, 98% or 99% sequence identity.
21. A fragment as recited in any one of claims 13-20 having an antigenic determinant in common with a polypeptide according to part i) of any one of claims 13-18, which consists of 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more) amino acid residues from the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45,47,49,51,53,55,57,59,63,67,69,73,75,77,85,87,89,91,93,95,99,103,113,115,119,121, 129, 131, 133, 137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 or the amino acid sequence encoded by a nucleic acid as recited in any one of SEQ ID Nos: 2, 4, 6, 8, 10,
12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216,
22. A purified and isolated nucleic acid molecule that encodes a polypeptide according to any one of claims 13-21.
23. A purified nucleic acid molecule according to claim 22, which consists of the nucleic acid sequence as recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92,
92a, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214 and 216, or is a redundant equivalent or fragment thereof.
24. A purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule according to claim 22 or claim 23.
25, A vector comprising a nucleic acid molecule as recited in any one of claims 22-24,
26. A delivery vehicle comprising a nucleic acid according to any one of claims 22-24 or a vector according to claim 25.
27. A host cell transformed with a vector according to claim 25.
28. An antagonist ligand which binds specifically to a polypeptide according to any one of claims 13-21, preferably a ligand which inhibits the hypoxia-induced activity of said polypeptide.
29. An agonist ligand which binds specifically to a polypeptide according to any one of claims 13-21, preferably a ligand which augments or potentiates a hypoxia-induced activity of said polypeptide.
30. A ligand according to claim 28 or claim 29, which is an antibody.
31. A ligand according to claim 28 or claim 29, which is a peptide, a peptidomimetic, or a drug molecule, such as a small natural or synthetic organic molecule of up to 2000Da, preferably 800Da or less.
32. A polypeptide according to any one of claims 13-21, a nucleic acid molecule according to any one of claims 22-24, a vector according to claim 25 or a ligand according to claim 30 or 31, for use in therapy or diagnosis of disease.
33. A polypeptide, nucleic acid molecule, vector or ligand as recited in claim 32, wherein said disease is a hypoxia-regulated condition.
34. A polypeptide, nucleic acid molecule, vector or ligand as recited in claim 33, wherein said hypoxia- regulated condition is tumourigenesis, angiogenesis, apoptosis, inflammation, erythropoiesis, the biological response to hypoxia conditions (including processes such as glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport or nitric oxide synthesis).
35. A substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,
63,67,69,73,75,77,85,87,89,91,93,95,99,103,113, 115, 119,121, 129, 131, 133,
137, 139, 141, 145, 151, 153, 157, 159, 163, 169, 181, 187, 201, 205, 207 and 209 or SEQ
ID Nos.: 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247,
249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295,297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319,
321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355,
357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391,
393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427,
429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485 and 487; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ
ID Nos: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,
38, 40, 42, 44, 46 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 92a 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164
166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200 202, 204, 206, 208, 210, 212, 214 and 216, or has an amino acid sequence encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragm ent of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determ inant in comm on with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii). for use in the diagnosis or therapy of the disease or abnorm al physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapm sia, atherosclerosis, inflammatory conditions, w ound healing, tumourigenesis, angiogenesis, apoptosis, inflamm ation, erythropoiesis, hair loss, or the biological response to hypoxia conditions, including processes such as glycolysis, gluconeogenesis, glucose transportation, catecholam ine synthesis, iron transport and nitric oxide synthesis. , A purified and isolated nucleic acid m olecule that encodes a polypeptide as recited in claim 35, for use in the diagnosis or therapy of for use in the diagnosis or therapy of a disease or abnorm al physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflam m atory conditions, w ound healing, tum ourigenesis, angiogenesis, apoptosis, inflammation, erythropoiesis or hair loss, , A purified nucleic acid m olecule as recited in claim 36, which consists of the nucleic acid sequence as recited in any one of SEQ ID Nos.: 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282,
284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482,
484, 486 and 488, or w hich is a redundant equivalent or fragment thereof, for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflamm atory conditions, w ound healing, tum ourigenesis, angiogenesis, apoptosis, inflammation, erythropoiesis or hair loss. , A purified nucleic acid m olecule which hydridizes under high stringency conditions with a nucleic acid m olecule as recited in claim 36 or claim 37, for use in the diagnosis or therapy of a disease or abnorm al physiological condition that is affected by hypoxia, such as cancer, ischaem ic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapm sia, atherosclerosis, inflam m atory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflam m ation, erythropoiesis, or hair loss,
39. A vector comprising a nucleic acid m olecule as recited in any one of claim s 36-38 , for use in the diagnosis or therapy of a disease or abnorm al physiological condition that is affected by hypoxia, such as cancer, ischaem ic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapm sia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflam m ation, erythropoiesis, or hair loss.
40. A ligand w hich binds specifically' to, and which preferably inhibits the hypoxia-induced activity of, a polypeptide as recited in claim 35, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology,
41. A pharm aceutical composition suitable for m odulating hypoxia and/or ischaemia, comprising a therapeutically-effective am ount of a polypeptide as recited in any one of claim s 13-21 or 35 , a nucleic acid m olecule according to any one of claim s 22-24 or 36-38, a vector according to claim 25 or 39, or a ligand according to claim 30, 31 or 40, in conjunction with a pharm aceutically-acceptable carrier.
42. A pharmaceutical composition according to claim 41 , w herein said pharm aceutically-acceptable carrier is a liposom e.
43. A vaccine composition comprising a polypeptide as recited in any one of claim s 13-21 or 35, a nucleic acid molecule as recited in any one of claims 22-24 or 36-38, or a vector according to claim 25 or 39.
44. A method of treating a disease in a patient in need of such treatment by administering to a patient a therapeutically effective amount of a polypeptide as recited in any one of claims 13-21 or 35, an antagonist of said polypeptide, or a nucleic acid molecule as recited in any one of claim s 22-24 or 36- 38.
45. A method of regulating tum ourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology in a patient in need of such treatment by adm inistering to a patient a therapeutically effective am ount of a polypeptide according to any one of claims 13-21 or 35, a nucleic acid m olecule according to any one of claim s 22-24 or 36-38, or a vector according to claim 25 or 39, or a ligand according to claim 30, 31 or 40 or a pharm aceutical composition according to claim 41 or 42.
46. A method according to claim 45, wherein, for diseases in w hich the expression of the natural gene or the activity of the polypeptide is lower in a diseased patient w hen compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid m olecule, ligand, compound or composition adm inistered to the patient is an agonist.
47. A m ethod according to claim 45, wherein, for diseases in which the expression of the natural gene or activity of the polypeptide is higher in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid m olecule, vector, ligand, compound or composition administered to the patient is an antagonist.
48. A polypeptide according to any one of claim s 13-21 or 35, a nucleic acid m olecule according to any one of claim s 22-24 or 36-38 , a vector according to claim 25 or 39, a ligand according to claim 30, 31 or 40 or a pharm aceutical composition according to claim 41 or 42, for use in the m anufacture of a m edicam ent for the treatment of a hypoxia-regulated condition.
49. A method of monitoring the therapeutic treatment of a disease or physiological condition in a patient, comprising monitoring over a period of time the level of expression or activity of polypeptide according to any one of claim s 13-21 or 35, a nucleic acid m olecule according to any one of claim s 22-
24 or 36-38, in tissue from said patient, wherein altering said level of expression or activity over the period of time tow ards a control level is indicative of regression of said disease.
50. A m ethod of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by adm inistering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or m ore of the nucleic acid molecules recited in claim s 22-24 or 36-38.
51. A method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of claim s 13-21 or 35 , or assessing the activity of such a polypeptide, in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition.
52. A method according to claim 51 that is carried out in vitro.
53. A method according to claim 51 or claim 52, which comprises the steps of: (a) contacting a ligand according to claim 30, 31 or 40 with a biological sample under conditions suitable for the form ation of a ligand-polypeptide complex ; and (b) detecting said complex.
54. A m ethod according to claim 51 or claim 52, comprising the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the form ation of a hybrid complex between a nucleic acid m olecule according to any one of claim s 22-24 or 36-38 and the probe; b) contacting a control sample w ith said probe under the sam e conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of the hypoxia-related condition.
55. A method according to claim 51 or.claim 52, comprising the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid prim er under stringent conditions that allow the formation of a hybrid complex between a nucleic acid m olecule according to any one of claim s 22-24 or 36-38 and the prim er; b) contacting a control sample w ith said prim er under the sam e conditions used in step a); c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; w herein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the am plified nucleic acid in the control sample is indicative of the hypoxia-related condition.
56. A method according to claim 51 or claim 52, comprising the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of claim s 22-24 or 36-38 from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a m utation which is associated with the hypoxia-related condition in the nucleic acid molecule as an indication of the hypoxia-related condition.
57. The m ethod of claim 56, further comprising amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
58. A method according to any one of claim s 49-57, wherein said disease is cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, w ound healing, tum ourigenesis, angiogenesis, apoptosis, inflamm ation, erythropoiesis, or hair loss.
59. A method according to claim 58, wherein said hypoxia or ischaemia-related tissue damage is due to a disorder of the cerebral, coronary or peripheral circulation.
60. A method according to any one of claim s 49, and 54-59, wherein the tissue is a cancer tissue,
61. A method for the identification of a compound that is effective in the treatm ent and/or diagnosis of disease, comprising contacting a polypeptide according to any one of claim s 13-21 or 35, a nucleic acid molecule according to any one of claim s 22-24 or 36-38 with one or m ore compounds suspected of possessing binding affinity for said polypeptide or nucleic acid m olecule, and selecting a compound that binds specifically to said nucleic acid m olecule or polypeptide.
62. A method for the identification of a compound that is effective in the treatm ent and/or diagnosis of disease, comprising contacting a cell or cell m embrane preparation comprising a polypeptide according to any one of claims 13-21 or 35 or a nucleic acid m olecule according to any one of claim s 22-24 or 36-38 with one or m ore candidate compounds and detecting the degree of compound binding, or the stim ulation or inhibition of a functional response in said cell or cell m em brane.
63. A compound identified or identifiable by a method according to claim 61 or claim 62.
64. A compound according to claim 63 , which is a natural or m odified substrate, an enzyme, a receptor, a sm all organic molecule, such as a sm all natural or synthetic organic m olecule of up to 2000Da, preferably 800Da or less, a peptidomimetic, an inorganic molecule, a peptide, a polypeptide, an antibody, or a structural or functional mimetics of any of these compounds.
65. A kit useful for diagnosing disease comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of claims 22- 24 or 36-38 ; a second container containing primers useful for amplifying said nucleic acid m olecule; and instructions for using the probe and primers for facilitating the diagnosis of disease.
66. The kit of claim 65, further comprising a third container holding an agent for digesting unhybridised RNA .
67. An array of at least tw o nucleic acid molecules, wherein each of said nucleic acid m olecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of claim s 22-24 or 36-38.
68. An array according to claim 67, which contains nucleic acid molecules that either correspond to the sequence of, are complementary to the sequence of, or hybridise specifically to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13,14, 15,16, 17,18,19,20,21,22,23,24,25,26,27,28,29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,
85, 86, 87, 88, 89, 90, 91, 92, 92a, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,
188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287,
288, 289, 290, 291, 292, 293, 294 or 295 of the nucleic acid molecules implicated in a hypoxia- regulated condition as recited in claims 22-24 or 36-38.
69. An array according to any claim 67 or claim 68, wherein said nucleic acid molecules consist of between twelve and two thousand nucleotides.
70. An array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia-regulated condition as recited in any one of claims 13-21 or 35.
71. An array of polypeptides, comprising at least two polypeptide species as recited in any one of claims 13-21 or 35, wherein each polypeptide species is implicated in a hypoxia-regulated condition, or is a functional equivalent variant or fragment thereof.
72. A kit comprising an array of nucleic acid molecules according to any one of claims 67-69.
73. A kit comprising one or more antibodies that bind to a polypeptide as recited in any one of claims 13- 21 or 35; and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide.
74. A transgenic or knockout non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of claims 13-21 or 35.
75. A method for screening for a compound effective to treat disease, by contacting a* non- human transgenic animal according to claim 74 with a candidate compound and determining the effect of the compound on the disease or physiological condition of the anim al.
76. A substantially purified polypeptide comprising the consensus sequence: KAMVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEPI FDRLLFFW SDRRNPHEVQPSYATRYAM TVW YFDAEERAEAKKK, or a variant thereof.
77. A substantially purified polypeptide according to claim 76, for use in the diagnosis or treatment of a hypoxia-related disease or condition.
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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003044197A1 (en) * 2001-11-21 2003-05-30 Japan Science And Technology Agency Huntington’s disease gene transcriptional factors
WO2004012817A2 (en) * 2002-07-31 2004-02-12 Kylix B.V. Use of genes identified to be involved in tumor development for the development of anti-cancer drugs
WO2004035615A2 (en) * 2002-10-18 2004-04-29 Atugen Ag Factor involved in metastasis and uses thereof
WO2004048520A2 (en) * 2002-11-21 2004-06-10 The General Hospital Corporation Redd1, a transcriptional target of p63 and p53, and methods of use therefor
WO2004058817A1 (en) * 2002-12-26 2004-07-15 Takeda Pharmaceutical Company Limited Novel proteins and use thereof
WO2004111641A2 (en) * 2003-06-12 2004-12-23 University Of Manitoba Methods for detecting cancer and monitoring cancer progression
WO2005012564A1 (en) * 2003-07-22 2005-02-10 Astrazeneca Ab Genetic marker for coronary artery disease
WO2005061704A1 (en) * 2003-12-24 2005-07-07 Takeda Pharmaceutical Company Limited Preventive/remedy for cancer
WO2005111239A2 (en) * 2004-04-30 2005-11-24 Decode Genetics Ehf. Haplotypes in the human thioredoxin interacting protein homologue (arrdc3) gene associated with obesity
WO2005118631A1 (en) 2004-06-03 2005-12-15 Takeda Pharmaceutical Company Limited Novel protein complex and use thereof
WO2005123955A2 (en) * 2004-06-09 2005-12-29 Children's Medical Center Corporation Methods and compositions for modifying gene regulation and dna damage in ageing
EP1709152A2 (en) * 2003-12-15 2006-10-11 The Regents Of The University Of California Molecular signature of the pten tumor suppressor
US7585954B2 (en) 2001-03-29 2009-09-08 Ucb Sa Antibodies for diagnosing psoriasis
US7626015B2 (en) 2006-06-09 2009-12-01 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801L
US7723052B2 (en) 2006-05-11 2010-05-25 Quark Pharmaceuticals, Inc. Screening systems utilizing RTP801
US7741299B2 (en) 2004-08-16 2010-06-22 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
US7872119B2 (en) 2007-02-26 2011-01-18 Quark Pharmaceuticals, Inc. Inhibitors of RTP801 and their use in disease treatment
US8067570B2 (en) 2006-01-20 2011-11-29 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
US8158356B2 (en) 2006-10-16 2012-04-17 Agrigenomics, Inc. Screening for the genetic defect causing tibial hemimelia in bovines
US8283158B2 (en) 2002-11-25 2012-10-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method and apparatus for performing multiple simultaneous manipulations of biomolecules in a two dimensional array
US8318795B2 (en) 2007-03-01 2012-11-27 Cedars-Sinai Medical Center Antioxidant polymers containing [1,2]-dithiolane moieties and uses thereof
US8404654B2 (en) 2006-01-20 2013-03-26 Quark Pharmaceuticals, Inc. Treatment or prevention of oto-pathologies by inhibition of pro-apoptotic genes
US8431346B2 (en) 2009-12-18 2013-04-30 Agrigenomics, Inc. Screening for arthrogryposis multiplex in bovines
US8603531B2 (en) 2008-06-02 2013-12-10 Cedars-Sinai Medical Center Nanometer-sized prodrugs of NSAIDs
US8614311B2 (en) 2007-12-12 2013-12-24 Quark Pharmaceuticals, Inc. RTP801L siRNA compounds and methods of use thereof
US8697743B2 (en) 2008-11-24 2014-04-15 Cedars-Sinai Medical Center Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof
US8771942B2 (en) 2002-03-01 2014-07-08 Exelixis, Inc. SCDs as modifiers of the p53 pathway and methods of use
US9028874B2 (en) 2008-01-03 2015-05-12 Cedars-Sinai Medical Center Antioxidant nanosphere comprising [1,2]-dithiolane moieties
US9068991B2 (en) 2009-06-08 2015-06-30 Singulex, Inc. Highly sensitive biomarker panels
WO2016183119A1 (en) * 2015-05-11 2016-11-17 Mimetics, Llc Methods for identifying targets for antimicrobial and antiproliferative compounds and compositions therefrom
US9719999B2 (en) 2006-04-04 2017-08-01 Singulex, Inc. Highly sensitive system and method for analysis of troponin
US9963745B2 (en) 2011-12-02 2018-05-08 3D Signatures Holdings Inc. Hematological disorder diagnosis by 3D q-FISH
US9977031B2 (en) 2006-04-04 2018-05-22 Singulex, Inc. Highly sensitive system and method for analysis of troponin
US20190192631A1 (en) * 2011-08-10 2019-06-27 Follicum Ab Novel compositions and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; October 2000 (2000-10) TANAKA TOSHIO: "Transcriptome analysis and pharmacogenomics." Database accession no. PREV200000485122 XP002234129 & FOLIA PHARMACOLOGICA JAPONICA, vol. 116, no. 4, October 2000 (2000-10), pages 241-246, ISSN: 0015-5691 *
EISEN M B ET AL: "Cluster analysis and display of genome-wide expression patterns" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 95, December 1998 (1998-12), pages 14863-14868, XP002140966 ISSN: 0027-8424 *
PEROU C M ET AL: "Distinctive gene expression patterns in human mammary epithelial cells and breast cancers" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 96, no. 16, 3 August 1999 (1999-08-03), pages 9212-9217, XP002203005 ISSN: 0027-8424 *
PEROU C M ET AL: "Molecular portraits of human breast tumours" NATURE, MACMILLAN JOURNALS LTD. LONDON, GB, vol. 406, no. 6797, 17 August 2000 (2000-08-17), pages 747-752, XP002203006 ISSN: 0028-0836 cited in the application *

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* Cited by examiner, † Cited by third party
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US7585954B2 (en) 2001-03-29 2009-09-08 Ucb Sa Antibodies for diagnosing psoriasis
US7879982B2 (en) 2001-03-29 2011-02-01 Celltech R&D, Inc. 19.5 polypeptide antibodies useful for diagnosing or treating psoriasis
WO2003044197A1 (en) * 2001-11-21 2003-05-30 Japan Science And Technology Agency Huntington’s disease gene transcriptional factors
US8771942B2 (en) 2002-03-01 2014-07-08 Exelixis, Inc. SCDs as modifiers of the p53 pathway and methods of use
WO2004012817A3 (en) * 2002-07-31 2004-10-28 Kylix B V Use of genes identified to be involved in tumor development for the development of anti-cancer drugs
WO2004012817A2 (en) * 2002-07-31 2004-02-12 Kylix B.V. Use of genes identified to be involved in tumor development for the development of anti-cancer drugs
JP4820092B2 (en) * 2002-10-18 2011-11-24 サイレンス・セラピューティクス・アーゲー Novel factors for metastasis and their use
JP2011125339A (en) * 2002-10-18 2011-06-30 Silence Therapeutics Ag New factor involved in metastasis and use thereof
WO2004035615A3 (en) * 2002-10-18 2004-06-03 Atugen Ag Factor involved in metastasis and uses thereof
WO2004035615A2 (en) * 2002-10-18 2004-04-29 Atugen Ag Factor involved in metastasis and uses thereof
JP2006520183A (en) * 2002-10-18 2006-09-07 アトゥーゲン・アーゲー Novel factors for metastasis and their use
EP2072619A1 (en) * 2002-10-18 2009-06-24 Silence Therapeutics Aktiengesellschaft Factor involved in metastasis and uses thereof
WO2004048520A3 (en) * 2002-11-21 2005-09-01 Gen Hospital Corp Redd1, a transcriptional target of p63 and p53, and methods of use therefor
WO2004048520A2 (en) * 2002-11-21 2004-06-10 The General Hospital Corporation Redd1, a transcriptional target of p63 and p53, and methods of use therefor
US8283158B2 (en) 2002-11-25 2012-10-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method and apparatus for performing multiple simultaneous manipulations of biomolecules in a two dimensional array
WO2004058817A1 (en) * 2002-12-26 2004-07-15 Takeda Pharmaceutical Company Limited Novel proteins and use thereof
WO2004111641A2 (en) * 2003-06-12 2004-12-23 University Of Manitoba Methods for detecting cancer and monitoring cancer progression
US7393637B2 (en) * 2003-06-12 2008-07-01 University Of Manitoba Methods for detecting cancer and monitoring cancer progression
WO2004111641A3 (en) * 2003-06-12 2005-10-27 Univ Manitoba Methods for detecting cancer and monitoring cancer progression
WO2005012564A1 (en) * 2003-07-22 2005-02-10 Astrazeneca Ab Genetic marker for coronary artery disease
EP1709152A2 (en) * 2003-12-15 2006-10-11 The Regents Of The University Of California Molecular signature of the pten tumor suppressor
EP1709152A4 (en) * 2003-12-15 2007-11-07 Univ California Molecular signature of the pten tumor suppressor
AU2004298604B2 (en) * 2003-12-15 2010-09-23 The Regents Of The University Of California Molecular signature of the PTEN tumor suppressor
EP1712619A4 (en) * 2003-12-24 2008-01-02 Takeda Pharmaceutical Preventive/remedy for cancer
EP1712619A1 (en) * 2003-12-24 2006-10-18 Takeda Pharmaceutical Company Limited Preventive/remedy for cancer
WO2005061704A1 (en) * 2003-12-24 2005-07-07 Takeda Pharmaceutical Company Limited Preventive/remedy for cancer
WO2005111239A2 (en) * 2004-04-30 2005-11-24 Decode Genetics Ehf. Haplotypes in the human thioredoxin interacting protein homologue (arrdc3) gene associated with obesity
WO2005111239A3 (en) * 2004-04-30 2006-05-04 Decode Genetics Ehf Haplotypes in the human thioredoxin interacting protein homologue (arrdc3) gene associated with obesity
WO2005118631A1 (en) 2004-06-03 2005-12-15 Takeda Pharmaceutical Company Limited Novel protein complex and use thereof
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US8642571B2 (en) 2004-08-06 2014-02-04 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
US8168607B2 (en) 2004-08-06 2012-05-01 Quark Pharmaceuticals Inc. Methods of treating eye diseases in diabetic patients
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US8309532B2 (en) 2004-08-16 2012-11-13 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
US8404654B2 (en) 2006-01-20 2013-03-26 Quark Pharmaceuticals, Inc. Treatment or prevention of oto-pathologies by inhibition of pro-apoptotic genes
US8067570B2 (en) 2006-01-20 2011-11-29 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
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US9056903B2 (en) 2006-01-20 2015-06-16 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801
US9977031B2 (en) 2006-04-04 2018-05-22 Singulex, Inc. Highly sensitive system and method for analysis of troponin
US9719999B2 (en) 2006-04-04 2017-08-01 Singulex, Inc. Highly sensitive system and method for analysis of troponin
US7723052B2 (en) 2006-05-11 2010-05-25 Quark Pharmaceuticals, Inc. Screening systems utilizing RTP801
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US8034575B2 (en) 2006-05-11 2011-10-11 Quark Pharmaceuticals, Inc. Screening systems utilizing RTP801
US8017764B2 (en) 2006-06-09 2011-09-13 Quark Pharmaceuticals Inc. Therapeutic uses of inhibitors of RTP801L
US7626015B2 (en) 2006-06-09 2009-12-01 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of RTP801L
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