CA2313957C - Method for producing mass-coded combinatorial libraries - Google Patents

Abstract

The present invention provides a method for producing a mass-coded combinatorial library comprising a set of compounds having the general formula X(Y)n, where X is a scaffold, each Y is, independently, a peripheral moiety, and n is an integer greater than 1. The method comprises selecting a peripheral moiety precursor subset from a peripheral moiety precursor set. The subset includes a sufficient number of peripheral moiety precursors that at least about 50 distinct combinations of n peripheral moieties derived from the peripheral moiety precursors in the subset exist. The subset of peripheral moiety precursors is selected so that at least about 90 % of all possible combinations of n peripheral moieties derived from the subset have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties. The method further comprises contacting the peripheral moiety precursor subset with a scaffold precursor which has n reactive groups. Methods of use of the mass-coded combinatorial library produced by this method for identifying a ligand to a particular biomolecule are also disclosed.

Description

-la-METHOD FOR PRODUCING MASS-CODED COMBINATORIAL LIBRARIES
BACKGROUND OF THE INVENTION
Genomics is identifying the genes responsible for all human functions and diseases. With 80,000 genes in the human genome, the thousands of genes involved in development, stature, intelligence, and other features of a human being are being defined. Humans suffer from hundreds of inherited and infectious diseases, and the genes involved in such are also being identified. Proteins encoded by all these genes are targets for therapeutic drugs. However, drugs that can be applied to human function and disease will not simply emerge from genomic information. Conventional drug development for a single disease is a lengthy, tedious and extremely expensive process. Technologies that eliminate the major hurdles facing drug development in the post-genomic era would be of substantial value.

SUMMARY OF THE INVENTION
The present invention provides a method for producing a mass-coded set of chemical compounds having the general formula X(Y)n, where X is a scaffold, each Y is, independently, a peripheral moiety, and n is an integer greater than 1, typically from 2 to about 6. The method comprises selecting a peripheral moiety precursor subset from a peripheral moiety precursor set. The subset includes a sufficient number of peripheral moiety precursors that at least about 50, 100, 250 or 500 distinct CA 02313957 2000-07-14.

combinations of n peripheral moieties derived from the peripheral moiety precursors in the subset exist. The subset of peripheral moiety precursors is selected so that at least about 90% of all possible combinations of n peripheral moieties derived from the subset of peripheral moiety precursors have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties. The method further comprises contacting the peripheral moiety precursor subset with a scaffold precursor which has n reactive groups, each of which is capable of reacting with at least one peripheral moiety precursor to form a covalent bond. The peripheral moiety precursor subset is contacted with the scaffold precursor under conditions sufficient for the reaction of each reactive group with a peripheral moiety precursor, resulting in a mass-coded set of compounds of the general formula X(Y),,.
In another embodiment, the invention provides a method of identifying a member or members of a mass-coded combinatorial library which are ligands for a biomolecule, for example, a protein or a nucleic acid molecule, such as .DNA or RNA. The method comprises the steps of (1) contacting the biomolecule with the mass-coded molecular library, whereby members of the mass-coded molecular library which are ligands for the biomolecule bind to the biomolecule to form biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the biomolecule remain unbound; (2) separating the biomolecule-ligand complexes from the unbound members of CA 02313957 2000-07-14`

the mass-coded molecular library; (3) dissociating the biomolecule-ligand complexes; and (4) determining the molecular mass of each ligand to identify the set of n peripheral moieties present in each ligand.
In a further embodiment, the invention provides a method for identifying a member or members of a mass-coded molecular library which are ligands'for a biomolecule and bind to the biomolecule at the binding site of a ligand known to bind the biomolecule (a known ligand). The method comprises the steps of: (1) contacting the biomolecule with the mass-coded molecular library, so that members of the mass-coded molecular library which are ligands for the biomolecule bind to the biomolecule to form biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the biomolecule remain unbound;
(2) separating the biomolecule-ligand complexes from the unbound members of the mass-coded molecular library; (3) contacting the biomolecule-ligand complexes with a ligand known to bind the biomolecule, to dissociate biomolecule-ligand complexes in which the ligand binds to the biomolecule at the binding site of the known ligand, thereby forming biomolecule-known ligand complexes and dissociated ligands; (4) separating the dissociated ligands and biomolecule-ligand complexes; and (5) determining the molecular mass of each dissociated ligand to identify the set of n peripheral moieties present in each dissociated ligand.
In a yet further embodiment, the invention provides a method for identifying a member or members of a mass-coded combinatorial library which are ligands for a first biomolecule but are not ligands for a second biomolecule.
The method comprises the steps of: (1) contacting the first biomolecule with the mass-coded molecular library, whereby members of the mass-coded molecular library which are ligands for the first biomolecule bind to the first biomolecule to form first biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the first biomolecule remain unbound; (2) separating the first biomolecule-ligand complexes from the unbound members of the mass-coded molecular library; (3) dissociating the first biomolecule-ligand complexes; (4) determining the molecular mass of each ligand for the first biomolecule;

(5) contacting the second biomolecule with the mass-coded molecular library, whereby members of the mass-coded molecular library which are ligands for the second biomolecule bind to the second biomolecule to form second biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the second biomolecule remain unbound; (6) separating the second biomolecule-ligand complexes from the unbound members of the mass-coded molecular library; (7) dissociating the second biomolecule-ligand complexes; (8) determining the molecular mass of each ligand for the second biomolecule; and (9) determining which molecular masses determined in step (4) are not determined in step (8). This provides the molecular masses of members of the mass-coded combinatorial library which are ligands for the first biomolecule, but are not ligands for the second biomolecule.

In another embodiment, the method for identifying a member or members of a mass-coded combinatorial library which are ligands for a first biomolecule but are not ligands for a second biomolecule comprises the steps of:
(1) contacting the second biomolecule with the mass-coded molecular library, so that members of the mass-coded molecular library which are ligands for the second biomolecule bind to the second biomolecule to form second biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the second biomolecule remain unbound; (2) separating the second biomolecule-ligand complexes from the unbound members of the mass-coded molecular library; (3) contacting the first biomolecule with the unbound members of the mass-coded molecular library of step (2), whereby members of the mass-coded molecular library which are ligands for the first biomolecule bind to the first biomolecule to form first biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the first biomolecule remain unbound; (4) dissociating the first biomolecule-ligand complexes; and (5) determining the molecular mass of each ligand for the first biomolecule. Each molecular mass determined corresponds to a set of n peripheral moieties present in a ligand for the first biomolecule which is not a ligand for the second biomolecule.
In yet another embodiment, the present invention relates to a method for identifying a member of a mass-coded combinatorial library which is a ligand for a biomolecule and assessing the the effect of the binding of the ligand to the biomolecule. The method comprises the steps of: contacting the biomolecule with the mass-coded molecular library, whereby members of the mass-coded molecular library which are ligands for the biomolecule bind to the biomolecule to form biomolecule-ligand complexes and members of the mass-coded library which are not ligands for the biomolecule remain unbound; separating the biomolecule-ligand complexes from the unbound members of the mass-coded molecular library; dissociating the biomolecule-ligand complexes; determining the molecular mass of each ligand to identify the set of n peripheral moieties present in each ligand. The molecular mass of each ligand corresponds to a set of n peripheral moieties present in that ligand, thereby identifying a member of the mass-coded combinatorial library which is a ligand for the biomolecule. The method further comprisies assessing in an in vivo or in vitro assay the effect of the binding of the ligand to the biomolecule on the function of the biomolecule.
The method of the invention allows rapid production of mass-coded combinatorial libraries comprising large numbers of compounds. The mass-coding enables the identification of individual combinations of scaffold and peripheral moieties by molecular mass. The libraries prepared by the method of the invention also allow the rapid identification of compounds which are ligands for a given biomolecule.

CA 02313957 2000-07-14.

BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1A and 1B are flow charts illustrating a procedure and alternative procedure, respectively, for selecting a subset of peripheral moiety precursors from among a larger set of peripheral moiety precursors for the production of a mass-coded combinatorial library.
Figure 2A is a graph illustrating the mass redundancy of the combinatorial libraries resulting from a computer selected set of peripheral moiety precursors selected using a mass-coding algorithm.
Figure 2B is a graph illustrating the mass redundancy of the combinatorial libraries resulting from a set of peripheral moiety precursors selected randomly.
Figure 2C presents graphs illustrating the mass redundancy of the combinatorial libraries resulting from (1) a computer optimized set of peripheral moiety precursors selected using a mass-coding algorithm (...) and (2) a set of peripheral moiety precursors selected randomly Figure 3 is a schematic diagram of a computer system employing a digital processor assembly embodying the invention method of selecting a subset of peripheral moiety precursors which minimize or eliminate mass redundancy in a library.

DETAILED DESCRIPTION OF THE INVENTION
The major hurdles in drug development include a need for: 1) combinatorial chemistry technology that enables rapid production of nearly unlimited numbers of compounds while incorporating the ability to identify efficiently single chemical compounds that bind tightly to a specific biomolecule target, such as a protein or nucleic acid molecule; 2) extremely efficient target-based screening technologies that permit rapid identification of chemical compounds within a large library mixture that become tightly associated with a target biomolecule, even when the function of that biomolecule is not well understood and 3) an information data set that describes how chemical components interact with biomolecules of medical importance.
The present invention provides a method of producing a mass-coded set of compounds, such as a mass-coded combinatorial library. The compounds are of the general formula X(Y)n, wherein X is a scaffold, each Y is a peripheral moiety and n is an integer greater than 1, typically from 2 to about 6. The term "scaffold", as used herein, refers to a molecular fragment to which two or more peripheral moieties are attached via a covalent bond. The scaffold is a molecular fragment which is common to each member of the mass-coded set of compounds. The term "peripheral moiety", as used herein, refers to a molecular fragment which is bonded to a scaffold. Each member of the set of mass-coded compounds will include a combination of n peripheral moieties bonded to the scaffold and this set of compounds forms a mass coded combinatorial library.
The term "combination", as used herein, refers to all permutations of m moieties having n members where m is an integer greater than 2, n is an integer greater than 1 and m is greater than or equal to n, such that:
(1) Permutations having n members in which a given moiety is present from 0 to n times are included..
(2) Permutations having the same n moieties but ordered differently are included once and only once.
The number of combinations of all permutations of m moieties having n members may be calculated from the formula:

Combinations = k! / ((k-n)!*n!) where k = m + (n-1) For example, the combinations of the four moieties labeled A, B, C, D which have 3 members are: A A A; A A B; A A C;
A A D; A B B; A B C; A B D; A C C; A C D; A D D; B B B;
B B C; B B D; B C C; B C D; B D D; C C C; C C D; C D D
and D D D. B A A and A B A, for example, are not counted as separate combinations; only A A B is counted. In this example, m = 4, n = 3 and the number of combinations is given by 6! / ((6-3)!*31) = 20.

The terms "mass-coded set of compounds" and "mass-coded combinatorial library", as used herein, refer to a set of compounds of the formula XY, where X is a scaffold, each Y is, independently, a peripheral moiety and n is an integer greater than 1, typically from 2 to about 6. Such a set of compounds is synthesized as a mixture by the combination of a set of peripheral moiety precursors with a scaffold precursor, and is designed to possess minimum mass redundancy, given the requirement that a fixed number (subset) of peripheral moiety precursors must be chosen from a set of available peripheral moiety precursors.
The term "mass" or "molecular mass', as used herein, refers to the exact mass of a molecule or collection of chemical moieties in which each atom is the most abundant naturally occurring isotope for the particular element.
Exact masses and their determination by mass spectrometry are discussed by Pretsch et al., Tables of Spectral Data for Structure Determination of Organic Compounds, second edition, Springer-Verlag (:1989), and Holden et al., Pure Appl. Chem. 55 : 1119-1136 (1983).

"Minimum mass redundancy", as the term is used herein, is exhibited by a set of compounds of the formula X(Y),, formed by reaction of a scaffold precursor having n reactive groups, where n is an integer greater than 1, typically from 2 to about 6, with a subset of peripheral moiety precursors in which at least about 90% of the possible combinations of n peripheral moieties derived from the subset of peripheral moiety precursors have a molecular mass sum which is distinct from the molecular mass sum of any other combination of n peripheral moieties derived from the subset. The molecular mass sum of a combination of peripheral moieties is the sum of the masses of each peripheral moiety within the combination. For the present purposes, two molecular masses are distinct if they can be distinguished by mass spectrometry or high resolution mass spectrometry. For example, molecular masses which differ by at least 0.001 atomic mass units can be distinguished by high resolution mass spectrometry.
It is to be understood that the molecular mass sum of the combination of the n peripheral moieties in a particular compound of the formula X(Y),, is the collective contribution of the n peripheral moieties to the molecular mass of the compound. As each compound within the set includes a constant scaffold, the difference in the molecular masses of two compounds within the mass-coded set of compounds is the difference in the molecular mass sums of the set of peripheral moieties in each compound.
The method of the invention comprises selecting a peripheral moiety precursor subset from a larger peripheral moiety precursor set. Details of the preferred selection process are discussed later with reference to Figures 1A, 1B and 3. The subset includes a sufficient number of peripheral moiety precursors so that, in one embodiment, at least about 50 distinct combinations of n peripheral moieties derived from the peripheral moiety precursors in the subset can be formed. In another embodiment, at least about 100 distinct combinations of n peripheral moieties can be formed. In a further embodiment, at least about 250 distinct combinations of n peripheral moiety precursors can be formed, and, in yet another embodiment, at least about 500 distinct combinations of n peripheral moieties can be formed.
The subset of peripheral moiety precursors is selected so that at least about 90% of all possible combinations of n peripheral moieties derived from the subset have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties. The method further comprises contacting the peripheral moiety precursor subset with a scaffold precursor which has n reactive groups, each of which is capable of reacting with at least one peripheral moiety precursor to form a covalent bond. The peripheral moiety precursor subset is contacted with the scaffold precursor under conditions sufficient for the reaction of each reactive group with a peripheral moiety precursor, resulting in a mass-coded set of compounds.
In one embodiment, at least about 950 of all possible combinations of n peripheral moieties derived from the peripheral moiety precursor subset have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties. In another embodiment, each of the possible combinations of n peripheral moieties derived from the subset has a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties.
The scaffold precursor can be any molecule comprising two or more reactive groups which are capable of reacting with a peripheral moiety precursor reactive group to form a covalent bond. For example, suitable scaffold precursors can have a wide range of sizes, shapes, degrees of flexibility and charges. The reactive groups should be incapable of intramolecular reaction under the conditions employed. Further, a scaffold precursor molecule should not react with another scaffold precursor molecule under the conditions employed. The scaffold precursor can also include any additional functional groups which are masked or protected or which do not interfere with the reaction of the reactive groups with the peripheral moiety precursors.
Preferably, the scaffold precursor comprises one or more saturated, partially unsaturated or aromatic cyclic groups, such as a cyclic hydrocarbon or heterocyclic group.
In scaffold precursors comprising two or more cyclic groups, the cyclic groups can be fused, connected via a direct bond or connected via an intervening group, such as an oxygen atom, an NH group or a C1_6-alkylene group. At least one cyclic group is substituted by one or more reactive groups. The reactive groups can be attached to the cyclic group directly or via an intervening group, such as a C,-,-alkylene group, preferably a methylene group.
Examples of suitable scaffold precursors include reactive group-substituted benzene, biphenyl, cyclohexane, bipyridyl, N-phenylpyrrole, diphenyl ether, naphthalene and benzophenone. Other suitable classes of scaffold precursors are shown below.

R R N R R
R R
(a) 0/ (b) (c) Rz p R R R R

OIBU
(f) N-(d) N (R} / \ R R /N
R R R

R
R
R H

In these examples, each of the indicated substituents R is, independently, a reactive group, and the scaffold precursor can include one or more additional functional groups which are either (1) masked or protected to prevent their reaction with a peripheral moiety precursor (e.g., scaffold precursors f and g, above) or (2) do not react either with R or with a peripheral moiety precursor under the given reaction conditions (e.g., scaffold precursor h, above, in which R = C(O)O(C6F5) and the peripheral moiety precursors include primary amino groups).
A peripheral moiety precursor is a compound which includes a reactive group which is complementary to one or more of the reactive groups of the scaffold precursor. In addition to the reactive group, a peripheral moiety precursor can include a wide variety of structural features. For example, the peripheral moiety precursor can include one or more functional groups in addition to the reactive group. Any additional functional group should be appropriately masked or not interfere with the reaction between the scaffold precursor and the peripheral moiety precursor. In addition, two peripheral moiety precursors should not react together under the conditions employed.
For example, a subset of peripheral moiety precursors can include, in addition to the reactive groups, functionalities selected from groups spanning a range of charge, hydrophobicity/hydropholicity, and sizes. For example, the peripheral moiety precursor can include a negative charge, a positive charge, a hydrophilic group or a hydrophobic group.
In addition to the reactive groups, peripheral moiety precursors can include, for example, functionalities selected from among amino acid side chains, a nucleotide base or nucleotide base analogue, sugar moieties, sulfonamides, peptidomimetic groups, charged or polar functional groups, alkyl groups and aryl groups.
For the present purposes, two reactive groups are complementary if they are capable of reacting together to form a covalent bond, In a preferred embodiment, the bond forming reactions occur rapidly under ambient conditions without substantial formation of side products.
Preferably, a given reactive group will react with a given complementary reactive group exactly once.
In one embodiment, the reactive group of the scaffold precursor and the reactive group of the peripheral moiety precursor react, for example, via nucleophilic substitution, to form a covalent bond. In one embodiment, the reactive group of the scaffold precursor is an electrophilic group and the reactive group of the peripheral moiety precursor is a nucleophilic group. In another embodiment, the reactive group of the scaffold precursor is a nucleophilic group, while the reactive group of the peripheral moiety precursor is an electrophilic group.
Complementary electrophilic and nucleophilic groups include any two groups which react via nucleophilic substitution under suitable conditions to form a covalent bond. A variety of suitable bond-forming reactions are known in the art. See, for example, March, Advanced Organic Chemistry, fourth edition, New York: John Wiley and Sons (1992), Chapters 10 to 16; Carey and Sundberg, Advanced Organic Chemistry, Part B, Plenum (1990), Chapters 1-il; and Collman et al., Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, CA (1987), Chapters 13 to 20.
Examples of suitable electrophilic groups include reactive carbonyl groups, such as carbonyl chloride (acyl chloride) and carbonyl pentafluorophenyl ester groups, reactive sulfonyl groups, such as the sulfonyl chloride group, and reactive phosphonyl groups. Other electrophilic groups which can be used include terminal epoxide groups and the isocyanate group. Suitable nucleophilic groups include primary and secondary amino groups and alcohol (hydroxyl) groups.
Examples of suitable scaffold precursors with specified reactive groups are shown below.

R ~ \ \ SO ~ ~ ..
/ /
R
R
010 Me O HN \
O O

CI

CI / \ - 0 O CI

CI
In these examples, each R is, independently, an additional reactive group which can be the same as the specified reactive group or a different group.
Illustrated below are examples of suitable peripheral moiety precursors having amino groups.

AcO OAc tBuO NH2 28 H2N. CO2tBu Ac0 CO2tBu tBocNH N . p R NH
N `
J ~/ CFg H2N
H2N N U N NHtBoc N~ NH2 H O CO2tB H
N
H2N /~ \\ //--J
-\ ~-{ N HN HN H ; HN

HN~p/ H2N N 0 \--/ NH
4-~
NH

R in this case is an amino acid side chain, tBoc is tbutoxycarbonyl, Ac is acetyl and 'Bu is tertiary butyl.
Examples of scaffold precursors and peripheral moiety precursors which have complementary reactive groups include the following, which are provided for the purposes of illustration and are not to be construed as limiting in any way:
1. The scaffold precursor includes from two to about six reactive carbonyl groups, reactive sulfonyl groups or reactive phosphonyl groups, or a combination thereof. Each peripheral moiety precursor includes a primary or secondary amino group which reacts with the scaffold precursor to form an amide, sulfonamide or phosphonamidate bond.

2. The scaffold precursor includes from two to about six primary or secondary amino groups or a combination thereof.
Each peripheral moiety precursor includes a reactive carbonyl group, a reactive sulfonyl group or a reactive phosphonyl group.

3. The scaffold precursor includes from two to about six terminal epoxide groups. Each peripheral moiety precursor includes a primary or secondary amino group. In the presence of a suitable Lewis acid, the scaffold precursor and the peripheral moiety precursors react to form R-amino alcohols.

4. The scaffold precursor includes from two to about six primary or secondary amino groups. Each peripheral moiety precursor contains a terminal epoxide group.

5. The scaffold precursor includes from two to about six isocyanate groups. Each peripheral moiety precursor contains a primary or secondary amino group which reacts with the scaffold precursor to form a urea.

6. The scaffold precursor includes from two to about six primary or secondary amino groups, or a combination thereof. Each peripheral moiety precursor contains an isocyanate group.

7. The scaffold precursor includes from two to about six isocyanate groups. Each peripheral moiety precursor contains an alcohol group which reacts with the scaffold precursor to form a carbamate.

8. The scaffold precursor includes from 2 to about 6 aromatic bromides. Each peripheral moiety precursor is an organo-tributyl-tin compound. The scaffold precursor and the peripheral moiety precursors are reacted in the presence of a suitable palladium catalyst to form one or more carbon-carbon bonds.

9. The scaffold precursor includes from 2 to about 6 aromatic halides or triflates. Each peripheral moiety precursor includes a primary or secondary amino groups.
The scaffold precursor and the peripheral moiety precursors are reacted in the presence of a suitable palladium catalyst to form one or more carbon-nitrogen bonds.

10. The scaffold precursor includes from two to about six amino groups. Each peripheral moiety precursor contains an aldehyde or ketone group which reacts with the scaffold precursor under reducing conditions (reductive amination) to form an amine.

11. The scaffold precursor includes from two to about six aldehyde or ketone groups. Each peripheral moiety precursor contains an amino group which reacts with the scaffold precursor under reducing conditions (reductive amination) to form an amine.

12. The scaffold precursor includes from two to about six phosphorous ylide groups. Each peripheral moiety precursor contains an aldehyde or ketone group which reacts with the scaffold precursor (Wittig type reaction) to form an alkene.

13. The scaffold precursor includes from two to about six aldehyde or ketone groups. Each peripheral moiety precursor contains a phosphorous ylide group which relacts with the scaffold precursor (Wittig type reaction) to form an alkene.

The scaffold is that portion of the scaffold precursor which remains after each reactive group of the scaffold precursor has reacted with a peripheral moiety precursor.
A peripheral moiety is that portion of the peripheral moiety precursor which is bonded to the scaffold following the bond-forming reaction. A peripheral moiety which results from the reaction of a particular peripheral moiety precursor with a reactive functional group of a scaffold precursor is said to be "derived" from that peripheral moiety precursor.
A peripheral moiety precursor can include one or more functional groups in addition to the reactive group. One or more of these additional functional groups can be protected to prevent undesired reactions of these functional groups. Suitable protecting groups are known in the art for a variety of functional groups (Greene and Wuts, Protective Groups in Organic Synthesis, second edition, New York: John Wiley and Sons (1991)).
Particularly useful protecting groups include t-butyl esters and ethers, acetals, trityl ethers and amines, acetyl esters, trimethylsilyl ethers and trichloroethyl ethers and esters.
The compounds within the set are mass-coded as a result of the selection of a subset of suitable peripheral moiety precursors. The subset of peripheral moiety precursors is selected such that for a scaffold precursor having n reactive groups, where n is an integer from 2 to about 6, there exist at least about 50, 100, 250 or 500 different combinations of ri peripheral moieties derived from the peripheral moiety precursor subset. At least about 90% of the possible combinations of n peripheral moieties derived from the peripheral moiety precursors within the subset will have a distinct mass sum. In one embodiment, the selection of suitable peripheral moiety precursors for the production of a mass-coded set of compounds includes one or more automated steps utilizing hardware apparatus, software apparatus or any combination thereof. In the preferred embodiment, a digital processor assembly employs a suitable software routine which selects a subset of peripheral moiety precursors which minimize or eliminate mass redundancy in the library. Figure 3 is illustrative of such apparatus employing a digital processor assembly for carrying out the present invention method.
Referring to Figure 3, there is shown a computer system 25 formed of (a) a digital processor 11 having working memory 17 for executing programs, routines, procedures and the like, (b) input means 21 coupled to the digital processor 11 for providing data, parameters and the like to support execution of the programs, routines and/or S procedures in the digital processor working memory 17, and (c) output means 23 coupled to the digital processor 11 for displaying results, prompts, messages and the like from operation of the digital processor 11. The input means 21 include a keyboard, mouse and the like common in the art.
The output means 23 include a viewing monitor, printer and the like common in the art. The invention' software routine 27 is executed in the working memory 17 by the digital processor 11 as follows.
First, a user interface prompts the end-user to input indications of an initial set 13 of peripheral moiety precursors and the exact masses of the peripheral moieties which are derived therefrom. This initial set 13 may be copied, transferred or otherwise obtained from a database or other source such as is known in the art. The user interface also obtains from the end-user a set of user determined/desired criteria 19. In the preferred embodiment, the user selected criteria 19 includes (i) the total count j of peripheral moiety precursors in the initial set, (ii) the value of n indicating the number of reactive groups of a subject scaffold precursor for which the invention software routine 27 is to select a subset of peripheral moiety precursors from the input initial set 13 and (iii) the number of members of the subset, k.
Preferably, the user interface enables the end-user to CA 02313957 2000-07-14, interactively provide the user selected criteria 19 through the input means 21 as indicated at 15 in Figure 3.
The digital processor 11 is responsive to the foregoing input and stores the indications of the initial set.13 of peripheral moiety precursors in a memory area 29 or data storage system associated locally or off disk with the software routine 27. That is, the memory area 29 or data storage system supports the invention software routine 27. For each peripheral moiety precursor in the initial l0 set 13 as indicated in memory area 29, an identifier and indication of respective exact mass of the the peripheral moiety derived from the peripheral moiety precursor is provided to the software routine 27. Upon receipt of the peripheral moiety precursor identifiers, indications of exact mass, and user selected criteria (n, j and k), the software routine 27 determines and generates a subset of k peripheral moiety precursors which minimize or eliminate mass redundancy in a resulting library of compounds of the formula XY, wherein X is a scaffold, each Y is, independently, a peripheral moiety, and n is an integer greater than 1, typically from 2 to about 6. Preferably, the software routine 27 determines a subset of peripheral moiety precursors in which at least about 90% of the possible combinations of n peripheral moieties derived from the subset have a distinct mass sum. The details of the software routine 27 employed in the preferred embodiment are discussed next for purposes of illustration and not limitation. It is understood that other software or firmware routines for accomplishing the present invention method of selecting a subset of the initial set 13 of peripheral moiety precursors are suitable and within the purview of one skilled in the art given this disclosure.
A typical situation involves a scaffold precursor with n reactive groups, where n is an integer, a set of j peripheral moiety precursors, where j is an integer 6 or greater, where the peripheral moieties derived from the peripheral moiety precursors have molecular masses y,, y2, ...yj . An example of a software routine which can be employed to select a suitable subset of k peripheral moiety precursors (kSj) from the set of j peripheral moiety precursors includes the following steps:

1. From an initial set of j peripheral moiety precursors, choose every set of two peripheral moiety precursors.
If Ya = yb , randomly remove either ya or yb.

2. From the remaining set of peripheral moiety precursors, choose every set of four peripheral moiety precursors. If Ya+ Yb = yr+ Yd , randomly remove either ya, Yb1 Yc or Yd-3. From the remaining set of peripheral moiety precursors, choose every set of six peripheral moiety precursors. If ya+ Yb + Yc = Yd + Ye + yt, randomly remove either ya, Yb' Y, Ya' Ye or y,-If at any step 1 through 3 the remaining number of peripheral moiety precursors becomes < k, then there is no mass coded subset k which can be made from set j, and a new set j must be employed.

4. From the remaining computer selected set of peripheral moiety precursors, choose any or all subsets of k S peripheral moiety precursors.

5. Generate all possible combinations of n peripheral moiety precursors from this subset.

6. If the % mass redundancy of the resulting set of combinations is found to be unacceptable, repeat step 5 until a desired mass coded library has been obtained or no further possible combinations of peripheral moiety precursors remain. In the latter case, begin again with step 1.

Once an above subset of mass-coded peripheral moiety precursors is determined, the scaffold precursor is contacted with the subset of complementary peripheral moiety precursors under conditions suitable for bond-forming reactions to occur between the peripheral moiety precursors and the scaffold precursor. The mass-coded set of compounds is, preferably, synthesized in solution as a combinatorial library.
The foregoing selection of a subset from a larger peripheral moiety precursor set and generation of a mass-coded set of compounds using the selected subset is more generally illustrated in Figures lA and 1B. Referring to Figure lA, the larger set of peripheral moiety precursors is provided at 31 from known sources. The end-user (e.g., chemist) selects an initial set of j peripheral moiety precursors from the larger set 31 at step 33. Typically the chemist chooses all of the larger set to form the initial set at 33. The invention mass coding selection procedure 35 is applied to the initial set. The result of the mass-coding procedure 35 is a subset 37 of peripheral moiety precursors that satisfies the mass-coding criteria outlined above. In step 39, this subset of peripheral moiety precursors is used to generate all theoretical subsets of of k peripheral moiety precursors. Also in step 39, the mass redundancies of the libraries obtained from all theoretical subsets of k peripheral moieties are calculated, and only those subsets which yield mass-coded libraries, as defined above, are passed to 41. The net result is one or more subsets 41 of k peripheral moiety precursors in which there are 50, 100, 250, or 500 distinct combinations of n peripheral moiety precursors in a given subset and at least 90% of all possible combinations of n peripheral moieties derived from a given subset have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties, as discussed above. The subset(s) 41 of peripheral moiety precursors would subsequently yield mass-coded sets of compounds when contacted with an appropriate scaffold precursor in the manner discussed above.
As an alternative to the single-step application of the invention mass-coding selection procedure 35 in Figure 1A, multiple or stepped application of procedure 35 is suitable and in certain cases may be advantageous. For instance, using mass-coding procedures at each level allows for rapid sorting into distinct sets, each of which may yield optimal mass-coding. During the mass-coding process, certain criteria reduce the set size as it is passed into the next layer through mass-coding. This multi-layer approach yields advantages in speed and the elimination of mass redundancy.
Multiple application of mass-coding selection procedure 35 on initial set 33 is illustrated in Figure 1B.
Here initial set 33 is divided into plural parts (the starting larger set of peripheral moiety precursors 31 and chemist selection 33 being similar to that in Fig. lA).
The mass-coding selection procedure 35 is applied to each plural part and results in intermediate resultant sets 43A, 43B, 43C. The mass-coded selection procedure 35 is applied in a second round/level. but this time with intermediate resultant sets 43A, 439, 43C. This produces final sets 45A, 455, 45C. Step 39 is as in Figure 1A and generates the subsets 47A, 47B, 47C of k peripheral moiety precursors that would subsequently yield mass-coded stes of compounds when contacted with an appropriate scaffold precursor in a manner discussed above.
it is understood that other variations between the approach illustrated in Figure lA and that in Figure lB are within the purview of one skilled in the art. The foregoing discussion and Figures are for purposes of illustrating and not limiting the present invention method.

In one embodiment, the scaffold precursor is contacted with all members of the peripheral moiety precursor subset simultaneously. In general, a scaffold precursor having n reactive groups, where n is an integer from 2 to about 6, will be contacted with at least about n molar equivalents relative to the scaffold precursor of peripheral moiety precursors from the selected subset. For example, the scaffold precursor can be contacted with a solution comprising each member of the subset in approximately equal concentrations. For example, if the scaffold precursor includes n reactive groups, where n is an integer greater than 1, and the number of peripheral moiety precursors in the subset is denoted by p, the scaffold precursor can be contacted with about n/p to about (1.1)n/p molar equivalents of each peripheral moiety precursor.
in another embodiment, the scaffold precursor is contacted with the members of the peripheral moiety precursor subset sequentially. This results in the formation of intermediate partially reacted scaffold precursor molecules which include at least one peripheral moiety and at least one reactive group. For example, the scaffold precursor can be contacted with one or more peripheral moiety precursors under conditions suitable for bond formation to occur. The resulting intermediates can then be contacted with one or more additional peripheral moiety precursors under suitable conditions for bond formation to occur. These steps can be repeated until each scaffold precursor reactive group has reacted with a peripheral moiety precursor.

In one embodiment, the reactive groups of the scaffold precursor can react sequentially with the subset of peripheral moiety precursors using a suitable reactive group protection/deprotection scheme. For example, the scaffold precursor can include two or more sets of reactive groups, where one set is unprotected and another set is protected, or where two sets are masked by different protecting groups. An example is the use of the scaffold precursor F O O-~
F F I \
I \ \
/ p / OCH2 F
.#F
F

which contains one unprotected reactive group and two protected reactive groups. In this case, the unprotected pentafluorophenyl ester can react with a peripheral moiety precursor first (e.g., a primary amine). Either the C13CCH2O-protected group or the benzyloxy-protected group can then be deprotected using standard methods and reacted with a set of peripheral moiety precursors. Finally, the remaining protected group or groups can be deprotected and reacted with a set of peripheral moiety precursors.
Following the reaction of each scaffold precursor reactive group with a peripheral moiety precursor, any peripheral moiety having a protected functional group can be deprotected using methods known in the art.
The ability to identify individual scaffold plus peripheral moiety combinations derived from such a mixture is a consequence of the mass-coding of the library and the ability of mass spectrometry to identify a molecular mass.
This allows the identification of individual scaffold plus peripheral moiety combinations within the set which have a particular activity, such as binding to a particular biomolecule.
In one embodiment, the present invention provides a method for identifying a compound or compounds within a mass-coded combinatorial library which bind to, or are ligands for, a biomolecule, such as a protein or nucleic acid molecule. The mass-coded combinatorial library can be produced, for example, by the method of the invention disclosed above. The target biomolecule, such as a protein, is contacted with the mass-coded combinatorial library, and, if any members of the library are ligands for the biomolecule, biomolecule-ligand complexes form. Compounds which do not bind the biomolecule are separated from the biomolecule-ligand complexes. The biomolecule-ligand complexes are dissociated and the ligands are separated and their molecular masses are determined. Due to the mass-coding of the combinatorial library, a given molecular mass is characteristic of a unique combination of peripheral moieties or only a small number of such combinations.
Thus, a ligand's molecular mass allows the determination of its composition.
In one embodiment, the target is immobilized on a solid support by any known immobilization technique. The solid support can be, for example, a water-insoluble matrix contained within a chromatography column or a membrane.

The mass-coded set of compounds can be applied to a water-insoluble matrix contained within a chromatography column.
The column is then washed to remove non-specific binders.
Target-bound compounds (ligands) can then be dissociated by changing the pH, salt concentration, organic solvent concentration, or other methods, such as competition with a known ligand to the target. The dissociated ligands are injected directly onto a reverse phase column. The reverse phase column acts as a concentrator/collector and can be interfaced directly to a mass spectrometer, such as an electrospray mass spectrometer (ES-MS). Mass information provided by the mass spectrometer is sufficient for identifying the combination of scaffold and peripheral moieties within the ligand.
In another embodiment, the target is free in solution and is incubated with the mass-coded set of compounds.
Compounds which bind to the target (ligands) are selectively isolated by a size separation step such as gel filtration or ultrafiltration. In one embodiment, the mixture of mass-coded compounds and the target biomolecule are passed through a size exclusion chromatography column (gel filtration), which separates any ligand-target complexes from the unbound compounds. The ligand-target complexes are transferred to a reverse-phase chromatography column, which dissociates the ligands from the target. The dissociated ligands are then analyzed by mass spectrometry.
Mass information provided by the mass spectrometer is sufficient for identifying the scaffold and peripheral moiety composition of the ligand. This approach is particularly advantageous in situations where immobilization of the target may result in a loss of activity.
Once single ligands are identified by the above-described process, various levels of analysis can be applied to yield SAR information and to guide further optimization of the affinity, specificity and bioactivity of the ligand. For ligands derived from the same scaffold, three-dimensional molecular modeling can be employed to identify significant structural features common to the ligands, thereby generating families of small-molecule ligands that presumably bind at a common site on the target biomolecule.
In order to identify a consensus, highest affinity, ligand for a particular binding site, this analysis should include a ranking of the members of a given ligand family with respect to their affinities for the target. This process can provide this information by identifying both low and high affinity ligands for a target biomolecule in one experiment. For example, when the screen utilizes an immobilized target, the dissociation rate of the ligand is inversely correlated with the number of column volumes employed during of the ligand from its target. When the screen utilizes the target free in solution, weak affinity ligands can be selected by using a higher concentration of the target.
Given that each mass-coded set of compounds is synthesized with a limited number of peripheral moiety precursors, the disclosed approach can, in certain cases, identify a superior ligand which combines structural features.of molecules synthesized in separate libraries.
When possible, the analysis of ligand structural features is based on information regarding the target biomolecule's structure, wherein the hypothetical consensus ligand is computationally docked with the putative binding site. Further computational analysis can involve a dynamic search of multiple lowest energy conformations, which allows comparison of high affinity ligands that are derived from different scaffolds. The end goal is the identification of both the optimal functionality and the optimal vectorial presentation of the peripheral moieties that yields the highest binding affinity/specificity. This may provide the basis for the synthesis of an improved, second-generation scaffold.
Due to the modular design of the mass-coded compounds, computational analysis may identify the point of attachment on the scaffold that has the least functional importance with respect to affinity for the target. In many cases, the ligand will not be completely engulfed by the target biomolecule, and one peripheral moiety will be pointed away from the biomolecule towards the bulk solvent. Three-dimensional alignment of a family of ligands will reveal a high degree of functional variability at the site that is presented to the solvent. Modification at this site can then be used to optimize the affinity. For example, the noncritical reactive site can be removed and replaced with a small unreactive group, such as a hydrogen atom or a methyl group. A set of compounds structurally identical except for the peripheral moiety at this position can be examined to identify compounds that most effectively inhibit or promote the binding of another protein/DNA/RNA
molecule. Also, the peripheral moiety at this position can be modified to link two ligands together. The joining of two ligands could in certain cases yield a ligand with improved affinity and specificity, if one joins molecules that bind to adjacent sites, or yield a designed biomolecule dimerizer.
A variety of screening approaches can be used to obtain ligands that possess high affinity for one target but significantly weaker affinity for another closely related target. One screening strategy is to identify ligands for both biomolecules in parallel experiments and to subsequently eliminate common ligands by a cross-referencing comparison. In this method, ligands for each biomolecule can be separately identified as disclosed above. This method is compatible with both immobilized target biomolecules and target biomolecules free in solution.
For immobilized target biomolecules, another strategy is to add a preselection step that eliminates all ligands that bind to the non-target biomolecule from the library.
For example, a first biomolecule can be contacted with a mass-coded combinatorial library as described above.
Compounds which do not bond to the first biomolecule are then separated from any first biomolecule-ligand complexes which form. The second biomolecule is then contacted with the compounds which did not bind to the first biomolecule.

Compounds which bind to the second biomolecule can be identified as described above and have significantly greater affinity for the second biomolecule than to the first biomolecule.
The screening approach detailed above can also be applied to identify ligands that selectively interact with an altered version of the same biomolecule, wherein the first biomolecule is the unaltered biomolecule and the second biomolecule is an altered or variant version of the biomolecule. The second biomolecule can, for example, have an amino acid sequence which differs from the amino acid sequence of the first biomolecule by the insertion, deletion or substitution of one or more amino acid residues. For example, the second biomolecule can include a specific amino acid mutation that is linked to the progression of a particular disease. Alternatively, the second biomolecule can also differ from the first biomolecule in having a different post-translational modification, such as an extra site of phosphorylation or glycosylation, or it may be truncated or aberrantly fused with another biomolecule.
The screening approach detailed above can also serve as a method for identifying small molecule ligands that bind at the same site on a biomolecule as another known, biologically relevant ligand. This known ligand can be another biomolecule, such as a protein or peptide, or it can be a DNA or RNA molecule, or a substrate or cofactor involved in an enzymatic reaction. In one embodiment, the first and second biomolecules are both proteins. The first protein is a complex of the protein and the known ligand, while the second protein is the protein alone. Compounds which bind to the protein alone, but not to the complex of the protein with the known ligand, bind to the protein at the binding site of the known ligand. This approach is especially well suited to the development of small molecule replacements of known therapeutic ligands, such as peptides or proteins.
An advantage of the present method is that it can be used to identify chemical compounds that bind tightly to any biomolecule of interest, even when the function of that biomolecule is not well understood, as is often the case with gene products defined through genomics, or when a functional assay is not available. The screening technologies described can be miniaturized to provide massive parallel screening capabilities.
A ligand for a biomolecule of unknown function which is identified by the method disclosed above can also be used to determine the biological function of the biomolecule. This is advantageous because although new gene sequences continue to be identified, the functions of the proteins encoded by these sequences and the validity of these proteins as targets for new drug discovery and development are difficult to determine and represent perhaps the most significant obstacle to applying genomic information to the treatment of disease. Target-specific ligands obtained through the process described in this invention can be effectively employed in whole cell biological assays or in appropriate animal models to CA 02313957 2000-07-14, understand both the function of the target protein and the validity of the target protein for therapeutic intervention. This approach can also confirm that the target is specifically amenable to small molecule drug discovery. The ligands obtained through the process described in this invention are small molecules and are, thus, similar to actual human therapeutics (small molecule drugs).
In one embodiment, a member of a combinatorial library to is identified as a ligand for a particular biomolecule using the method described above. The ligand can then be assessed in an in vitro assay for the effect of the binding of the ligand to the biomolecule on the function of the biomolecule. For a biomolecule having a known function, the assay can include a comparison of the activity of the biomolecule in the presence and absence of the ligand. If the biomolecule is of unknown function, a cell which expresses the biomolecule can be contacted with the ligand and the effect of the ligand on the viability or function of the cell is assessed. The in vitro assay can be, for example, a cell death assay, a cell proliferation assay or a viral replication assay. For example, if the biomolecule is a protein expressed by a virus, the a cell infected with the virus can be contacted with a ligand for the protein.
The affect of the binding of binding of the ligand to the protein on viral viability can then be assessed.
A ligand identified by the method of the invention can also be assessed in an in vivo model or in a human. For example, the ligand can be evaluated in an animal or organism which produces the biomolecule. Any resulting change in the health status (e.g., disease progression) of the animal or organism can be determined.
For a biomolecule, such as a protein or a nucleic acid molecule, of unknown function, the effect of a ligand which binds to the biomolecule on a cell or organism which produces the biomolecule can provide information regarding the biological function of the biomolecule. For example, the observation that a particular cellular process is inhibited in the presence of the ligand indicates that the process depends, at least in part, on the function of the biomolecule.
The mass-coded libraries provided by the present method enable the development of an information set that describes how the universe of small molecules interacts with any biomolecule encoded within the human and other genomes. This information set would include data regarding: 1) those libraries and components therein which bind to the target biomolecule, 2) quantitative structure-activity relationships (SAR) on chemical functionalities which contribute to the binding affinity of a compound for a biomolecule target, and 3) the domains of the biomolecule that are bound by chemical compounds. The database can be used to expedite drug development in a number of ways, for example, by identifying chemical pharmacophores that interact with high affinity with a specific drug binding site.
The invention will now be further and more specifically described in the following examples.

EXAMPLES

Example 1 Application of Mass-coding by Computer Algorithms: Comparison of Mass-coded and Non-Mass-coded Combinatorial Libraries The following is an analysis of the application of mass-coding algorithms towards the design of combinatorial libraries. The sequence of steps involved in identifying subsets of peripheral moiety precursors that can be allowed to react with a predetermined scaffold precursor to yield a mass-coded combinatorial library of compounds with the molecular formula X(Y),, is shown in Figure 1A; Figure 1B is an alternate sequence of steps. It is to be understood that the molecular mass sum of the combination of the n peripheral moieties in a particular compound of the formula X(Y),, is the collective contribution of the n peripheral moieties to the molecular mass of the compound. As each compound within the library includes a constant scaffold, the mass redundancy of the mass-coded library is equivalent to the molecular mass sum redundancy of all combinations of n peripheral moieties derived from the identified subset of peripheral moiety precursors.
The mass-coding analysis was performed on the initial set of 22 peripheral moieties shown below. This initial set was selected arbitrarily. Included were peripheral moiety precursors having the same exact mass. The master set consisted of the peripheral moiety precursors shown below, along with the exact masses of the resulting peripheral moieties. The molecular masses given are the exact molecular masses and not the isotope averages. The exact molecular masses are also adjusted for-any atoms which are lost as a result of the reaction with the scaffold precursor (in this case the loss of a hydrogen atom). From the initial set of 22 peripheral moiety precursors, two sets of 16 peripheral moiety precursors were generated. One set was chosen by the computer using the mass coding algorithm described herein (computer selected set). The other set was randomly chosen.
From each set of 16 peripheral moiety precursors the computer generated every possible subset of 12 peripheral moiety precursors. These subsets were used to generate all combinations of peripheral moiety precursors taken 4 at a time (representing libraries synthesized with a scaffold precursor having four reactive groups, such as four pentafluorophenyl esters). This process yielded two sets of 16 peripheral moiety precursors containing 1820 subsets of 12 each. Theoretically, these subsets of 12 peripheral moiety precursors would each yield a library of 1365 compounds containing different peripheral moiety combinations when allowed to react simultaneously with an appropriate scaffold precursor containing four reactive groups (151/[(15-4)!*4!1 = 1365). The computer sorted every precursor subset and checked for mass redundancy in the resultant libraries (in this example mass redundancies were checked to the second significant digit after the decimal point).

It is noteworthy that the mass coding algorithms and the mass redundancy check are both flexible in that it is possible to adjust the computational filter to check mass redundancy to any significant figure. This architecture S for mass-coding allows for rapid automated mass-coding, insures that a significant portion of the libraries generated with the computer selected set have less than 10%
redundancy, and includes parameters for peripheral moiety precursor selection outside of exact mass. The to computational requirements for this selection are fairly significant. The mass-coding algorithms are essential because it is computationally intractable to brute force calculate and check every possible set of peripheral moiety precursors from a master set of 60 or more peripheral 15 moiety precursors.

HN ~` H2N NH2 la 202.1232 97a 73.0402 N
13a 112.1126 19a 196.1126 H
N H
N
20a 72.0813 21a 44.0500 24a 100.1126 26a 58.0657 NH2 No HN
H
36a 74.0606 52a 153.1392 H
HNaNo H2N

53a 153.1392 54a 100.0762 N N_ U HN/ N ( N
69a 68.0500 70a 163.0984 CI
~ Br HN
HN\ N \ `

/ 77a 161.9918 76a 195.0689 CI CI
H
/

78a 140.0034 79a 210.1283 O~ O
~O
~~~NH2 O

94a 186.1494 86a 230.1756 104a 116.0711 108a 101.0351 RESULTS
The computer selected set of 16 peripheral moiety precursors contained 86a, 79a, 13a, 108a, 76a, 20a, 69a, la, 70a, 26a, 24a, 36a, 97a, 94a, 104a, and 21a. The set of 16 randomly chosen peripheral moiety precursors contained 79a, 13a, 20a, 69a, la, 26a, 24a, 104a, 52a, 54a, 19a, 77a, 53a, 21a, 55a, 36a. The libraries generated from the computer selected set of peripheral moiety precursors had an average mass redundancy of 11.5% per library with 234 libraries having mass redundancies of less than 5% and 972 libraries having mass redundancies of less than 10%
(Figure 2A). The libraries generated from the randomly chosen set of peripheral moiety precursors had an average mass redundancy of 60.7% with no libraries having a mass redundancy of less than 10% (Figure 2B). A direct graphical comparison of the mass redundancies of the two sets of libraries is shown in Figure 2C. The libraries derived from the computer-selected set of peripheral moiety precursors and the corresponding mass redundancies are listed in the Table below.

Example 2 Development of ligands for a monofunctional protein A mass-coded combinatorial library can be used to identify ligands that have a high affinity for a monofunctional protein. One such monofunctional protein is the serine protease trypsin. Ligands that exhibit a high affinity for trypsin would be candidates to screen further for their ability to inhibit the proteolytic activity of trypsin. The identification of ligands to trypsin involves the following steps: trypsin is covalently biotinylated by incubation of the protein with a chemically activated biotin precursor. The biotin-trypsin conjugate is immobilized by binding to a streptavidin-derivatized water-insoluble column matrix. The mass-coded combinatorial library is solubilized in an appropriate binding buffer and injected onto a column containing the trypsin+streptavidin complex. Compounds that do not bind to the column are CA 02313957 2000-07-14.

washed off with binding buffer. Compounds that bind to the column are dissociated by a change in the buffer conditions, such as a change in the pH or an increase in the percentage of organic solvent. These compounds are then loaded onto a reversed-phase column that is placed downstream of the trypsin+streptavidin column. The compounds are eluted from the reversed-phase column and analyzed by mass spectrometry. Molecular masses that correspond to ligands for trypsin are identified by eliminating those masses which are also observed when the library is similarly screened with a streptavidin column.
The molecular mass of each trypsin ligand identifies one combination of peripheral moieties plus scaffold. The individual compound or compounds that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their in vitro activity as inhibitors of trypsin.

Example 3 Development of ligands for a multifunctional protein Many proteins, especially human proteins, are multifunctional, and these functions are often mediated through interactions with multiple proteins. Ligands that bind to different sites on the protein might therefore yield different therapeutic results. The human protein HSP70 is one such example of a multifunctional protein.
HSP70 has been shown to interact with multiple polypeptides, which are largely unfolded, to facilitate their translocation and folding. This role of HSP70 has been implicated in a variety of physiological processes, including antigen processing/presentation, development of certain cancers, and replication of a variety of human viruses. A mass-coded combinatorial library can be used to identify ligands that have a high affinity for HSP70 and bind at different sites. These ligands for HSP70 can be further evaluated in secondary assays to establish their effects on the immune response, cancer progression, and l0 viral infection.
The identification of ligands to HSP70 involves the following steps: HSP70 is covalently biotinylated by incubation of the protein with a chemically activated biotin precursor. The biotin-HSP70 conjugate is immobilized by binding to a streptavidin-derivatized water-insoluble column matrix. The mass-coded library is solubilized in an appropriate binding buffer and injected onto a column containing the HSP70-streptavidin complex.
Compounds that do not bind to the column are washed off with binding buffer. Compounds that bind to the column are dissociated by a change in the buffer conditions, such as a change in the pH or an increase in the percentage of organic solvent. Compounds that are dissociated from the column are loaded onto a reversed-phase column that is placed downstream of the HSP70-streptavidin column.
Compounds are eluted from the reversed-phase column and analyzed by mass spectrometry. Masses that correspond to ligands for HSP70 are identified by eliminating those masses which are also observed when the library is similarly screened with a streptavidin column. The mass of each HSP70 ligand identifies one combination of peripheral moieties plus scaffold. The individual compound(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their in vivo ability to affect the immune response, cancer progression, and viral infection.

Example 3 Development of ligands that affect the binding of a known ligand to a protein It is often the situation that a biologically important ligand is known for a target protein, but development of a high-throughput screen for molecules that modulate the binding of that ligand is not practical. For instance, it is known that HSP70 binds unfolded polypeptides in the presence of ADP, and that the binding of ATP to HSP70 leads to the dissociation of the polypeptide. Mass-coded combinatorial libraries can be used in the discovery of small molecule ligands that affect the binding of ATP, ADP, or unfolded peptides to HSP70, and one configuration is listed below: HSP70 is covalently biotinylated by incubation of the protein with a chemically activated biotin precursor. The biotin-HSP70 conjugate is immobilized by binding to a streptavidiri-derivatized water-insoluble column matrix. The mass-coded library is solubilized in an appropriate binding buffer and injected onto a column containing the HSP70-streptavidiri complex.
Compounds that do not bind to the column are washed off with binding buffer. Compounds that bind to the column are dissociated upon addition of ATP, ADP, or ADP plus an unfolded peptide. Only compounds that bind to the same sites on HSP70 as these known ligands will be eluted under these conditions. Compounds that are dissociated from the column are loaded onto a reversed-phase column that is placed downstream of the HSP70-streptavidin column.
Compounds are eluted from the reversed-phase column and analyzed by mass spectrometry. Masses that correspond to ligands for HSP70 are identified by eliminating those masses which are also observed when the library is similarly screened with a streptavidin column. The mass of each HSP70 ligand identifies one combination of peripheral moieties plus scaffold. The individual compound(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested in vitro for the ability to compete with these known ligands to HSP70 and for their in vivo ability to affect the immune response, cancer progression, and viral infection.

Example 4 Discovery of small molecule replacements for protein therapeutics In.some instances, the known ligand to a target protein is in fact another protein, and the binding of these two proteins confers a therapeutic benefit. An example of such an interaction is the binding of granulocyte colony stimulating factor (G-CSF) to the G-CSF
receptor (G-CSF-R). Replacement of G-CSF with a non-peptide 'small molecule can be undertaken using a mass-coded combinatorial library, and one approach is detailed below:
in two separate and parallel experiments, the mass-coded library is solubilized in an appropriate binding buffer and incubated with either the G-CSF-R alone or the G-CSF-R plus G-CSF. Compounds that bind to the protein(s) are separated from the unbound compounds by rapid size exclusion chromatography. The binding compounds are loaded with the protein(s) onto a reversed-phase column that is placed downstream of the size exclusion column. The binding compounds are dissociated from the protein(s) and are eluted from the reversed-phase column and analyzed by mass spectrometry. Masses that correspond to compounds that bind to the G-CSF/G-CSF-R interface are identified as those masses which are only observed when the library is screened with G-CSF-R alone; masses which are also observed in the screen with the G-CSF/G-CSF-R complex are ignored. The mass of each interface-specific compound identifies one combination of peripheral moieties plus scaffold. The individual compound(s) that result from the identified combination of-peripheral moieties plus scaffold are then synthesized and tested for their in vitro or in vivo ability to mimic G-CSF.

Example 5 Development of small molecules that dimerize two proteins Certain therapeutic proteins, such as erythropoietin (EPO), are multivalent and act by binding two molar equivalents of the target protein, thereby dimerizing the target protein, which, in the case of EPO is the EPO
receptor (EPO-R). The protein replacement strategy outlined in Example 3 can be extended to yield non-peptide compounds that act therapeutically by inducing the dimerization of two EPO-R molecules. In two separate and parallel experiments, the mass-coded library is solubilized in an appropriate binding buffer and incubated with either EPO-R alone or EPO-R plus EPO. Compounds that bind to the protein(s) are separated from the unbound compounds by rapid size exclusion chromatography. The bound compounds are loaded with the protein(s) onto a reversed-phase column that is placed downstream of the size exclusion column.
The bound compounds are dissociated from the protein(s) and are eluted from the reversed-phase column and analyzed by mass spectrometry. Masses that correspond to compounds that bind to the EPO/EPO-R interface are identified as those masses which are observed only when the library is screened with EPO-R alone; masses which are also observed in the screen with the EPO/EPO-R complex are ignored. The mass of each interface-specific compound identifies one combination of peripheral moieties plus scaffold. The individual compound(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their in vitro ability to bind to the target protein, EPO-R. Those compounds exhibiting the highest affinity for the target protein are compared to identify similarities among them. Ideally, it is observed that one site of derivatization on the scaffold is relatively unimportant for high affinity binding. The peripheral moiety at this site is subsequently replaced with a covalent tether that joins two molecules of the highest affinity compound to yield a non-peptide compound that dimerizes the target protein, EPO-R.

Example 6 Simultaneous target validation and small-molecule drug discovery An example of a class of target proteins whose roles in a disease process can be validated by application of target-specific ligands to a bioassay are the proteins encoded by the open reading frames (ORF) of the Herpes Simplex Virus. The identification of ligands to an ORF-encoded protein and the use of the resulting ligands to determine the function of the ORF-encoded protein and its validity as a target for anti-viral drug discovery involves the following steps : the ORF-encoded protein is covalently biotinylated by incubation of the ORF-encoded protein with a chemically activated biotin precursor. The ORF-encoded protein-biotin conjugate is immobilized by binding to a streptavidin-derivatized water-insoluble column matrix.
The mass-coded library is solubilized in an appropriate binding buffer and injected onto a column containing the ORF-encoded protein+streptavidin complex. Compounds that do not bind to the column are washed off with binding buffer. Compounds that bind to the column are dissociated by a change in the buffer conditions, such as a change in the pH or an increase in the percentage of organic solvent.

These compounds are loaded onto a reversed-phase column placed downstream of the ORF-encoded protein+streptavidin column. The binding compounds are eluted from the reversed-phase column and analyzed by mass spectrometry.
Molecular masses that correspond to ligands for the ORF-encoded protein are identified by eliminating those masses that are also observed when the library is similarly screened with a streptavidin column. The molecular mass of each ligand for the ORF-encoded protein identifies one combination of peripheral moieties plus scaffold. The individual compound(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their ability to inhibit the replication or transmission of the virus in a mammalian cell bioassay or animal model.
The observation of a virus-specific inhibitory activity implicates the ORF-encoded protein as a critical component of the viral disease process and confirms that the ORF-encoded protein is specifically amenable to small molecule anti-viral drug discovery. Observation of a direct correlation between the relative binding affinities of the ORF-encoded protein-specific ligands and the relative inhibitory concentrations of the ORF-encoded protein-specific ligands further strengthens the identification of the ORF-encoded protein as a target for small molecule anti-viral drug discovery.

Example 7 Development of small molecules that can be applied to the affinity purification of a target protein A mass-coded combinatorial library can be used to identify ligands that have a high affinity for a target protein. One such target protein is human erythropoietin (EPO), which is expressed and purified industrially for use as a therapeutic drug. Ligands that exhibit a high affinity for EPO can be immobilized on a solid support to generate an EPO-specific affinity matrix.
The identification of ligands to EPO and the construction of an EPO-specific affinity matrix involves the following steps: the mass coded library is solubilized in an appropriate binding buffer and incubated with the EPO
protein. Compounds that bind to the EPO protein are separated from the unbound compounds by rapid size exclusion chromatography. These compounds are loaded with the EPO protein onto a reversed-phase column that is placed downstream of the size exclusion column. The compounds are dissociated from the EPO protein and are eluted from the reversed-phase column and analyzed by mass spectrometry.
The molecular mass of each EPO protein-specific ligand identifies one combination of peripheral moieties plus scaffold. The individual ligand(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their in vitro ability to bind to the EPO protein. Compounds exhibiting the highest affinity for the EPO protein are compared to identify similarities between the compounds. If it is observed that one reactive site on the scaffold is relatively unimportant for high affinity binding, the peripheral moiety at this site is subsequently replaced with a covalent tether that joins the EPO-specific ligand to a water insoluble matrix, thereby generating an EPO-specific affinity matrix.
Alternatively, the covalent tether is used to join the EPO-specific ligand to a another molecule, such as biotin, which possesses a high affinity for a commercially l0 available affinity matrix (streptavidin-derivatized agarose). The biotin-streptavidin interaction is used as a strong, non-covalent immobilization technique.

Example 8 Development of small molecules that can be applied to the visualization of a target protein A mass-coded combinatorial library can be used to identify ligands that have a high affinity for a target protein. One such target protein is the human protein telomerase, the expression of which is linked to cancer progression and aging. Ligands that exhibit a high affinity for telomerase can be functionalized.with a radioactive or non-radioactive tag to thereby generate a telomerase-specific affinity probe for visualization of the enzyme in vitro or in vivo. The identification of ligands to telomerase and the construction of a telomerase-specific affinity probe would involve the following steps: a mass-coded library is solubilized in an appropriate binding buffer and incubated with telomerase protein alone.
Compounds that bind to the telomerase protein are separated from the unbound compounds by rapid size exclusion chromatography. The binding compounds are loaded with the telomerase protein onto a reversed-phase column that is placed downstream of the size exclusion column. The compounds are dissociated from the telomerase protein and are eluted from the reversed-phase column and analyzed by mass spectrometry.mass of each telomerase protein-specific ligand identifies one combination of peripheral moieties plus scaffold. The individual ligand(s) that result from the identified combination of peripheral moieties plus scaffold are synthesized and tested for their in vitro ability to bind to the telomerase protein. Compounds exhibiting the highest affinity for the telomerase protein are compared to identify similarities between the compounds. Ideally, it is observed that one reactive site on the scaffold is relatively unimportant for high affinity binding. The peripheral moiety at this site is subsequently replaced with a covalent tether that joins the telomerase-specific ligand to a radioactive moiety or a non-radioactive moiety such as a fluorophore, thereby generating a telomerase-specific affinity probe.

Example 9 Identification of a small molecule inhibitor of bovine trypsin by affinity selection with a mass coded combinatorial library mixture A mass-coded library mixture was synthesized by the reaction of the scaffold precursor O CI CI O
O
O O

CI OI
with a set of ten peripheral moiety precursors selected as described in Example 1. This set of peripheral moiety precursors is shown below. The peripheral moiety precursors were selected to yield a mass coded combinatorial library mixture of compounds of the formula X(Y)9, where X is this scaffold and each Y is, independently,' a peripheral moiety derived from one of the peripheral moiety precursors. This library includes 715 distinct combinations of 4 peripheral moieties and 715 distinct masses.

HN

CI CI
0 / \ N N H CI N NH CI / \ NH2 y ~_J

CI
~NH2 0 NH2 S~
ONN
omogeneous solution containing 2 mM mass coded A h library mixture and 50 .cM bovine trypsin in binding buffer (50 mM Tris, pH 7.75; 40 mM CaCl2; 10% DMSO total v/v) was incubated for 30 minutes at room temperature and then incubated on ice for 5 minutes. 20 yL of this mixture was injected onto a 4.6x200 mm size-exclusion HPLC column and eluted with binding buffer at 1.5 ml/min. The protein eluted slightly before the unbound library components, and this protein peak was collected. Formic acid and acetonitrile were added to final concentrations of 10% each to dissociate any ligands from the protein, and the resultant mixture was analyzed by LC-MS. Mass spectroscopic analysis yielded one mass which matched with one combination of 4 peripheral moieties plus scaffold, and synthesis of a single isomer having this combination confirmed the identity of the trypsin ligand, which is shown below.

O

O O
NH N
6 This molecule was a potent inhibitor of trypsin when assayed by a standard in vitro trypsin activity assay.
EQUIVALENTS
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.

2.197802 868 798 13a 1088 76a 20a la 170a 268 94a 121 a 197a 2.490843 86a 108a 76a 69a 1 a 70a 26a 24a 36a 194a 21 a 97a 2.637363 86a 13a 108a 76a 69a la 70a 126a 124a 136a 94a 97a 2.783883 86a 79a 113a 108a 76a 20a 169a 11 a 708 126a 94a 21 a 2.78388386a79a 132 108a 76a 20a 169a 1a 1708 36a 94a 21a 2.7838838613a 1108a 768 20a 1698 1 a 170a 248 368 1948 97a 2.78388386a1793 1138 108a 76a 1708 126a 24a 36a1943 21a 197a 2.930403 868138 1083 76a 20a 69a 11 a 170a 136a 94a 21a 97a 2.930403 86a 138 1083 768 la 70a 26a 124a 136a 94a 21a 197a 2.930403 86a 13a 1108a 768 69a 11 a 708 268 36a 194a 21a 97a 2.930403186a79a 13a 108a176a 120a 169a la 170a 26a 24a 1104a 3.003663 868 798 13a 1088 76a 20a 69a 708 1262124a 948 1104a 3.003663 868 79a 113a 108a 1208 698 1 a 70a 136a 94a 2l a 978 3.076923 862113a 1108a 1768 208 169a h1 a 70a 26a 124a 94a 97a 3.076923 8681138 1088 768 69a 1a b70a 26a 124a 136a 94a 1104a 3.07692 8681138 1108a 176a 120a 169a 1 a 170a 268 948 21 a 197a 3.0769231868 1088 76a 1208 698 1 a 70a 124a 1368 948 104a 197a 3.0769237981138 10881768 1208 698 118 170a 136a 94a 1218 197a 3.076923869179a 132 11088 768 120a 698 170a 1268 94a 11048 121a 3.07692386a179a 13a 1088 76a 120a 13 1708 368 94a 213 97a 3.99344386a 13a 1088 76a 698 11 a 70a 268 136a 94a 104a 21 a 3.223443186a 79a 13a 1087 768 169a la 708 268 948 1048121 a 3.223443186a 79a 13a 108a2Oa {69a la 1708 124a 36a 1948 97a 3.369963 868 798 13a 11088 208 698 11 a 170a 126a 194a 121 a 97a 3.36996386a113a 1083 76a 1208 169a la 1708 126a194a 11048 21a 3,359963 86 798 138 1082176a 1208 Ila 170a 26a 948 104a 121a 3.516484868 13a `1088 76a 20a 698 1la 170a 26a 24a 36a 97a 3.516484868 79a 113a 1088 208 169a 119 70a 268 248 94a 97a 3.516484186a113a 108a 76a 20a 69a la 170a 268 248 948 104a 3.5164841868 798 138 1088 768 20a 698 11 a 1708 26a 11048121 a 3.51648486a113a 108a 76a 120a 169a h1a 70a 1268 36a 121a 197a 3.6630048681793 13a 108aj76a 120a 169a 1a 1708 268 194a 11048 3.66300479a 138 108a 768 69a 1a 70a 136a 948 104a 218 97a 3.663004798138 108a 76a 20a 1a 708 126a 948 104a 21a 97a 3.663004868 798 108a 76a 169a 708 268 248 36a 94a 121 a 197a 3.663004 86a 792 13a 108a 76a 20a 169a 118 1708 94a 104a 218 3.66300 86813a 108a 76a 20a 69a la 70a 6a 36a 194a 97a 3.8095248621132 1083 768 698 h1 a 70a 24a 36a 948 104a 978 3.8095247991132 1088 76a 69a la 1708 126a 94a 1048 21a 97a 3.809524 86a 79a 138 108a 768 1 a 708 268 248 94a 21a 97a 3.80952479a 13a 108a 176a 20a 698 1a 26a 948 104a 21a 97a 3.80952479a 13a 1088 768 698 70a 126a 24a 36a194a 104a 97a 3.80952479a13a 108aJ76a 208 69a la 708 1262194a 21a 97a 3.88278479a 13a 108a 768 698 70a 126a 36a 948 1048 21a 97a 3.95604486a179a 1088 76a 20a 69a 708 263 24a194a 104a 97a 3.95604486a 798 113a 1088 76a 20a 169a 1 a 708 24a 36a 94a 3.956044 868 798 1138 11088 768 208 169a 1 a 368 948 121 8 97a 3.95604 868 138 1108a 76a 1698 1a 170a 1268 24a 36a 1948 121a 3.95604486a179a 113a 1088 76a 69a 1a 1709 26a 94a 121a 97a 3,95604486a108a76a 169a '1a 70a 124a 36a 948 1048 21a 197a 3.956044798138 1088 76a 20a 69a 1a 70a 268 248 104a 97a 3.956044186a179a 13a 108a120a 69a 11a 70a 24a 94a 1048 978 3.956044868 798 108B176@ 2081698 18 70a 2681948 11048 21a 3.95604 868 79a 13a 1088 768 20a 698 1 a 26a 94a 11043 ,21a 4.02930486a79a 113a 76a 20a 69a la 708 268 24a 94a 1104a 4.10256 86a179a 138 1088 76a 1208 169a 1a 170a 268 248 94a 4.10256486a113a 11088 76a 169a 1a 70a 24a 136a 94a 121a 197a 4.102564186a1108a 76a 169a 1a 70a (26a (248 368 94a 104a 21a 4.10256479a113a 11088 768 20a 69a 1a 170a 194211043 121a 978 4.102564868 798 1138 108a1768 208 69a la 1708 268 124a 1368 4.102564;868 13a 1083 76a 120a 69a I1a 26a 24a 36a 94a 197a 4,17582 8681798 138 108al20a 169a 1a 1708 26a 248 194a 1048 4.1758248631793 113a 1108a176a 692 170a 126a 36a194a 21a ~97a 4.1758248681798 10Sa 76a 20a 169a Ila 170a 36a 94a 21a 197a 4.249084862179a 1138 108a176a la 70a 126a 36a 94a 121a 197a 4.2490841868 13a 1088 768 69a Ila 26a 124a 36a 94a 121a 97a 4.24908 86a 79a 138 108976a 69a 170a 126a 36a 94a 104a 21a 4.24908486a 13a 1088 768 1208 692 1a 70a 1263 24a 136a 94a 4.249084 86a 79a 1138 11088 76 a 169a la 708 36a 194a 121 a 197a 4.24906 868 798 13a 1088 76a 208 11 a 1702 268 248 94a 97a 4.249084 79a113a 108a 76a 20a 1698 708 126a 24a 1948 104a 97a 4.249084 8079a 108a 76a 20a 69a 11 a 170a 126a 1948 21 a 97a 4.249084868798 132 1088 76a 20a 1698 1la 708 248 368 97a 4.32234417981138 108a 768 20a 69a 170a 1262 1368 94a 218 97a 4.39560586a179a 13a 1088 69a 1a 1708 126a 248 36a 94a 97a 4.39560579a113a 108a 76a 20a 69a 708 126a 94a 104a 218 97a 4.39560586ai79a 113a 108a176a 20a 169a 1la 708 36a 948 197a 4.395605798 13a 1108a 76a 20a 69a 70a 268 24a 36a 948 978 4.395605 868 798 138 108a 76a 20a 69a h1a 70a 26a 24a 97a 4.395605 868 798 13a 1088 76a 20a 69a 1 a 70a 26a 36a 194a 4.395605798133 108a 76a 20a 69a. 12 708 26a 104a 21a 97a 4.395605 86a 79a 138 108a 20a 69a 12708 26a 94a 104a 21a 4.395605179a 13a 11082 76a 20a 69a la 170a 26a 94a 104a 21a 4.395605i86a 798 138 1088 768 208 7081268 368 948 21a 978 4.395605868 79a 132 1088 768 208 70a 26a 24a 94a 104a 97a 4.3956051868 79a 13a 1088 76a 69a 708 26a 24a 36a 94a 21a 4.3956051138 1082176a 69a 1a 70a 126a 36a 94a 104a 21a 97a 4.395605 86a179a 13a 108a 76a 20a 169a la 70a 94a 21 a 97a 4.39560 86811088 76a 20a 69a 1a 70a 26a 24a 36a 948 97a 4.395605 868 79a 13a 1088 76a 20a 1a 170a 26a 1368 94a 978 4.395605 668 798 13a 108a 76a 169a 70a 126a 248 368 948 97a 4.46886486a179a 13a 1088 20a 69a 708 26a 24a 948 104a 97a 4.468864868 798 13a 108a 76a 20a 1a 170a 26a 24a 36a 97a 4.46886486a110821763 120a 169a 1a 708 36a 94a 104a 21a 97a 62, 4.468864186a179a 113a 108a176a, 20a 169a 170a 26a 124a 136a 94a 4.468864869799 1139 769 is 70a 26a 24a 369 94a 21a 979 4.468864869 799 13a 11082 76a 20a 70a 1269 24a 36a 94a 97a 4.542125 86al79a 113a 11089 699 1 a 170a 24a 36a 94a 1049 97a 4.542125 869 799 13a 1108a 176a 20a 169a 70a 26a 36a 1949 21 a 4.542125186a179a 13a 108a 76a 169a 170a 262 24a 36a 94a 1104a 4.542125 869 79a 13a 108a 76a 20a 169a 11 a 26a 94a 121a 979 4.5421251863!79a 13a 76a 120a 699 1la 170a 24a 36a 194a 97a 4.5421251869 1089 76a 1209 699 1a 709 26a 36a 1949 219 979 4.54212586a 13a 108a 76a 699 70a 26a 249 36a 194a 21a 979 4.542125 869 799 139 i 1089 769 1 a 709 124a 369 94a 121 a 97a 4.5421.25139 108a,76a 209 699 19 709 269 949 104a 121a 97a 4.542125 869139 1089 769 20a 69a la 1262 362 949 121a 97a 4.5421258691799 13a 108a769 69a 1a 170a 26a124a 949 11049 4.5421251862 799 113a 1089 76a 120a 169a 70a 36a 94a 121a 1979 4.542125186a179a 113a 11089 769 20a 69a l a 70a 26a 94a 197a 4.615385 792 1089 76a 209 699 1a 709 369 949 1049 219 97a 4.688645 86a 79a 13a 11089 76a 120a 69a l a 70a 26a 121a 97a 4.68864586a 799 13a 1089 202 699 1 a 1249 136a 94a 104a 97a 4.688645 79a1108a 769 69a 70a 126a 24a 136a 94a 104a 121a 97a 4.688645869 108a176a 1699 1a 70a 26a 1249 36a 1949 1049 97a 4.688645179a 108a176a 120a 69a 19 70a 126a 949 1049 121a 97a 4,68864513a108a176a 1699 la 170a 26a 24a 36a194a 11049 97a 4.68864586a 79a 113a 108a 76a 120a 69a 70a 24a 36a 194a 97a 4.688645 86a 799 113a 76a 20a 69a la 70a 26a 94a 104a 21 a 4.688645 8691089 76a 120a 699 la 70a 126a 249 949 1049 97a 4.688645 869139 1089 76a 120a 1 a 70a 126a 24a 1369 94a 97a 4.688645 869 799 13a 1089 769 20a 699 1 a 369 94a 11049 21a 4.688645869799 139 108a76a 69a h1a 170a 36a194a 1048 21a 4.761905 869 13a 11083 76a 20a 69a 1 a 170a 269 24a 136a 104a 4.761905869 9a 113a 108a 1a 70a 26a ~24a 369 94a 121a 97a 4.761905 869 799 139 1108a 20a 69a la 70a 269 249 36a 97a 4.761905 869 79a 13a 1769 20a 69a la 70a 36a 94a 21a 197a 4.83516579a13a 108a769 120a 69a 1a 126a 24a 94a. 104a 979 4.835165186a 79a 13a 1089 76a 209 1693 h1 a 26a 24a 194a 104a 4.835165179a 13a 108a 769 69a 1a 70a ,249 36a 94a 104a 97a 4.835165 86a 13a 108a (76a 120a 1 a 70a 26a 369 949 21a 97a 4.83516586a 9a 13a 108a 699 1a '70a 269 249 94a 21a 979 4.835165 79a 10891769 120a 699 709 269 249 36a 94a 104a 97a 4.835165186a 10891762 699 1a 70a 26a 24a 36a 104a 21a 979 4.835165j86a13a 10891769 20a 69a 1a 70a 24a 36a 1949 104a 4.8351651799132 108a 769 209 699 1a 1369 94a 104a 21a 97a 4.8351651391089 769 20a 699 1 a 7091269 249 369 949 97a 4.835165 869139 11089 769 209 699 70a 126a 36a 94a 21 a 97a 4.835165139 108al76a 20a 69a 1a 170a 26a 36a 94a 21a 97a 4.8351551869799 13a 1089 769 209 la 1709 24a 36a 194a 97a 4.835165 869 799 13a 108a 176a 120a 169a 1709 269 24a 194a 197a " Feld i ". ' ~ 3'~ r 4 1 5.
7 i8 9`t34.' 0 1r eh 1 2`.
Ix .111, 4.8351651868179a 1132 176a 169a 1 a 70a 126a 124a 36a 194a 104a 4.83516 79a 13a 11082 76a 20a 1a 170a 26a 36a 94a 121a 97a 4.83516586a113a 176a 120a 69a 1a 170a 268 24a 36a 194a 197a 4.835165 86a 132 1108a 176a 1202 1692 11 a 1702 24a 94a 11042 97a 4.908425 8621792 113a 11082 768 202 1692 la 70a 36a 21 a 1972 4.9084251862792 13a 11083 176a 1la 170a 1262 24a 36a 21a j97a 4.98168517921132 108a 76a 120a 169a 1a 170a 12421362 94a 97a 4.981685186a 132 1108a 76a 20a 169a 11a 702 36a194a 11042 121a 4.981685 86a 132 108a j76a 20a 69a 1 a 70a 26a 136a 194a 121 a 4.98168579a 13a 11082 20a 69a 1la 170a 262 24a 94a 1042 97a 4.981685186a.1 3a 11082 76a 20a 69a 170a 26a 24a 362 194a 97a 4.9816851862110881769 120a 169a h1 a 702 262 242 362 194a 104a 4.98168579a113a 11082 176a 120a 1693 11 a 170a 126a 194a 11042 972 4.98 i 6851860 79a 1762 692 1 a 1702 242 36a 94211042 121a 197a 4.98168518681792 13a 1108a169a 112 170a j24a 36a1942 212 197a 4.981685186a1792 10821762 20a 169a jla 170a 2621242 94a 11042 4.9816851862132 176a 169a la 170a 126a 124a 136a 194a 21a 197a 4.981685186a179a 132 108a176a 120a 69a 1702 126a 194a 121 a 97a 4.981685186a179a 11082 20a 169a 11 a 170a 124a 136a 1942 1104a 97a 4.98168686a1138 11082 76a 1692 1a 170a 126a 242 36a 121a 197a 4.981685 862113@ 1082 176a 169a 170a 126a j24a 362 94a 1042 97a 4.9816851862 792 113a 1108aj76a 120a 1la 1702 2621362 21a 972 4.981685186a179a 113a 1108a76a 169a j1a 70a )26a 124a 104a1212 5.128205132108a176a 120a 169a 1a j70a 126a 1242 942 {104a 197a 5.128205 862 792 1132 76a 20a 1692 la 702 68 242 94a 197a 5.12820586a108a176a 20a 692 1a 1702 26a 136a 942 1042 21a 5.128205 792 132 1082 202 692 la 170a 26a 1942 104a 121a 197a 5.128205 862 792 132 762 692 la 702 1262 242 362 942 197a 5.128205 86a179a 113a 11082 20a 69a 1a 170a 6a 24a 11042 97a 5.12820579213a 76a 202 169a la 1702 262 24a194a (10421972 5.128205 Hall 3a 1108a 176a 169a 11 a 1702 26a 24a 1942 121a 197a 5.128205 86a 79a 1762 120a 69a j1a 170a 1242 362 942 104a 197a 5.128205 79a 132 176a 120a 692 1 a 702 1262 942 1042 21 a 97a 5.128205 86a 132 76a 20a j69a 11 a 70a 26a 136a 942 _21a 197a 5.128205 86a 132 1082 69a 1 a 702 26a 24a 3621942 121a ; 97a 5.201465 86a 132 108a 76a 20a 69a 1 a 702 262 362 104a 121 a 5.27472 862 79a 13a 108a 20a 169a h1 a 262 242 942 104a j97a 5.274725 792 13a 1082 762. 20a 169a 170a 24a 362 94a 104a 197a 5,274725 86al792 132 1108a20a _69a h1a 702 942 1104a 212 97a 5.27472586a 13a 108a 20a 69a _ia 70a 262 36a 94a 21 a 97a 5.274725 86a 792 113a 108a 76a 69a ila 702 26a 24a 94a 121a 5.274725 86a179a 132 1082 76a 202 69a 1 a 70a 24a 94a 104a 5.274725 862 79a 13a 1763 202 1698 11 a 70a 2194a 1104a 5.274725 86a 79a 13a 1108a 762 20a 11 a 70a 262 242 942 1104a 5.274 225 86a 792 1082 768 20a 69a 11 a 70a 262 36a 194a 97a 5.347985 862 792 1082176a 202 1698 1 a 702 1394a 1042 21 a 5.347985186a 79a 10821762 1202 692 70a 24a 136a 94a 11042 97a 5.34798579913a 1108a176a 169a 170a (26a 249 (36a 194a 121a 97a 5,347985 869 799 13a 1089 209 69a la 709 269 136a 194a 97a 5.347985~79a113a 1108a 76a 209 69a 70a 26a 36a 94a 11049 21a 5.34798586a 13a 108a 76a 20a 169a 1 a 70a 26a 36a 94a 104a 5.421246 86a 79a 13a 76a 209 169a la 70a 26a 94a 121 a 97a 5.421246869139 10Ba176a 20a 69a 70a 26a 24a 94a 1104aI97a 5.421 246 86079a 13a 1089 76a 69a 1 a 70a 26a 36a 943 1979 5.42124679a 139 11089 76a 120a 69a 11 a 1709 26a 24a 194a 197a 5,42124679a13a 1108a176a 20a 69a 1a 170a 24a 36a 1043 97a 5.421246186a179a 1089 76a 69a 70a 26a 248 36a 94a 1104a 21a 5.421 246 1 08 76a 169a 1a 70a 26a 24a 363 94a 104a 121a 979 5.421246799139 176a 20a 69a 1la 709 126a 24a 36a 1949 197a 5.42124686a179a 11082 76a 120a 69a 70a 26a 364194a 121a 97a 5.42124686a179a 1108x1762 209 69a 170a 26a 24a 36a 194a 97a 5.421 246 869 79a 1089 20a 1699 1a 1709 126a 24a 94a 1049 97a 5.421246 86al799 108a 76a 169a 709 26a 124a 369 94a 11049 97a 5.421 2461799 1 3a 11089 76a 202 69a 170a 136a 194a 1104a 121a I97a 5.4212461869 79a 113a 1108a176a 699 11a 1709 126a 124a 194a 197a 5.4945051862179a 13a 108a 120a 69a 170a 126a 124a 369 194a 97a 5.494505 86a1799 108a 76a 120a 699 1 a 170a 26a 124a 36a 97a 5.494505869799 11089 76a 1209 69a 70a 126a 369 949 104a 21a 5.494505 86a 799 1139 769 169a 1 a 70a I24a 36a 94a 1049 97a 5.49450586a79a 13a 108a 76a 20a 170a 26a 94a 104a 1213 97a 5.494505 86a1792 108a 1769 120a 69a 1708 26a 24a 1369 194a 104a 5.5667766 79a 139 108a 176a 120a la 170a 363 949 1049 J21 a I97a 5.567766 869 799 13a 11089 76a 69a 11 a 70a 249 369 94a 97a 5.567766 869 799 13a 76a 20a 699 11 a 170a 26a 24a 36a 979 5.56776686a179a 108a 76a 209 69a 11a 170a 26a 24a 94a 97a 5.567766 863 798 108a 76a 69a h1 a 170a 1269 24a 949 la 97a 5.5677661792 108a 769 20a 693 70a 126a 136a 1111 94a 104a 21a 979 5.567766 86a 79a 1139 1082120a 699 709 126a 369 94a 121a I97a 5.56776686a179a 1139 1089 76a 120a 1699 70a 269 24a 136a I97a 5.56776 86a 79a 132 108a 76a 20a 693 1 a 24a 369 1949 197a 5.567766 669 79a 11 13a 1089 769 20a 69a 1 a 126a 24a 194a 197a 5.567766869 792 13a 108a 769 69a 26a, 24a 136a 94a 11049 97a 5.56776 869133 108a 20a 69a la 70a 24a 36a 94a 104a 97a 5.5677667991089 769 69a 1a 70a 24a 36a 94a 104a 21a 97a 5.567766 869 799 108a 769 69a la 70a 24a 36a 94a 21a 97a 5.56776613a1108a 76a 69a 1 a 70a 26a 249 36a 94a 21a 1979 5.567766862 79a 139 10Ba1693 709 26a 24a 136a 949 21a I97a 5.6410261869 799 139 1089 76a 209 699 709 269 36a 121 a 979 5.64102686aj79a 13a 1089 76a 20a 1699 26a 242 369 94a 97.a 5.641026 86a 799 139 108a 76a 20a 1699 1 a 126a 24a 136a 979 5.641026 86a 79a 139 108a 769 709 269 249 36a 94a 11049 197a 5.64102686a 13a 108a 76a 20a 69a 1a 70a 949 1049 21a 979 5.641026186a 79a 76a 20a 69a 1a 170a 362 949 1049 121a 97a 5.6410261869 139 11089 769 209 699 f 1a (269 24a194a 11049 979 Fria ' M.
5.64102686a79a 13a 1083176a 20a la 702 262 104a 1212 197a 5,64102679a 13a 1082 762 20a (69a 1 a 702 26a 36a 942 97a 5.64102686a113a 11082 76a 693 1a 702 1362 94a1104a 21a 97a 5.714286 862 792 13a 1082 69a 11 a 70a 26a 242 94a 1042 97a 5.71428679a 13a 1108a 76a 1a (70a 263 36a 94a 1042 21a 97a 5.714266 86a 79a 113a 1082 69a 70a (26a 24a 136a 194a 1104a 97a 5.71428679a 132 1082 76a 120a--69a Ila 70a 1262 24a 136a 197a 5.71428679a 13a 11088 76a 69a la (70a 26a 24a 94a j1042 978 6.7142868621132 (1083 20a 89a la 70a 263 24a 363 194a (97a 5.714286792 13a 1082 76a 69a 11 a 70a. (26a 1242 1042 21a 97a 5.71428 79a 133 1082 76a 120a 169a .1a (702 36a 194a 11043 21a 5.71428686a179a 13a 11088176a 120a (692 la 702 24a 94a 97a 5.71428679a113a 1082 6a 69a 11 a , 702 26a 24a 36a 104a 97a 5,714286792 13a 11082 76a 1202 69a 1702 26a 24a 363 194a 104a 5.71428686a179a 1762 169a 702 26a (248 136a 94a 104a 121a 97a 5.714286862792 13a 1108a176a _69a 11a 1702 26a 24a 136a 97a 5.71428617921132 76a 202 169a 170a 126a 24a 1362 94a 1104a 197a 5.714286 863 79a 13a 11082 76a 69a 1 a 1702 26a 124a 136a 194a 5.714286186a79a 1132 108a176a 202 69a 1a 1242 36a 194a 104a 5.714286 132 1082 76a 202 _ 6 9 1 2 3709 36a 1942 104a 21a 97a 5.714286 86a 79a ~76a 20a 1692 702 26a 24a 36a 94a 1042 979 5.787546 86a 79a 113a 1062 76a la 1702 26a 24a 36a 194a 197a 5.78754679a 132 1082 76a 1692 1a 170a 126a 136a 94a 1104a 197a 5,76754679a 132 108a 1202 169911a 70a 1262 24a 36a 94a 197a 5.860806862 79a 13a 108a176a 692 1a 170a 26a 24a 36a _104a 5.660806862 79a 13a 1108a176a 20a 169a 1a 26a 36a 94a 97a 5.860806 86a 79a 11082 76a 112 70a 1262 24a 368 94a 121 a 97a 5.860806 86a 79a 113a 1762 169a 170a 1262 24a _368 94a 121 a 97a 5.860806186a 79a 1132 108a 176a 11 a 126a 24a 136a 94a 21a 197a 5.860806 86a 108a1763 169a 170a 126a 124a 36a 9421104a 121 a 97a 5.86D806179a176a 202 169a 11a 70a 26a 124a 1362 94a 1104a197a 5.860806 86a 79a 113a 1082 76a 69a 26a 24a 36a 94a 21a 197a 5.860806 79a 1082176a 20a _69a 1a 702 26a 242 94a _104ab97a 5.86080679a113a 1082 76a 20a 69a 11a 70a 26a124a 94a--Fl 042 5.860806862 79a 108a 76a 20a 169a 1a 0a 24a 36a 94a 197a 5.860806 86a 79a 1082 76a 20a 69a 1 a 70a 26a 24a 1042 97a 5.860806792138 76a 69a la 702 26a 24a 36a 94a 1042 97a 5,66080686a79a 13a 108a120a 1a 70a 26a 24a 94a 104197a 5.860806792132 1082 762 202 692 1a 70a 362 942 104a l97a 5.860806 863 79a 133 1082 762 69a 11 a 70a 242 362 _942 1104a 5.86080686a179a 13a 1062 76a 20a 692 6a 242 942 104197a 5.860806862793 13a 76a 20a 1 a 702 26a 242 362 94a 97a 5.860806 86a 79a 13a 762 69a la 702 262 242 94a 2l a 197a 5,86080666a79a 13a 76a 1692 1a 70a 24a (362 942 21a 1972 5.860806862 792 13a 76a 20a 1692 1a 70a 362 94a _104a 121a 5.8608061862 792 13a 108a 76a 20a 112 262 362 942 21 a 97a 5.93406686a.79a 132 (762 20a ,69a 1a 70a 26a 24a 136a 94.

5,9340661863179a 1108a 120a 169a 1 a 170a 1262 24a 36a 943 97a 5,934066186a179a 113a 1083 76a 12Oa 169a 70a 24a 36a 1943 104a 5.934066863793 133 1083 763 1a 703 126a 24a 104a 121a 197a 5,934066 86all 3a 11083 76a 693 1a 263 24a 363 94a 104a 97a 5.934066 863 13a 11083 76a 693 703 26a 36a 94a 104a 21a 97a 5.934066 863 793 13a 11083 76a 20a 69a 1 a 1263 24a 36a 1043 5.934066 86a 793 133 1083 76a 202 la 70a 26a 24a 104a 1973 5.93406679a 13a 1083 203 69a 1a 703 36a 94a 104a 121a 197a 6.007326 86all 3a 1108276a 69a 1a 703 24a 136a 94a 1C4a 121a 6.007326186a179a 13a 108a 76a 1'a 1703 26a 24a 36a 194a 121 a 6.007326 793 1 3a 1108a176a 69a 1a 1708 24a 36a 94a 21a 197a 6.00732,6186a 79a 13a 203 69a la 1703 24a 36a 194a 11043 97a 6.0073261108 76a 120a '69a la 70a 263 136a 94a 1043 121 a 97a 6.007326186a 79a 1108a 76a j20a 169a 70a 1263 94a 1043 121a 97a 6.0073261331082,76a 20a 69a la 70a 126a 1362194@ (10431213 6,00732 86a179a 108a176a 203 1a 1703 1263 36a 194a 121a 197a 6.007326 86a113a 1108@1762 i20a 69a 1 a 1242 363 94a 11043 197a 6.0073261300076a 202 69a la 170a 243 363 94a 1104a 97a 6.00732686a179a 113a 76a 169a 170a 26a 124a 36a 943 1043 97a 6.00732 86a 793 108a 76a 20a 693 la 703 124a 36a 104a 97a 6.007326 863 13a 1083 763 I1 a 170a 1268 1242 1363 94a 11043 21 a 6.007326 863 793 13a 10831202 692 1 a 1702 26a 1043 21a 97a 6.0073261792 1083 76a 20a 69a le 1703 124a 136a 94a 1104a 97a 6.00732 793133 108a 203 693 Il a 70a 24a 1363 94a 11043 97a 6.080586i79a 133 108a76a 203 69a la 170a 136a 1043 121a 97a 6.08058 fB6aj79a j13a 1082 76a 203 1693 1703 36a 94a 104a 121a 6.080586 863 793 130 1083 76a 203 169a 11 a 170a 24a 1043 973 6.08058 863 793 133 11083 763 203 la 170a 943 104a 121a _97a 6.08058179all 3a 1763 203 693 703 263 136a 94a1104a 1213 97a 6.08058 863 793 13a 1763 203 693 la 1703 263 36a 1943 97a 6.15384 863 79a 1133 108a176a 1203 69a 170a 1243 94a 104a 1973 6.15384 8631793 133 1083 76a 1693 703 `26a 1243 943 21a 197a 6.15384686a79a 1133 1083 763 69a 703 26a 1243 94a 11043 21a 6.153846793133 1763 202 _69a h1 a 703 243 36a 194a 104a 97a 6.153846108 763 203 69a 1 a 1703 26a 1243 36a 194a 104a 97a 6.153 846 863 793 13a 1083 76a 69a la 70a 124a 136a 943 121a_ 6.153846 86a 79a 1133 763 69a 703 1263 363 948 1043 21 a 197a 6.15384613a 1083 763 693 1 a 703 243 136a 943 1043 21a J97a 6,153846,86a 79a 13a 108a176a 113 70a 126a 242 194a 1043 121 a 6.15384679a 13a 1108a 763 203 693 la 70a 124a 1943 1043 _97a 6.153846 86a 793 13a 76a 1203 1 a 70a 263 363 943 21a 97a 6.153846 863 793 1133 108a!202 1693 70a 26a 194a 1104a 121 a 97a 6.153846 863 793 _13a 1108@176a 693 _la 70a 26a 363 94a 121 a 6.153846186a 793 13a 11082 763 203 1 a 703 262136A 194a 212 6.15384686a 1083 76a 20a 693 703 26a 243 363 94a 1043 97a 6.153846 86a 793 133 108a 69a la (70a 136a 1943 _104a 21 a 97a 6.1538468631798 76a 1202 1693 703 26a 136a 1943 1043 218 1972 ;Feldl '~5 ir3 ~4 x'si 6.' ; R9 6.227106186a 13a 1108a176a 1a 170a 126a 24a 368 948 104a 197a 6.227106868 798 1108a 76a 208 698 1 a 708 36a 94a 104a 197a 6.227106j79a 13a 176a 120a 698 la 70a {36a 194a 104a 21a 978 6.22710686a 108a176a 1208 69a 1a 170a 126a 124a 36a 104a 97a 6227106 86a 138 1088 76a 1208 la 170a {26a 124a 36a 94a 104a 6.22710686a 1088 76a 120a 69a 1a 170a 26a 94a 104a 21a 197a 6.227106 868 768 69a I@ I70a 1268 124a 362 94a 1048 218 197a 6.227106868 798 1138 10881768 208 69a h a 1708 36a 194a 1104a 6.227106 868 79a 13a 108a176a 120a 69a 126a 1248 36a 1948 1048 6.2271061868 13a 1108a 76a 120a la 1708 {26a 124a 94a 1048197a 6.2271061869139 11088 76a 6991 a 708 26a 124a 36a 11048 21 a 6.227106 86a 138 108a 176a 120a 69a 1 a 708 26a 1048 21 a 19Th 6.22710679a 13a 108a 76a 70a 26a 248 36a 94a 11049 121a 197a 6.300366179a 13a 1088 76a 1208 1 a 70a 26a 243948 1104a 197a 6.3003661868 79a 1108a 176a 1208 169a 1 a 170a 1268 24a 136a 104a 6.300366186a 79a 113a 108a176a 20a 169a 26a 136a 1194a 121a 97a 6.3003668681798 13a 108a176a 169a la 170a 1268 249 1218 197a 6.3003661798 13a 1108a 76a 208 69a 1 a 124a 136a 194a 1104a 197a 6.300366 86a 13a 11088 76a 20a h1 a 170a 126a 136a 94a 104a 121 a 6.300366868798 138 108a120a 69a 1la I26a 1248 36a 1948 197a 6.300366186a179a 1088 76a 169a 112 70a 262 124a 104a 21a 197a 6.3003661868 9a 1138 76a 1208 69a 70a 126a 124a 363 94a 1104a '6.300366 86a 138 1088 20a 69a 1 a 170a 126a 24894a 1048 97a 6.300366 86a 79a 113a 1088 20a 11 a 170a 126a 369 194a 21a 97a 6.300366 86a 79a 113a 108@ 76a 69a 170a 24a 136a 194a 21a 97a 6.300366 798 13a 1108a 176a 1698 70a 124a 136a 1948 104a 21a 97a 6.373626 86a 79a 113a 176a 20a 1699 1 a 70a 268 24a 36a 104a 6.373626 868 79a 113a 1108@762120a 169a la 268 368 94a 1104a 6.37362679a113a 1108a 768 Oa 69a 118 26a 36a 94a 121a 197a 6.3736268681138 1108a 76a 208 1698 la 26a 24a 36a j94a 104a 6.373626{86a1132 11 1768 20a 169a 170a I26a 194a 1048 218 197a 6.373626 86a 79a 1108a1169a hla 70a 26a 24a 136a 948 212 197a 6.373626 868 1 3a 1088 76a I20a 698 170a 26a 36a 94a 11048 21 a 6.373626 86a 798 1088 76a 69a 1 a 170a 24a 36a 1048 121 a 97a 6.373626 868 798 108a 76a 120a 1698 la 703 248 36a 194a 1104a 6.37362679a 108a 76a 20a 169a 1a 70a 26a 1248 368 194a 97a 6.373626 86a 1088 768 69a 1 a 708 26a 36a 194a 11048 21a 197a 6.37362686a 79a 108a 76a 20a 69a 1 a 708 26a 36a 1194a 11042 6.373626.868 798 13a 108a 698 1 a 70a 26a I36a 94a 21a 97a 6.373626186a 798 13a 108a 698 1 a 26a 24a 368 948 104a 97a 6.446887 86a 79a 113a 11088 76a 20a la 1708 36a 194a 104a 21 a 6.446887 868 798 108a 176a 120a 69a 26a '24a 136a 948 1048 97a 6.44688713911082768 20a h1 a 70a 1268 36a 94a 104a 121 a 97a 6.44688786a1792 1138 1088 768 69a 70a 26a 24a 94a 1104a 978 6.446887 868 792 1138 1088 768 69a 1 a 70a 26a 36a 1948 104a 6.446887 86a 138 1088 768 208 169a i1 a 70a 136a 949 104a 97a 6.446887 86a 79a 1108a 176a 169a I1 a 170a I26a 24a 194a 11048 21 a M .114 6.446887186a113a 1108a 1762 202 1 a 70a 24a 1362 94a 1042 97a 6.44688713a 108a176a la 170a 262 24a 36a 94a 1104a 21a 197a 6.44688718631792 1108a 762 20a (69a 12 J 24a 36a 94a 1042 97a 6.44688786a 79a' 1132 108a 76a'202 69a 70a 26-a 124a 1042 97a 6.446887 86a 79a 132 76a 202 1692 70a 1262 36394a 21a 197a 6.44688786a79a 76a 20a 69a 1a 170a 1262 24a 36a 94a 1104a 6.44688786a79a 108a 692 112 170a 1242 362 1942 1042 21a 97a 6.4468871862 13a 11082 69a h1 a 702 262 242 36a 942 104a 197a 6.446887186a 79a 1132 10821762 169a 1a 262 1242 368 1942 1104a 6.44688786a 792 _108a 762 _69a 70a 262 24a 362 1042 21a 972 6.4468877921132 10821762 1a 170a 26a 124a 36a 942 21a 97a 6.446887186a179213a 1108a176a 20a 69a 112 70a 1042 212 97a 6.446887186a 13a 11081176a 1202 69a 11a 70a 248 362 104a 197a 6.446887862792 13a 11088 762 202 69a 1a 1702 24a 1362 1042 6.446887862792 132 1108a1203 169a 1a 70a 262 942 104a197a 6.446887 862 79a 13a 11082 76a 120a 692 la 170a 1262 36a 21a 6.4468871862 792 13a 1082 20a 1la 170a 1262 242 362 942 197a 6.52014613a1108a 762 20a 69a 112 702 1262 24a 136a 1942 1104a 6.520146792 13a 11082 1762 20a 1692 12 1262 242 363 942 _97a 6.52014686a79a 113a 176a 20a _69a 702 2242 36a 942 97a 6.52014686a 792 13a 108a 762 202 _Ia 702 262 94a 1104a 197a 6.52014686a 79a 1132 1082 762 702 26a I36a _94aJ104a 21a 197a 6.520146862132 10821762 69a la 1702 262 242 36a 104a 972 6.52014679a 132 1082 1762 120a 170a 126a 1362 94a 104a 21a 97a 6.5201461862 13a 11082 76a 120a 169a 11 a 170a 1262 24a 1042 972 6.520146 862 1082 762 202 691 la j70a 262 362 94a 11042 97a 6,520146 862 132 1082 762 169a la 702 262 36a 94a 1042 97a 6.52014686a113a 1082 76a 169a 1a 70a 1262 362 1042 212 97a 6.593407 862 792 1082 76a 120a 11 a 702 362 942 104a 21a 197a 6.59340779a113a 11082 76a 169a 1 a 1702 262 242 942 21a 972 6.593407862132 11082 76a 120a 69a h1a 262 362 942 104a121a 6.5934071862 792 13a 11082 76a 20a 169a 11 a 702 94a 1104a 197a 6.593407 86a 79a 1132 1762 1 a 702 1242 1362 942 1042 212 _97a 6.59340786a 79a 1132 11082 76a 202 692 70a 262 24a 1362 1042 6.593407 86a 79a 1132 76a 692 la 702 26a 242 942 _104a21a 6.593407186a, 792 108a 176a 69a 12 70a 24a 362 942 _1042 21a 6.593407792 132 76a 120a 1a 702 26a. 36a 94a 104a 21a 97a 6.593407 862 79a 113a 108a 762 20a 1691 70a 26a 104a 21a 972 6.593407 86a 79a 113a 108a 202 _69a 11 a 170a 242 362 104a 97a 6.593407 86a 762 203 692 la 702 262 24a 36a 942 1042 97a 6.593407 862 792 113a 76a 692 1 a _7031363 942 1042 121a 972 6.593407 86a 792 132 1108a 76a 112 70a 1262 362 94a 1042 212 6.59340786a 79a 113a 108a 76a 20a 169a 170a 126-a 362 942 197a 6.593407186a79a ,1082 762 20a 1692 _Ia 7Da 262 942 1042 972 6.59340779a 132 108a 7a 69a 11a _702 24a 94a 1042 212 97a 6.59340786a 792 76a 20a 69a la 702 26a 24a 1942 104a 97a 6.59340786a 792 13a 20a 692 1a 170a 136a 194211042 21a 97a õ Fretd "i 2. ; 3 MGM ~;71~ ~x,,g. ,,,9 : yr10 > ^ tiAA t .
t}a4 a, }
6.59340779a 13a 11089 76a 20a 169a 26a 24a 136a 94a 1104a 197a 6.59340786a 139 108aj76a 209 1699 170a 1249 369 94a 1104a 97a 6.593407 869 799 108a 76a 20a 11 a 1709. 26a 94a 1049 218 97a 6.66666 86a 1089 763 20a 69a 1 a 170a 126a 36a 104a 121 a 97a 6.666667 86a 79a 139 76a 20a 1 a 1709 26a 94a 104a 21 a 97a 6,666667 79a 139 108a 69a la 70a 126a 24a 136a 94a 104a 197a 6.66666779913a 108a 76a 69a 1 a 170a 126a 124a 36a 194a 197a 6.6666671863 799 13a 76a 20a 69a 70a 26a 36a 94a 1104a 121 a 6.666667 86a 79a 113a 1089,699 11 a 170a 126a 94a 1049 21 a (97a 6,739927186a 79a 113a 1089 76a 169a j1 a 1249 36a 194a 1104a 97a 6.73992779813a 1108a768 la 1709 24a 136a 1949 1049 21a 97a 6.739927186a 79a 1133 1089 76a 169a 1 a 170a 124a 1369 121a 979 6.739927166a 799 108a 76a 169a 11 a 709 126a 1249 369 194a 97a 6.739927186a79a 13s 76a 120a 11 a 170a 249 1369 94a 1104a 97a 6,73992779a110881768 209 169a is 170a 269 36a 94a 1219 97a 6.739927186a 79a )13a 1108a169a 1 a 70a 1249 194a 1104a 121a 1979 6.739927186a179a 1108a )76a 1209 1699 11 a 70a 126a 11049 121a 197a 6,739927186a179a 113a 176a 209 11 a 70a 136a 1949 104a 121a 979 6.7399271863 79a 113a 11089 20a 1699 l a 136a 949 1049 21 a 97a 6.73992,7186a 79a 13 a 1769 69a l a 1709 248 369 949 1104a 21 a 6.73992786a79a 1139 1089769 209 699 70a 269 369 1049 21a 6.739927179a 13a 110.8a 176a 20a 708 126a 124a j36s 1949 104a j97a 6.7399271869 799 1139 1089 20a 1692 11 a 1709 36a 949 1049 97a 6.739927186a 799 1108a1768 20a h1 a 1709 124a 1363 94a 1049 97a 6.7399271799 13a 11089 769 69a 11 a 1709 26a 1369 94a 121a 197a 6.739927186a 79a 139. 108a 20a 1,69a 11 a 170a 249 369 949 1049 6.7399271799 13a 108a 76a 20a 119 170a 126a 124a 36a 194a 197a 6.739927186a 799 13a 1089 209 1 a 170a 269 949 11049 121 a 197a 6.739927186a 79a 1139 108a 76a 1699 1a 170a 249 194a 1049 21a 6.813187186a 799 113a 108a169a 170a 126a 1369 94911049 121 a 197a 6.8131871799139 176a 120a 69a 1 a 126a 124a 1369 194a 11049 979 6.81318786a179a 1139 1108a 769 20a 699 1 a 170a 126a 136a 197a 6.8131 87 869 79a 13a 108a 20a 169a 1 a 170a 1269 24a 136a 194a-6.813187113a 76a 20a 69a 1a 709 126a 124a 3691949 11049 979 6.813187186a 799 13a 1089 769 209 699 26a 1369 94a 104a 21a 6.813187186a 139 76a 69a la 170a 26a 24a 36a 194a 104a 97a 6.81318 186a 799 108a 176a 70a 269 24a 36a 949 104a 21 a 97a 6.886447179a 138 108a 763 1208 1 a 70a 26a 36a 1949 104a 121 a 6.886447 869 799 1108a (76a 202 69a 1 a 70a 24a 194a 1104a 97a 6.886447186@179a 108a 1769 Oa la 709 26a 249 949 1049 979 6.886447 86al79a 1108a 1209 69a 1 a 170a 36a 949 104a 21 a 197a 6.88644 79a 13a 11089 76a 1699 709 26a 24a 94a 1049 21a 97a 6.88644786a79a 113a 176a 69a la 170a 26a 36a 94a 1042 21a 6.88644779a13a 110821768 120a 169a h1a 70a 26a 36a 94a 219 6.886447 86a 13a 108a 176a 69a 11 a )70a 26a 24a 94a 104a 21 a 6.886447139 768 20a 169a 1a 70a 26a 36a 949 104a 21 a 97a 6.8864471869 79a 11089176a 69a 1 a 1709 126a 124a 136a 194a 121a r DM -'2 ON
F le t '"t+".r71$ = X43' =~1 1 6.886447186a 13a 1108a 768 1208 69a 708 268 1248 136a 94a 104a 6.88644779a 13a 1108a 76a la 70a 26a 24a 948 1048 21a 97a 6.886447798138 76a 69a la 70a 2481368 948104a 121a 197a 6.88644786a179a )13a )108a 76a 169a 1la 70a 124a 36a 11048 97a 6.95970786a113a 176a 69a la 170a 26a 36a 94a 104a 21a 197a 6.959707179a 13a 11088 176a 1208 69a 126a 36a 194a 1048 21 a 1978 6.959707186a 13a 1108a176a 698 13 170a 26a 24a 94a 11048 97a 6.959707186a 79a 113a 208 698 is 70a 1262 248 94a 110481978 6.959707 868138 1088 768 20a 1698 1 a 70a 26a 94a 1104a 197a 6.95970786a179a 113a 108a 76a 1208 69a 70a 26a 36a 94a 104a 6.9597071798 10881768 69a la 170a 126a 124a 368 948 104a 97a 6.95970 798 138 1088 76a 20a 69a la 170a 26a124a 36a 104a 7.0329678681798 11088 76a 20a 70a 26a 24a 36a194a 1048 97a 7.032967186a 79a 1088 76a 120a 69a 702 26a 24a 1368 10481978 7.0329671868 138 108a 20a 169a 11 a 170a 136a 194a 104a 121 a 197a 7.0329671868798 13a 1108a120a 11a 70a 124a 136a 948 104a 97a 7.03296717981138 1108a 176a 20a 169a 11 a 170a 124a 136a 194a 11048 7.03296779811082 1762 169a la 170a 126a 124a 194a 11048 21 a 97a 7.032967 868 798 108a 768 120a 1692 1 a 170a 194a 1104a 121 a 97a 7.03296713a 108a176a 208 169a 11a 126a 136a 194a1104a 121a 97a 7.032967 868 13a 1108a 76a 208 69a 11 a 70a 1368 1048 21 a 197a 7.032967 868 76a 120a 693 1 a 1708 26a 36a 194a 1048 21 a 97a 7.032967793138 10831763 1698 1a 170a 248 36a1104a 21a 97a 7.03296779a 13a 108a 176a 120a 69a la 170a 126a 124a 136a 94a 7.032967186a 79a 113a 11088 69a 118 70a 26a 1248 948 1048 21a 7.032967186a 13a 176a 20a 698 1a 708 248 368 94a 1048 97a 7.032967179a 13a 1768 692 1 a 702 26a 124a 194a 11048 21 a 1978 7.106227798 13a 1088 768 118 70a 268 24a 36a 104a 21a 97a 7.106227186a 79a 11088 768 69a 70a 26a 136a 194a 104a 121 a 197a 7.1062271868 798 13a 1108a 768 208 70a 126a 368 94a 1104a 121 a 7.106227 8681799 13a 1108a 76a ,69a 170a 1248 36a 194a 104a 197a 7.106227 798 13a 176a 120a 69a 11 a 170a 1268 36a 1948 21 a 1978 7.106227 86a 79a 1138 768 20a 1la 70a 126a 124a 94a 11048 97a 7.106227 86a 798 138 108a 768 708 26a 24a 368 948 104a 21 a 7.106227 868 798 108a 176a 20a 698 la 36a 94a 11048 121a )97a 7.106227 86a 798 138 1108a 768 70a 126a 1248 948 104a 21 a 197a 7.106227,86a 138 _762 120a 698 la 70a 1268 248 36a 94a 104a 7,106227138 108a 768 202 69a 1a 126a 124a 36a194a 104a 97a 7.17948 868 798 13a 11088 768 69a 11 a 124a 1368 94a 21a 197a 7.179487186a 798 1088 768 69a 26a 1248 368 948 104a 21 a 97a 7,17948779811088 768 208 69a 1 a 170a 126a 24a 136a 1104a 97a 7.179487 86a 138 1088 208 698 la 708 268 36a 194a 1104a 21a 7.179487186a 798 138 1088 76a 20a 69a 124a 368 94a 104a 97a 7.179487186a1132 1088 768 20a la 170a 126a 948 1048 21 a 97a 7.179487 868 798 138 1088 76a la 1708 26a 948 104a 21a 97a 7.179487868 79a 138 10881768 698 1 a 268 368 _94a 1043 218 7.17948786a179a 1113a 108a176a 208 69a 11a 1248 368 104a 197a P' M 1-3, ;r ry i h+ rvr, .
7.1794871868)793 13a 20a 1692 1 a 70a 26a 24a 136a 948 97a 7.1794871862 792 13a 1082 202 69a 70a 24a 362 942 104a 97a 7.179487)86a 79a 113a 108a 20a 69a la 702 36a 94a 104a 21a 7.17948786a79a 113a 11082202 69a 11a 26a 94a 104a 21a 97a 7.25274779a 132 762 20a 1la 1702 26a 24a 36a 94a 104a 97a 7.252747 847R a 1132 1082 76a 202 1 a 1702 126a 243 36a 104a 7.25274786279a 1132 108a120a 69a la 70a 126a 36a 1212 )97a 7.252747186a179a 11082 76a 202 69a 1a 70a 36a 104a 21a 97a 7.252741862 79a 113a 108a J76a 20a 70a 26a 24a 36a 1942 104a 7.25274 86a 79a 13a 1082 76a 69a 11 a 136a 94a 1042 21 a 972 7.25274 B6a 79a 132 1108a176a 1692 1 a 70a 36a 942 1042 97a 7.252747 8621793 13a 76a 120a 169a 12 70a 26a 36a 94a 1042 7.2527477921132 1108a 76a 69a la 126a 124a 362 94a 104a 97a 7.2527471862 108a176a 320a 69a j1a 26a 124a 1362 94a -[1-04-197a 7.252747)86a 79a 108a 176a 169a 70a 124a 362 19421104a 212 97a 7.2527471862 79a 13a 1082 76a 169a 70a j26a 24a 136a 121a 197a 7.32600786a79a 1108a 76a 1202 169a 170a 36a 94a 1042 21a 197a 7.32600786a179a 113a 108a176a Ila 70a 136a 94a1104a 121a 197a 7.32-600786a179a ~76a 120a 1692 1a 70a 126a 94a 104a 121a 197a 7.3260071792 13a 1108a 1692 1 a 170a 1242 362 94a 1104a 121 a 97a 7.32600786a 79a j13a 1082 698 11 a 70a 126a 124a 136a 94a 1104a 7.32600786a 79a 13a 76a )20a 69a 11 a 24a 136a 194a 104a 197a 7.326007862 79a 13a 108a 76a 202 69a 11a 1362 94a 11042 197a 7.32600786a 79a 132 1082 76a 120a 1la 126a 9431042 21a 197a 7.326007186a 792 13a 108a176a 169a 1la - 26a 24a 36a 94a 197a 7.32600786a79a 113a 108a176a 69a 1a 26a 36a 94a 21a 97a 7.326007 862 792 13a 1108a 1762 20a 69a la 170a 36a 1042 21 a 7.326007862 79a 1082 76a 20a 1692 1 a 70a 26a 24a 1362 94a 7.399267)86a1792 176a 20a ;69a 11 a 170a 26a 24a 1362 104a 97a 7.399267862 79a 1082 76a 20a 69a 170a ,26a 136a 194a 11042 197a 7.39926779a108a176a 20a 69a la 1702 26a 1362 942 104a 197a 7.399267 862 792 13a 1082 76a 1 a 170a 126a 124a (36a 104a 21 a 7.3992671862 792 132 76a 202 69a la 1702 24a 94a 104a 97a 7.399267113a 108a 76a 20a 1a 702 26a 24a 36a 94a 104a 97a 7.399267 86a 792 762 692 11 a 702 262 124a 36a 942 21 a 972 7.39926786a 792 13a 1082 762 20a 1 a 36a 94a 104a 21a 97a 7.39926786a179a 13a 108a 762 120a 1692 la 126a 248 104a 972 7.39926718621082 762 203 692 70a 126a 36a 94a 104a 121a 97a 7.39926 862792 132 76a 70a 26a 24a 136a 1942 104a 21a 97a 7.39926786a 79a 13a 1082 76a 120a I1 a 26a 124a 36a 194a 97a 7.39926779a 13a 76a 20a 169a la 70a 26a 24a 362 1042 972 7.39926786a 108a 76a 69a 1a 126a 24a 36a 1942 104a 1212 97a 7.399267186a 79a 132 1762 202 69a 70a 26a 124a 94a 1104a 197a 7.399267186a 792 76a 20a 69a la 70a 26a 24a 362 194a 197a 7.399267868 132 108a 20a 692 la 70a 126a 942 104a 121a 97a 7.399267 862 132 108a 69a 1 a 70a 262 362 942 1042 21a 97a 7.472528186a179a 1108a176a 69a 1la 702 124a 1362 942 104a 97a ,CA 02313957 2000-07-14 7.472528 86a 79a 13a 1108a 120a 69a 1 a 70a 36a 104a 121 a 97a 7.472528 86a 13a 76a 20a 69a 1 a 70a 126a 36a 94a 104a 121 a 7.47252886a79a (13a 76a 69a la 70a 26a 124a 36a 94a 21a 7.47252879a113a 108a 76a 20a 11a 70a 242 36a 94a 104a 97a 7.472528 79a 13a 108a 76a 20a 69a 70a 26a 24a 136a 104a 97a 7.47252886a.1 3a 176a 20a 169a 1a 170a 36a 194a 104a 21a 97a 7.472528 86a 79a 13a 76a 20a 69a 1 a 170a 194a 1104a 21 a 197a 7.472528186a 79a 13a 1088768120212 24a 136a 94a 104a 97a 7.472528 86a179a 108a 76a 69a 70a 26a 24a 94a 104a 21 a 197a 7.472528 86213a 1108a 176a 20a 69a 1 a 26a 94a 104a 121a )97a 7.472528862179a 108a 76a 69a 1a 70a 126a 362 94a 21a 97a 7.4725281862179a 113a 108a76a 120a Is 70a 1242 94a 104a 97a 7.472528186a 13a 1082 76a Is 70a 26a 36a 194a 104a 121 a 97a 7.472528 86a 79a 1133 108a 1762 69a 1 a 702 242 94a 121 a 97a 7.472528 86a179a 1132 10821768 169a 11 a 26a 242 94a 121 a 197a 7.545787 86all 3a 176a 20a 69a 12 702 26a 1242 94a 1104a 197a 7.54578786a1132 1082 76a 20a 1a 70a +36a 1942 1042 121a 197a 7.54578786a108a176a 1la 170a 26a 124a 36a 19421042 21a 197a 7.545787186a179a 1132 76a 120a 1702 126a 36a 94a 1042 212 97a 7.545787 86a 79a 13a 1082 76a 20a 11 a 1262 24a 94a 104a 97a 7.545787862 79a 113a 108a~762692 26a 36a 94a 1104a 121 a 97a 7.545787186a 79a 1132 108a176a 69a 702 126a 194a 1042 121 1972 7.54578786a 792 13a 1082 76a 69a l a 70a 194a 104a 21a 97a 7.545787186a 79a 13a 76a 69a 1la 170a 26a 136a 94a 21a 97a 7.545787792 13a 1762 69a 1 a 170a 126a 36a 94a 104a 21a 97a 7.6190 86a 132 1082 76a 169a Is 702 24a 94a 104a 21a 97a 7.619048 86a 79a 13a 108a176a 69a I1 a 170a' 26a 24a 1104a 97a 7.619048 86a 132 108a 76a 69a 1 a 26a 136a 94a 104a 21 a 97a 7.619048862 79a 113a 108a 76a 20a 19 126a 136a 94a 104a 121a 7.61904079a 1082 76a 20a Is 702 126a 36a 94a 104a 1212 97a 7.619048179a 132 108a 20a 69a Ia 170a 26a 36a 94a 21a 973 7.619048 86a 9a 13a 76a 1202 69a 1 a 26a 24a 36a 194a 197a 7.619048862 79a 108a 76a 20a 69a 1s 70a 26a 36a 194a 121a 7.619048186a 79a 13a 69a 1 a 70a 242 36a 94a 104a 21 a 97a 7.619048 86a 132 108a 76a 120a 69a 1 a 36a 94a 104a 121 a 97a 7.619048 86a 79a 13a 1082 76a 120a 169a l70a 26a 94a 1042 97a 7.61904879a 108a 76a 69a 13 70a 126a 24a 36a 1042 121 a 97a 7.61904886a79a 13a 1202 69a 70a 28a 24a 36a 94a 104a 97a 7.61904879a 13a 1108a 762 20a Is 26a 36a 94a 1042 21a 97a 7.619048 86a 79a 13a 108a 69a 1 a 70a 26a 24a 104a 21a 97a 7.61904886a 79a 11086 76a 20a 1a 70a 26a 24a 36a 94a L972 7.61904886a79a 13a 20a 69a 1a 70a 26a 94a 104a 1212 97a 7.692307862 79a 113a 108a 76a 20a 70a 24a 36a 94a 1042 97a 7.692307 86a 79a 1082 202 69a 1a 70a 26a 94a 104a 21a 97a 7.69230786a 79a 113a 082 76a 202 69a 26a 94a 104a 212 97a 7.69230779211082 202 69a 1a 702 126a 24a 36a 94a 104a 97a 7.69230786a179a 113a 76a 169a 170a 126a 242 136a194a 104a 21a 7.69230 799 139 108a 76a 699 la 26a 36a (949 104a 21 a 979 7.69230 869799 113a 108a76a120a 69a la 94a1104a 21a 97a 7.69230 86a(13a 108a 76a (69a 70a 26a 24a 36a 94a 104a 21 a 7,69230 86aJ79a 176a 1699 12 70a 26a 24a 36a 94a (1049 97a 7.692307 86a 13a 76a 1209 69a la 70a 26a 94a 104a 21a 97a 7.692307 Hall 3a 108a 176a 69a 1 a 709 26a 94a 104a '21 a 97a 7.692307 86a179a 139 108a 76a 1209 69a (1a 1269 94a 1049 97a 7.692307 8079a 1139 1089769 20a 69a 1a 26a 36a 1219 _97a 7.692307 86a 139 (1089 769 1 a 70a 24a _36a _949 104a 121 a 97a 7.692307 86a1799 132 1089 769 70a 1269 24a 1369 _104a 219 97a 7.692307 869 79a (13a 1089 76a la 709 249 369 949 104a 97a 7.692307 869 799 139 1089 769 699 la (709 24194a 104a 972 7.692307 8.6al108a(76a 209 la 1709 _26a 24a _36a 1949 1049 _97a 7.76556886a(79a (139 1089 76a (699 1a 709 126a 124a 369 21a 7.765568799 139 1089(769 69a _19 709 269 249 369 (94a (104a 7.785568 869 1 3a 1089 769 la 1709 1269 124a 1369 104a 121 a 97a 7.7655688691792 139 108a 69a 11a 1269 249 369 94a (2ia 97a 7.765568(869 79a (13a (769 la 70a _26a 1249 36a 194a 1049 21 a 7.765568 869 799 139 _108a 12 1709 24a 36a 1949 1049 121a 97a 7.765568 86a(79a 1139 _76a 1 a 1709 26a 24a 194a 1104a la 97a 7.765568(869 799 1089 76a 209 69a la 26a (249 36a (94a _104a 7.765568 869 79a 1089 76a 20a 169a (70a 126a _36a 104a 121a (97a 7.765568 869 799 13a 108a 76a 1699 1 a 249 36a 94a 11 21 a 7.765568 7991089 769 69a la 1709 26a 369 94a 104a 21 a 97a 7.765568 86a(79a 11089 (769 2699 1 a 269 124a 94a 104a 197a 7.765568 799 769 20a 699 la 709 269 _36a 94a 104a (21 a 1979 7.838828 869 79a (13a 1089 769 209 (699 709 94a 104a 21 a 979 7.838828 869 799 13a 76a (209 699 1 a 170a 24a 36a 104a 97a 7.838828869799 139 108a(76a (69a (1a (70a 26a 104a 21a 97a 7.838828 792139 176a 120a _69a _Ia 709 269 24a (36a 194a 104a 7.838828186a 799 139 108a 769 20a (1 a 709 249 369 104a 97a 7.838828 13a 108a 1769 _69a _Ia 709 269 249 36a 11049 21 a 97a 7.83882886a(79a 1139 108a 76a 20a (1a 170a '26a(36a (1049 21a 7.838828 799 1089 76a 69a la 709 269 249 369 949 21 a 972 7.838828 86a 799 13a 1089 76a 20a 1 a 70a (269 136a 949 104a 7.838828 86a 139 .108a 209 69a la 709 269 24a (369 949 104a 7.83882886a 139 108a 769 20a 69a 709 36a 94a(104a 219 97a 7.838828 86a 79a 13a 108a 76a (1 a 70a 249 94a 104a 21a 97a 7.838828 86a 799 13a 108a 769 20a 69a 1a 70a 26a - 104a 97a 7.83882886a 799 _133 108a 769 209 69a 1a 70a 269 36a 104a 7.83882886a79a 139 _76a 20a 70a 269 249 36a 94a 104a 97a 7.838828 86a 799 139 1089 769 20a la 709 126a 249 36a 94a 7.83882886a 79a 13a 699 la _702 26a 24a 36a 949 1104a 97,3 089 (769 699 la 70a 26a 24a 369 21 a 97a 7.838828 86a 799 -108-a--(76-a-7.83882886a79a 13a _108a76aJ20a 69a 1a 26a 249 36a (94a 7.838828 86a 79a 139 108a 209 69a la 26a 36a 949 21 a 97a 7.838828869 799 1139 108317621209 1a 709 369 949 (1049 97a Mid, OR I NO I W IN
7.912088186aJ79a 108a176a 11a 1702 (24a 36a 94a 104a 1212 97a 7,912088862 792 132 1082 692 1a 24a 36a 94a 104a 21a 97a 7.91208886a79a 108a 76a 69a (13 70a 26a 24a 94a 104a 97a 7,91208886a79a 132 76a 69a la 70a 24a 94a 104a 1212 (97a 7.912088862132 108a176a 1692 (12 26a 24a (36a 94a 104a 121a 7.912088 86all 082 76a 699 h1a 170a 26a 24a 94a 104a 21a 97a 7.912088 862 79a 13a 76a 120a 69a la 70a 26a 36a 94a 21 a 7.912088862 79a 13a 76a 169a la 170a 26a 24a 94a 1104a 97a 7.912088 86a1792 13a 1082 76a 120a 69a la 24a 94a 104a 97a 7,912088862792 76a 69a 1a 170a 126a 124a 36a 94a 11 042 21a 7.91208879a 13a 1082 76a 120a (69a 1a 170a 126a136a (21a 197a 7.912088 86a179a 132 1082 202 1 a 702 36a 942 1042 121 a 97a 7.912088 862 79a 13a (76a 202 69a 702 26a 94a 104a 21a 97a 7.912088862798 76a 20a (1a 70a 26a 24a 36a 94a 1042 97a 7.9120881798113a 1082 69a 1a 70a (26a 124a 194a 104a 121 a 97a 7.912088 86a 79a 113a (76a 20a I1 a 70a 26a 36a 94a 104a 21 a 7.912088 86a 79a 13a 1108a 176a 120a (69a 1 a 26a 36a 194a 21 a 7.98534 86aJ793 132 1i 08a176a 69a 11 a (70a 26a 94a 1104a 197a 7.985348 86a179a 113a 108a 11 a 70a 126a J24a (94a 1042 21a 978 7.985348 86a 79a 76a 69a 1 a 70a 26a 24a 948 104a 21a 97a 7.98534879a 13a -11 08a 76a 202 69a 70a (26a 36a 104a 21a 97a 7.985348 86a 79a 13a 1082 76a 20a 69a ~ la 26a 1042 21a 97a 7.985348 86a 79a 13a 108a 76a 169a 70a 26a 36a 942 1042 97a 7.98534886a79a 132 76a 1la 170a 26a 36a 942 104a 21a 97a 7.985348 86a 796 13a 1082 76a 69a (26a J24a 36a 94a 1042 21 a 7.985348 862 792 76a 202 169a la 702 1262 3621948 1042 97a 7.98534879a 13a 10821762 69a 70a (26a ~!24a 362 104a 121a 197a 7.9853481798113a 1082 762 20a 69a 1a 170a 26a 36a 194a (1042 7.985348 792 13a 1108a 762 20a 69a la 26a 24a 362 1042 97a 8.058608 86a 79a 1132 (76a 112 170a (262 24a (36a 94a 104a 197a 8.05860886a79a 132 108aI76a 169a la 26a 124a 194a 1104a 121a 8.058608 862 79a 13a 1082 762 1a 170a 24a 36a (942 104a 121a 8.058608 79a 108a 76a 20a 69a la 702 26a 24a136a 942 1042 8.058608,86a 792 108a 76a 69a la 702 26a 242 36a 94a 104a 8.058608 862 79a 13a 76a 20a la 702 262 24a 36a 94a 104a 8.05860886a179a 13a 1082 76a 120a 1a 70a 24a 362 94a 104a 8.058608792 132 108a 76a 69a h1a 70a 26a 36a 948 1042 21a 8.058608 862 79a 108a 120a 69a 70a 26a 24a 362 94a 11042 97a 8.058608 862 792 13a 76a 202 69a 1 a 170a 1269124a 1042 972 8.058608 86a 79a 113a 108a 20a 69a Ia 70a 26a 36a 94a 21a 8.058608 79a 132 1082 76a 69a la 24a 36a 94a 104a 21 a 97a 8.131868792132 176a20@ 69a 1a 1702 26a 3621942 104a 97a 8.131868862 13a 1108a 76a (202 692 702 26a 36a]104@ 21a 97a 8.131868 86a179a 76a 1 a 70a 26a 24a 36a 94a 1042 21 a 97a 8.131868 79a 132 108a 762 69a la 70a 26a 36a 1042 21 a 97a 8.13186 13a 108a 762 120a 69a 1a 70a 26a 1248 362 104a 97a 8.131868 86a 792 1082 692 70a 26a 242 1362 942 1042 21 a 972 OF =I IRILMI NO -I WAN
8.131868 86a 79a 108a 169a 1 a 70a 126a 24a 136a 94a 1104a 97a 8.13186813a 108a 76a 20a 69a 70a 26a 36a 94a 104a 21a 97a 8.131868 868 79a 13a 176a 20a 69a 1 a 26a 24a 94a 104a 97a 131868 86a 13a 108a 76a 69a la 70a 24a 36a 104a 121a 97a 8.13186813a 108a176a 120a 69a jla 70a 26a 136a 1104a 21a 97a 8.13186886a79a 1108al76a 1a 70a 126a 24a 36a1104a 21a 197a 8.13186886a79a 11-08a 76a 69a Ia 170a 26a ~24a 36a 1104a 21a 8.131868 86a 13a 76a 69a 1 a 170a 124a 36a 94a 104a 121a 197a 8.131868 86a 79a 11083 768 692 1 a 1703 26a 36a 94a 1043 21 a 8.13186886a79a 133 108a176a 1a 170a 26a 124a 94a 1043 97a 8.13186886a179a 113a 76a 69a 1a 703 26a 94a 1043 121 I97a 8.131868 86a 79a 108a 76a 69a 1 a 703 26a 94a 1043 21 a 197a 8.205129 868119a 13a 108a176a 1a 1703 24a _36a 104a 121a 197a 8.205129868f 79a 13a 76a 120a 69a .70a 126a 243 36a 11043 97a 8.205129 86al79a _13a 76a 1203 69a I1 a 362 94a 1043 213 97a 8.205129186a 79a 113a 1108a]762 26a 24a 136a 94a 11043 21 a 197a 8.20512986a 79a 13a 1083 76a 203 126a 248 ~36a 94a ~104a ~97a 8.205129132J108a 76a 69a 1a 70a 126a 1243 194a 104a 121a 197a 8.20512986aj792 133 76a 203 69a 170a 24a _36a 94a 1043 97a 8.20512986al79a 11083 76a _69a 1a 703 36a 194a 104a-] 213 97a 8.20512986a 79a Ina 1083 76a 69a la 703 24a 104a 21a 97a 8.205129 86a 79a 1082 76a _69a la 124a 36a 194a 104a 21a 197a 8.205129 86a 133 108a 69a 1 a 170a 24a _36a 194a ~ 1043 _21 a 97a 8.205129 86a 133 76a 69a la 70a _263 242 36a 94a 1043 28.205129 862179a 13a 108a 76a 69a _70a 1268 136a 1104a _213 97a 8.278388 79a 108a 76a 20a 69a la 126a 24a 1363 943 _104a _97a 8.2783888681793 108@120a 69a la _70a 26a 36a 94a 21 a 97a 8.278388186a 79a 108a 76a 203 69a 1 a 703 26a 36a 121 a 97a 8.351648 86a 79a 108a 76a 20a 170a 263 363 94a _104a 21a 97a 8.351648 86aj79a - 13a 1082 76a 1203 692 la 36a 1043 21a 97a 8.351648 863179a 108a 76a 69a _Ia 70a 24a 94311043 21a 197a 8.351648 86a 79a 13a 108a 76a 69a 170a 124a 362 194a 1043 21a 8.351648 8479a 13a 108a 76a 169a 70a 126a 24a 36a 11043 _21a 8.351648 86a 79a +108a 20a 6902 a 70a 26a 24a 36a 94a 104a 8.35164886a79a 13a10827681693 la 70a 36a1104a 21a 197a 8.35164879a(108a 76a 203 69a 1a 70a 26a 36a 942 1043 21a 8.351648 79all 3a 76a 69a 1a 703 26a 24a 36a 94a 121a 97a 8.35164879a 13a 108a 76a 1a ~70a 26a 24a 36a 94a 1104a 97a 8.35164879a 13a 108a 69a la 703 26a 36a 94a 104a 21a 97a-8.351648 86a 79a 13a 108a 76a 20a la 70a 36a 1043 21a 97a 8.42490 86a 79a 13a 20a 69a 703 26a 36a 94a 104a 121 a 97a 8.424909 79a 13a 108a 20a 69a 1a 703 26a 24a 36a 942 104a 8.424909 86a 13a 76a 20a 69a 70a 1263 36a 94a 104a 121 a 97a 8.42490986a 79a 13a 108a 76a 203 69a 1a i26a 36a 1043 213 8.424909 86a 13a 11083 76a 20a 69a _70a 26a 24a 36a 104a 97a 8.424909 86a 79a 133 1082 76a _69a _70a 26a 24a 36a 104a 97a 8.424909186a 79a 13a J108a 203 69a 26a ,24a 36a 94a 1043 97a teld`l 2"``3' 6 ',8'1.6 rslx1:2 8.424909186a 79a 113a 11083 763 693 170a 126a 24a 104a 121 a 97a 8.424909186a 79a 113a 1108a(69a 113 703 26a 36a 94a 1104a 972 8.424909186a 79a 1083 76a 20a 69a 1 a .126a 362 94a 1104a 97a 8.424909 86a 79a 133 108a 20a 69a 11 a 70a 262 24a 36a 104a 8.424909186a 79a 13a 108a 76a 69a la 70a (26a 36a 104a 21 a 8.498169793 13a 76a 1a 70a 126a 124a 1363 94a 104a 121a 97a 8.49816986a 79a 13a 108a 762 692 1a 170a 1263 36a 121a (97a 8.498169 86a 133 1083 20a 69a 1 a 703 126a (24a 36a 1104a (97a 8.49816986a ]79a 1108a 1762 ,69a 11 a 26a 124a 36a 194a 1104a 197a 8.4981686j a 133 76a 20a (69a la 70a (26a 124a 136a 104a 97a 8.49816166a 79a 76a 20a la 70a 26a 36a 94a 1043 213 97a 8.498169179a 13a 11083 76a 69a 1 a (263 24a 943 104a 121 a (97a 8.498169 86a 793 1083 76a 20a 693 la 263 124a 136a 94a 97a 8.498169793 133 108a 763 20a 1692 1a 126a 136a 194a 1043 97a 8.49816986310831693 1a 1703 (263 243 1363 I94a(104a 1213 973 8.498169179a113a 1108a 20a 693 1703 126a 24a 1363 943 104a (97a 8.498169863 79a 108a 693 1a 170a 26a 124a 194a 104a 21a 973 8.571428 863 792 13a 108a 76a 1703 243 136a 94311043 121 a 197a 8.57142818631793 1108a 762 20a 69a la 170a 126a 36a 104a 121a 8.5714288631793 133 1108a120a,169a 170a 36a 194a 104a 21a 97a 8.57142879a 13a 1083 76a 202 11 a 70a 26a 243 363 1043 197a 8.571428793 13a 763 69a 1703 263 24a 36a 94a 1104a 121a 197a 8.57142879a 133 1083 76a 693 703 26a 24a 136a 194a 1043 21a 8,5714281863793 133 176a 20a !69a is ;703 263 36a 21a 197a 8,571428186a179a 113a 11083 is 170a 26a 124a 1362 94a 104a 97a 8.571428 793133 108a 1763 69a 26a 1243 363 194a 104a 21 a 973 8.571428 793 133 11082 76a 203 la 170a 26a 136a 94a 104a 97a 8.644689 8631793 11083 76a 20a 692 1 a 26a 943 1104a 121a 97a 8.644689 86a1793 763 20a 693 1 a 703 263 363 942 104a 21 a 8.644689863133 76a 20a 693 170a 26a 24a 136a 194a 1104a 97a 8.644689 Ball 3a 1 108a 69a 1 a 170a 126a 24a 363 94a 1042 21 a 8.644689 863 79a 113a 1083 693 i a 1703 26a 124a 1363 943 21 a 8.6446891863792 108a176a 20a 169a 1a 126a 242362 104a 97a 8,64468986a79a 13a 1762 20a 69a 1a 170a 3631943 104a 97a 8.644689 86a 79a 11083 763 203 69a 1a 263 36a 94a 1043 21a 8.64468986a 79a 13a 1083 76a 20a 170a 1262 24a 36a 104a 197a 8.644689 86a 13a 108a 76a 169a la 24a 36a 94a 104a 21a 97a 8.64468979a 13a 76a 120a 169a 1a 263 36a 94a 104a 21a 97a 8.64468979a 13a 1083 763 69a h1a 703 24a 36a 94a 104a 21a 8.64468913a 1083 76a 20a 1693 703 26a 243 36a 943 1043 97a 8.717949 86a 79a 108a 763 20a 169a 26a 36a 94a 11043 21a 97a 8.717949,86a 1083 203 693 113 703 1263 24a 36a 943 104a 97a 8.71794986a 793 133 108a 76a 692 h1 a 26a (36a 94a 104a 97a 8.717949 863 793 133 108a 693 1 a 70a 1263 24a 36a 104a 97a 8.71794979a 133 1083 20a 69a 1702 262 36a 943 104a 21a 97a 8.71794 86a 793 763 20a 69a 1 a 126a 42 36a 94a 1043 97a 8.717949186a 79a 1133 1083 768 69a (1 a 1263 24a 94a 11043 97a 8.71794986a13a 1108a 76a 169a 170a 26a 24a 36a 104a 121a 97a 8.717949 86a 79a 13a 76a 20a I69a 1 a 26a 94@1104a 121 a 197a 8.717949(79a 13a 108a 76a 20a11a 170a 26a 36a 104a 121a 97a 8.791209862792 13a 20a 692 1a 70a 26a 124a 36a 1104a 972 8.79120986a79a 13a 1108al76a 69a (1a 70a 24a 36a 104a _21a 8.791209 79a~108a 76a 20a la 70a 126a 24a 36a 94a 1104a 97a 8.791209 86a 79a 13a 108a 76a 1 a 26a 24a _36a 104a 121 a _97a 8.79120986a~13a 108a 76a 70a 26a 24a 36a 194a 104a 121a 97a 8.791209 79a 13a 108a 176a 20a 69a 170a 26a 36a 94a 1104a 197a 8.791209,86a 79a 13a 1108a 76a 69a ~1a 26a 24a 36a 21a 97a 8.791209 86a 13a 108a 76a 69a 170a 24a 36a 194a 104a 121a 97a 8.79120986a79a 13a 1108a76a 69a 1a 26a 124a136a 104a197a 8.791209 86a 13a 1108a 120a 69a 11 a ~70a 126a 36a 104a 121a 97a 8.79120913a 108a 76a 69a 1a 170a 126a 24a 3 6a 94a 104a 121 a 8,79120 86a 13a 108a ~76a 120a 69a la 26a _24a 36a 1104a 197a I
8.79120979a 13a 108a 76a 169a _Ia 70a _26a 24a 94a ~104a 21 a 8.7 6al13a 1108a 176a 120a 1 a 170a 26a 136a 104a 21 a 97a 8.791209186a179a _13a 176a 20a-169a _70a 36a 94a 104a 21a 97a 8.791209792132 108a 20a Ila 170a 126a 36a 94a 104a 21a 197a 8.791209186a 79a 113a 108a 76a _Ia 170a 126a 24a 36a 194a 1104a 8.864469 86a 79a 13a 1108a 76a 1 a 126a 24a 36a 94a 104a 197a 8.864469 86a 79a 13a .169a I1 a 170a 26a 24a 36a 94a 121 a 197a 8.864469 86al79a 13a 176a 120a 69a 1 a 170a 2621104a 297a 8.86446986a 79a 13a 108a 76a 692 _70a 36a 94a 104a 21a _97a 8.864469 79a 76a 69a la 70a _26a 124a 36a 194a 104a 21a 97a 8.86446986a79a 13a _108a 69a 18 J70a 26a 136a 94a 104a 21a 8.86446986a79a 132 _76a _20a ~1a 70a 26a 124a 36a _104a 97a 8.86446918621792 108a 76a 169a 1 a 70a 26a 124a J36a 104a 97a 8,86446979a 13a 108a 76a _20a 69a 1a 26a 24a 36a 194a 104a 8.864469 86a 79a 13a 108a 762 1 a 24a 36a 94a 1104a 21 a 97a 8.864469793108a 76a 120a 69a 11a 1262 136a 194a 104a 21a 97a 8.864469 86a 19a 13a 108a 76a _20a _70a 36a 94a 104a 21 a 97a 8.937729179a 108a 76a la 170a 224a 394a 104a 21 a 97a 8.937729186a 79a 108a 176a 169a 1 a 26a 24a 36a 94a 121 a 97a 8.937729186a 79a 13a _76a 20a 169a j70a 126a 36a 104a 21 a 97a 8.937729 86a 79a 113a 76a 20a 69a 1 a 26a 24a 36a _94a 104a-8.937729 86a 79a 20a 69a 1 a 70a 26a 24a 136a 94a 104a 97a 8.937729 86a 79a 13a 108a 69a la _70aj26a 242 362 21 a 97a 8.937729 86a 79a 13a 76a _69a _la 26a 24a 36a 94a 104a 972 8.93772986a 108a 76a 20a 1a 70a 26a 36a 94a 104a 21a _97a 8.93772986a 79a 13a 108a 76a 69a 1a _26a 94a 1004a 21a 97a 8.937729 86a 13a 108a 76a 20a la 702262 36a 94a 104a 97a 8.937729 862 79a 13a 1082176a 20a 70a 26a 36a 104a 21 a _97a 8.937729868798 132108a176a Ila 26a 36a 94a 104a 21a 97a 8.937729179a 13a 1108a 76a 69a la 70a 26a 24a 36a 21a 97a 8.93772986a13a 108a176a 20a 1a 70a _26a 24a 36a 104a 97a 8.93772986a 79a _13a 108a 20a 69a 70a 26a 24a 362 J104a 97a 9.010989186a 79a 13a 108a 209 69a h1 a 709 269 369 949 104a 9.010989I86aI79a 13a 108a 69a 1 a 709 24a 36a 104a 21a 97a 9.010989139 10$a 769 20a 69a 1 a 708 26a 36a 94a 104a 97a 9.010989799 13a 1089 76a 20a 69a 1a 1709 26a 36a 104a 97a 9.010989799139 20a 69a 1a 709 26a 1249 36a 94a 104a 97a 9.084249 869 799 13a 1089 209 169a la 26a 249 369 94a 104a 9,08424913a 108a 76a 69a la 26a 24a 36a 94a 104a 21a 97a 9.084249179a 13a 108a 76a 209 69a 19 26a 36a 94a 104a 21a 9.0842491869 13a 769 20a 69a 1 a 709 26a 36a 104a 21 a 197a 9.084249 869 79a 113a 108a la 70a 126a 36a 194a 104a 21 a 97a 9.08424979a 13a 108a 20a 1699 I1a 126a 24a 36a 94a 104a 97a 9.084249186a 13a 108a 76a 699 1a 170a 26a 24a 104a 21a 97a 9.084249 869 799 108a 76a 20a 69a la 6a 136a 1949 21 a 97a 9.084249~79a 139 108a la 70a 26a 124a 36a 949 104a 21a 979 9.08424979al13a 1108a 69a I1a 70a 26a 24a 369 94a 21a 97a 9.15750986al79a 13a 769 20a 169a 26a 249 369 194a 1104a I97a 9.15750986a 13a 1083 699 is 170a 262 24a 36a1104a J21a 97a 9.1575098627931138 1082 76a 698 1 a 24a 36a 1104a 121 a 197a 9.157509 8079a 13a 76a 20a 69a 1 a 70a 26a 36a 104a 21a 9.15750986aj79a 1139 76a 1699 70a 124a 36a 94a 104a 21a 97a 9.157509 868 1089 769 20a 69a la 26a 36a 94a 104a 21 a 97a 9.157509186a 79a 13a 1089 20a 69a 70a 26a 36a 94a 104a 21a 9.15750986aJ79a 1108a 76a 20a la 70a 26a 36a 194a 1104a 97a 9.157509 869 799 133 106a 769 1 a 70a 26a 24a 36a 104a 97a 9.157509,179a 13a 1089 76a 209 la 709 26a 24a 36a 94a 104a 9.157509186a 799 13a 76a 69a la 26a 24a 36a 94a 21 a 97a 9.23076986a 79a 13a 76a 69a 1a 70a 26a 24a 369 104a 97a 9.230769 869 79a 13a 1089 76a I1 a 26a 24a 136a 94a 1049 21a 9.23076986a0a 13a 108aj76a 69a 1a 269 2491049 21a 97a 9.230769 86a 79a 108a 209 69a la 26a 249 36a 949 104a ~97a 9.230769 86a 139 108a 769 209 69a jla 269 369 104a 121 a 97a 9.23076986a79a 13a 11 082120a 692 170a 269 249 _36a 194a _104a 9.23076986a 139 76a 20a 169a 1a _70a 26a 369 949 1049 97a 9,230769186a 79a 13a 20a 69a la 709 26a 36a 94a 21 a 97a 9.23076 13a 1089 20a 69a la 70a 262 369 194&1104a 21a 97a 9.230769186a 79a 13a 1089 76a 20a _70a 126a 136a 94a 104a 97a 9.230769186a 79a 13a 108a 769 699 70a 24a 94a 104a 21 a 97a 9,230769 86a 79a 13a 76a 20a 69a 70a 26a 36a 94a 104197a 9.23076986a79a 108a 769 20a 1a 70a 26a 36a 94a 1049 21a 9.230769 86a 13a 108a 76a 20a 69a la 26a 369194a 104a 97a 9.304029 869132 108a 76a 20a 70a 26a 24a 36a 94a 104a 97a 9.304029186a 79a 13a 108a 76a 20a 69a 70a 249 _36a 104a 97a 9.304029186a 79a 13a 69a la 70a 26a 24a 949 104a 121a 979 9.30402986a 13a 1108a 76a 20a J69a 170a 26a 369 949 104a 97a 9.304029 i-3a,-10-8-a7769 69a 70a 26a 249 136a 94a ~104a 121a 97a 9.304029 869 79a 113a 1089 769 209 699 26a 249 369 1049 97a 9.304029 869 799 139 1089 769 209 699 1 a 709 369 1049 97a - 79 9.3040291863179a 113a 11083176a 20a 69a 1363 194a1104a 213 97a 9.30402 86213a 1108276a 69a la 126a 24a 363 104a 121 a 197a 9.304029179a 13a 108a 76a 20a 169a 1 a. 70a 262 36a 1043 21a 9.304029 86a 79a 13a 108a176a la 1703 263 36a 1043 21 a 97a 9.304029186a 79a 1108a 76a I1 a 70a 26a 24a 943 104a 121a 97a 9.304029 86a 79a 108a 76a 120a 1 a 170a 263 24a 36a 104a 97a 9.3772917921108a 69a -I@ 170a 26a 124a 36a 94a 1043 121 a 973 9.377291863 13a 176a 20a 169a 13 26a 242 36a 94a 104a 97a 9.3772913a1768 169a 1a 1702 26a 1242 136a 94a 104a 21a 97a 9.37729 86a 79a 13a 1693 11 a 70a 126a ,36a 1943 104a 21 a 197a 9.3772986a113a 108a 76a 20a 169a Ila 170a 126a 36a 11043 97a 9.377298621792 13a 76a 203 1a 703 263 36a 94a 1104a 197a 9.377291793 133 176s 20a 69a 11a 70a 26a 1362 94a 11043 121a 9.37729 863 79a 133 11082 69a 112 70a 24a 136a 94a 104a 121 a 9.37729 86a 79a 133 76a 169a 11 a 170a 1263 363 1943 1043 97a 9.37729 868179a 113a 176a 20a 1 a 170a 26a 1363 11042 121 a 1972 9.3772986a113a 76a 118 J70a 126a 124a 136a 194311043 121a 197a 9.37729863 79a 13a 1108a176a la 170a 126a 136a 194a 1104a 197a 9.45054986a79a 113a 176a 20a 169a ~la 126a 136a 942 1213 197a 9.450549 79a 133 1083 20a la 170a 26a 24a 136a 1943 1043 97a 9.450549862I79a 11083 203 69a 1a 703 26a 124a 36a 1043 197a 9.450549 79a 11 3a 1108a 20a 69a 11a 70a 26a 124a 136a 104a 197a 9.450549 8621138 176a 203 1 a 170a 126a 362 1943 11043 12-1a 97a 9.450549 86a 79a 138 69a 703 1262 124a )36a 94a 104a 121 a 97a 9.45054 86a 79a 113a 76a 69a 1 a 24a 136a 194a 104a 21a 197a 9.45054918681132 108a 76a la 170a 126a 124a 94a 104a 21a 97a 9.523809 86a 79a 108a 20a 69a 170a 1263 36a 94a 1043 21a 97a 9.523809 86a 79a 113a 108a 69a 70a 26a 1242 1943 104a 21a 97a 9.523809 868 79a 1083 76a 69a la 126a 24a 36a 104a 21a 97a 9.523809 869 79a 13a 76a 120a 69a 1 a 70a 36a 1043 21a 97a 9.5970779a 13a 108a 76a 120a 12 26a 124a 36a 94a ~104a 197a 9.59707186a 13a 76a 20a 69a le 126a 36a 194a 104a 21 a 1973 9.67033863 79a 108a 76a 69a 1 a 703 26a 36a 94a 1043 97a 9.67033 86a179a 13a 108a 76a 20a 1 a 126a 24a 36a 94a 104a 9.67033 863 79a 113a 1089120a 1 a 70a 126a 36a 94a 104a 121 a 9.67033 863 793 13a 1083 69a la 263 363 943 11 21a 97a 9.67033 79all 36 1108a 203 69a 1a 70a 26a 363 94a 104a 21a 9.67033 86a 133 1089 76a 20a 70a 26a 36a 94a 1043 21 a 97a 9.67033 86a 79a' 763 20a 69a la 70a 26a 36a 94a 21a 973 9.67033 863 133 176a 20a la 70a 263 243 36a 94a 1043 973 9.67033 863 793 13a 108a 76a 69a la 26a 24a ~36a 94a 21 a 9.67033863 79a 133 11083 703 26a 24a 36a 94a 104a 21a 97a 9.67033 86a 79a 13a 1083 20a 69a 70a 126a 36a 104a 21 a 97a 9.67033 86a 792 13a 1083 20a 69a la 263 24a 1363 1104197a 9.743589 86a179a 133 108a 69a la 26a 24a 94a 104a 121 a 97a 9.743589 867a,7 98 13a 108a 763 169a 126a 24a 36a 1104a 121 a 97a 9.743589 863 793 1133 203 693 11 a 1703 26a 243136a 194a 104a } q, {
r' :xr-.Ffeltll a ~>. 1! ~'=1. a = 5i. ~~.i7 ~~g=- ~:, _ ~
9.743589866 793 136 11086 202 69a la 126a 136a 94a 104a 97a 9.74358 86a1798 13a 76a 169a 170a 126a 124a 94a 104a 21 a 97a 9.8168586a179a 1108a 76a 13 1706 26a 24a 36a 94a 1104a197a 9.81685 866 13a 108a 206 69a la 170a 26a 1366 94a 1046 97a 9.81685 86a179a 108a 20a 69a la 70a 26a 36a 94a 1104a 97a 9.81685 86a 79a 13a 76a 69a 1 a 70a 126a 124136a 121 a 97a 9.81685186a 79a 13a 108a 76a 20a 126a 136a 194a 1104a 21 a 97a 9.816851866 136 76a 169a 170a 26a 24a 136a 194a 1046 21 a 97a 9.81685862179a 136 1086 1a 70a 26a 124a 36a 94a 104a121a 9.816851866 79a 1136 1086 76a 120a 69a 170a 368 94a 1046 97a 9.81685186a179a 113a 108a176a 20a 1a 268 124a 36a 1104a 197a 9.816851866 79a 113a 108a120a 169a 70a 26a 36a 94a j104a 197a 9.816857961136 1086 766 1a 26a 242136a 94a 1046 21a 97a 9.890111866796 76a 69a I1a 170a 262 136a 94aj104a 121a 197a 9.890111866 793 136 1086 76a 120a 692 126a 136a 1104a 121 a 197a 9.890111869113a 1086 1a 706 26a 24a 136a 941104a 212 97a 9.8901118661796 113a 120a 69a la 70a `26a 1366 94a 104a 97a 9.89011.866 136 1086 76a 20a 69a 26a J24a 136a 194a 1104a 97a 9.89011186a179a 13a 1108a176a 69a 1a 1266 2461366 104a 21a 9.890111796 136 176a 202 698 1a 170a 1266 36a 104a 121a 197a 9.89011 86a 108a120a 69a la 170a 126a 136a 94a 104a 21a 197a 9,9633786a79a 76a 696 1la 170a 126a 1248 366 104a 21a 97a 9.9633717961136 1086 20a 69a la 170a 126a 136a 94a 104a 97a 9.96337866 79a 1086 766 169a la 126a ,246 136a 94a 1046 21a 10.03663113a 108aJ20a 69a 11a 706 126a 24a 136a 94a 1046197a 10.03663186a 79a 13a 108a 69a 26a 24a 136a 94a 104a 21a 197a 10.03663186a 796 1086 696 12 70a 26a 124a 136a 94a 104a 121 a 10.03663186a 796 1136 108a11 a 1706 26a j24a 136a 1104a 121 a 97a 10-03668!86a 79a 1108a 69a 1 a 1706 26a 124a 1366 1104a 121 a 976 10.036631866 13a 11086 76a 11 a 126a 124a 136a ..194a 104a 21 a 97a 10.0366379a133 108a 69a 1706 126a 124a 136a 194a 104a 21a 97a 10.03663 86a 79a 13a 108a l76a 11 a 1266 124a 194611046 21a 97a 10, 10989 86a 79a 136 108a120a 69a 126a 1366 194a 1046 21 a 97a 10,10989186a 79a 13a 1086 766 206 1 a 1266 36a 1946 1046 97a 10.10989186a179a 13a 20a 16 70a 126a 136a 94a 1046 21 a 197a 10.10989796 136 108a 76a 69a 1a 70a 26a 246 366 946 21a 10.10989796 13a 108a 76a 69a 1a 126a 24a 366 94a 21a 97a 10. 10989 86a 13a 20a 696 la 70a 26a 366 94a 104a 21a 97a 10.1098979a 108a 20a 69a la 70a 26a 366 94a 104a 121 a 97a 10.18315 866 79a 13a 76a 69a la 262 24a 194a 104a 121a 97a 10.1831586a179a 13a 76a 169a la 706 26a 24a 366 1104a 21a 10.1 831 51866 79a 13a 1086 76a 20a 69a 26a 36a 94a 104a,9 a 10.1831586a79a 108a 20a 69a la 70a 26a 36a 94a 104a 21a 10.1 B315 866 796 113a 176a 20a 69a 26a 366 946 104a 21 a 976 10.256411868 79a 1108a 76a 20a 1a 706 26a 36a 104a 21a 97a 10.25641 86a 796 13a 76a la 26a 24a 36a 194a 104a 21a 197a 10.25641 86a 796 1086 768 I18 706 26a 36a 194a 104a 216 976 RFetd?!~5 ' . i-IM, 10 .0 10.25641186@179a 13a 108a 202 1a 17Oa 126a 124a 36a 194a 1104a 10.2564186@ 132 1082 j76a 20a 1 a 126a 124a 36a 94a 104a 197a 10.2564186a 79a 13a 108a 69a 70a 26a 24a 36a 104a 121 a 197a 10,25641 79a 1082 76a 202 69a 1a 70a 26a 36a 1042 21a 97a 10.2564186a 79a 13a 1 a Oa 26a 24a 36a 94004a 21 a 97a 10.2564186@ 13a 1082120@ 9a 70a 26a 1242 36a 94a 1042 97a 10,3296786a79a 69a Ala 70a 26a 24a 36a 94a 104a 21a 197a 10.3296786a 79a 13a 1082 76a 20a 698 70a 3621104@ 121 a 1978 10.3296786a 13a 76a 69a la 70a 126a 24a 94a 104a 21a 97a 10.32967 86a 79a 13a 176a 69a 70a 26a 24a 136a 1042 21a 1978 10.3296786aJ79a 113a 1108a 202 702 26a 24a 362 94a 11042 197a 10. 32967 86a 79a 13a 1108a 69a 70a 24a 36a 194a 104a 121 a 97a 10.3296786@ 79a 13a 176a 69a 1a 170a 26a 1248 104a 121a 197a 10.3296786al13a 120a 169a 1a 70a 126a 24a 1362 94a 1104a 97a 10.40293792 13a 1108al76a 69a Ila 26a 124a 136a 104a 21a 97a 10.4029379@ 132 1082 76a 1a 70a 26a 124a 136a 94a 11042 21a 10.4029386279@ 13a I76a 69a la 70a 24a 36a 104a 121a 197a 10.40293186a 79a 108a 176a 12 +702 126a 24a +36a 94a 1104a 121a 10.4029386a 13a 108a120a 69a 112 1268 124a 136a 94a 104a 197a 10.4029386a 13a 108a 20a I1a 170a 126a 124a 36a 94a j104a 197a 10.4761979a 13a 108@ 76a 120a 169a la 26a 3621042 21a 972 10.47619 86a 13a 176a 69a 1 a 26a 24a 36a 94a 104a 21a 197a 10.4761986@ 79a 13a 1082 1 a 126a 24a ~36a 94a 1104a 21 a 97a 10.47619 86a 79a 13a 176a 202 69a 1 a 126a 24a 1362 104@ 197a 10.47619 86a 79a 113a 176a 1 a 170a 26a 124a 36211048 12.1 a 97a 10.4761979a108a76a 169a 1a 26a 124a 136a 94aJ104a 212 197a 10.54945 86a 79a 13a 108a 76a 69a 1 a 124a 94a 1048 21a 97a 10.54945186@ 132 1082 20a 69a I70a 126a 36a 94a 104a 21 a 97a 10.54945186a 79a 113a. 108@ 76a 69a l26a 124a 194a 104a 21 a 97a 10,5494586@ 79a 113a 106a 76a 1698 24a 136a 194a 1042 21a 972 10.5494513a 1082 69a 1a 1702 26a 124a 36a 94a 104a 21 a 97a 10.6227186@ 792 11082 768 20a 1 a 126a 242 136@ 942 104a 97a 10.6227186all3a 76a 69a Ala 702 262 24a 136a 104a 212 197a 10.6227186@ 79a 13a 76a 20a la 26a 24a 36a 942 104@ 97a 10.62271792 13a 108@ 76a 69a ~la 170a 262 24a 36a 104a l21a 10.6227186a79a 13a 762 20a 1a 126a 36a 94a 104a 21a 97a 10.6227186a79a 132 108@ 69a la 170a 26a 36a 104a 21a 972 10.62271 79a 13a 108a 20a 692 1a 26a 36a 942 104a 21a 97a 10.6227179a 13a 20a 692 1a 702 26a 36a 942 104@ 21a 97a 10.62271166a 792 13a 76a 20a 69a 1 a 170a 26a 94a 104a 97a 10.69597186a 79a 76a 20a 69a la 702 126a 36a 104a 212 197a 10.6959 862 792 13a 762 692 262 242 362 194a 1043 21 a 197a 10.6959786a 79a 13a 108@ 762 20a 1 a 262 136a 104a 21 a 197a 10.69597186@ 13a 108a 76a 69a la 262 1242 1942 104a 21a 97a 10.6959786a 79a 108@ 76a 20a 69a la 170a j26a 36a j104a 97a 10.7692386a 13a 108a 76a 69a 26a 24a 362 942 104a 21a 97a 10.76923186a 79a 13a 108@ ~2Oa 1 a ~26a ,24a 36a 94a 104@ 972 -r - Id -.1 F : bv' x j, fir, ~. v, 1!, P21, 10.76923~86a179a 768 69a la 268 124a ~36a 194a 1048 21 a 197a 10.76923 86a 798 13a 108a 76a 169a la 170a 26a 136a 110421972 10.84249 86a 79a 108a 76a 208 1 a 1708 26a 24a 1368 94a 11048 10,8424986a 79a 13a 20a 169a 1a 26a 1242 368 =948 1048 97a 10.91575 86a 79a 108a 76a 69a 1 a 26a 368 194a 104a 21a 97a 10.9157586a79a 13a 20a la 70a 26a 24a .. 6a 94a 104a 97a 10.98901 86a79a 13a 76a 1202 169a 1a 126a 136a 94a 1104a 21a 10.98901868 79a 13a 108aj20a 69a la 262 136a 94a 1048 21a 10.98901 86a 13a 108a 20a la 70a 26a 36a 94a 104a 121a 197a-11.06227 86a 79a 13a 76a 120a 69a 18 26a 36a 94a 104a 197a 11.0622786a 79a 138 10800a 1a 70a 26a 124a 36a 104a 197a 11.06227 868 1318 108a 69a 70a 26a 24a 36a 94a ~104a 21a 197a 11.06227,86a 79a 113a 76a 69a 1 a ~26a 36a 94a 104a 21a 97a 11.0622786a~79a1088 69a la 126a 124a 36a 194a 104a 121a 97a 11.06227 86a 79a 108a 76a 11a 1268 24a 1368 94a 1048 121a 197a 11.0622786a 79a 113a 108a169a 70a 126a 124a 36a 94a 11048 212 11.13553868 79a 108a 76a 1208 119 26a 36a 94a 104a 21a 97a 11.13553186a 132 1108a 768 208 69a 26a 36a 948 1048 21a 978 11.1355386a 13a X1088 768 169a 1708 26a 242 194211048 I21a 197a 11..13553798 1088 768 698 ~1a 170a 224a 36a 94a ~104221a 11.20879186a 798 108a 1a 1708 126a 24a 36a 1948 104a 121a 1978 11.20879 868 798 138 768 208 69a 1 a 708 26a 36a 11048 97a 11.2087986aj79a 138 1088 208 70a 26a _36a 94a 104a 121a _97a 11.20879798138 _76a _698 1a 70a 268 248 36a 104a 121a 97a 11.20879868798 [108a 76a 69a _la 26a 124a 948 11048 I21a 97a . ' 11.28205 86a 798 13a 108a 20a 69a 1 a _70a 268 368 1048 211.2820586a 13a 1108a 698 la 170a.26a 248 194a 104a 1221a 97a 11.28205 8681798 120a 1692 1 a 708 268 36a 1948 104a 1218 978 11.3553186a179a 138 108a 20a Ila 708 26a 13621104a 21a 197a 11.35531868 798 113a 1088 69a la 26a 124a ~3621048 21 a 97a 11.35531 8681138 1088 76a 20a 1a 26a 1368 948 1048 21a 97a 11.3553186a79a 108a169a 1a 70a 26a 368 948 1048 21a 978 11.42857.86a 798 768 20a' 69a la 268 136a 1948 11 21 a 97a 11.4285786a 79a 13a 108a 208 la 70a 126a _36a 94a 11048 97a 11.5018386a 13a 169a la 170a 268 248 _36a 94a 1048 21a 978 11.50183 86a 798 108a 20a 1 a 70a 26a 248 36a 948 11048 978 11.50183 86a 79a 106a 76a 20a 699 1 a 268 36a 1048 121 a 19a 11.50183 86a 79a 13a 108a 76a 69a la 26a 36a 11048 218 97a 11,5750986a 138 1088 20a 69a is 26a 36a 941104a (218 978 11,6483586a 138 1088 698 1a 26a 124a 36a _94a 104a 21a 97a 11.72161 86a 79a 13a 1088 20a 69a 1 a 70a 26a 36a 104a 97a 11,7216186aI792 1138 1208 69a 1a 1702 26a _36a 104a 21a 97a 11.7216179a 13a 1088 69a 1a 70a 26a 24a 136a 104a 21a 97a 11.72161 868 798 1088 76a 69a la 70a 268 36a 104a 21a 197a 11.7948786a79a 13a 108a~76a 20a la j70a 126a 36a l04aj97a 11.86813 79al138 110881208 698 la 708 268 36a 1048 21 a 197a_ 11.94139186a 798 138 176a 169a l a 170a 1268 368 11048 21a 197a 12.01465186a 79a 132 108a 202 1 a 262 1362 194a 104a 21 a 197a 12.01465 86a 79a 1132 1082 76a 120a 1692 (7.Oa 26a 36a 1042 97a 12.01465186a 79a 113a 108a 76a 69a 702 (24a 36a 1042 21a 97a 12.08791862 79a 1132 108a 76a 120a 69a la 26a 36a 104a 97a 12.08791 86a 79a 13a 108a 202 69a 1 a 126a 36a 104a 21a 972 12.16117 86a 79a 13a 202 (69a 11 a 70a 26a 36a 94a 104a 21a 12,30769186a 79a (108a20a 69a 12 70a 26a 36a 104a 21a 97a 12.45421 86a 79a 113a 76a 169a la 26a 24a 36a 94a 104a 21a 12.60073186a 79a (13a 108a 69a 1a 126a 24a 36a 1942 104a 21a 12.6007379a 13a 76a 69a 12 26a 124a, 36a 194a 104a 21a 97a 12.74725186a 79a 113a 1082 692 1 a 170a 26a 242 36a 104a 121 a 12.74725179a 13a 176a 69a l a 702 263 24a 36a 94a 104a 21 a 12.8937779a 13a 1108a1692 (1a 26a 124a 36a 94a104a 212 97a 12.89377186a 79a 11082 J20a 1692 1 a 126a 36a 94a 104a 21a 97a 13.1 1 3551862 79a (132 120a 169a (1 a 126a 36a (94a 104a 121 a 197a 13.1868186a79a 1108a 20a is 170a 26a 136a 194a 104a 21a 1972 13.26007(862792 132 69a I1a 70a 126a 24a 136a 1042 21a 197a 13.260071868(79a 13a 1082 76a 20a 170a 126a 24a 94a 21a 97a 13.33333862792 13a 169a la 70a 26a 24a 36a 94a 104a 21a 13.62637 86a 108a 176a 120a 69a 1 a 70a 26a 24a f 94a 21a 97a 13.69963 86a 79a 132 108a176a 20a 1 a (70a 26a 24a 121a 97a 13.77289792 13a 11082 692 la 70a 262 24a 36a 94a 104a 21a 13.7728986a792 11 1108a 76a 120a h1a 70a 26a 24a 104a 21a 13.77289 86a 79a 113a 1108a 76a 20a 170a 262 242136a 21 a 972 13.772891862 79a 132 176a 202 69a I1 a 26a 36a 104a 21 a 97a 13.84615186a 79a 13a 1108a1 66a 2-6a ]70a 24a 36a 94a 21a 97a 13.84615 86a(1 08a 76a 20a 69a la 1702 24a 136a 94a 21 a 197a-13.8461586a-13a 1082 76a 202 la 70a 26a 24a I94a 21a 97a 13,99267792 1082 762 120a 692 702 26a 24a 362 942 21a 97a 13,9926786a(79a 1132 762 202 la 1702 262 24a 194a 21a 97a 13.992678621Oea176a 208 69a {1a 702 262 24a 36a 21a 97a 14.06593 86a 792 1132 692 la 126a 1242 36a 94a 104a 21a 97a 14.13919 86a 79a 13a 1108a 203 12 702 26a 24a 94a 21a 97a 14.21245186a 1088 76a 20a 692 1 a 70a 124a 36a 94a' j104a 21.a 14.21245868793 13a 762 208 1 a 1702 1242 36a 94a 21a 97a 14.28571862 79a (13a 6a 69a 1 a 26a 24a 36a (1042 21a 97a 14.2857186al3a 108a 76a 202 692 1a 26a 242 362 121a 97a 14.2857179a 1082 76a 202 692 702 24a 36a 94a (1042 21a 14.3589779a 132 108a 76a 20a 70a 26a 242 362 94a 1219 972 14.3589779a 13a 108a 76a 20a is 702 6a 24a 104a 212 97a 14.43223 86a 792 108a 20a 69a 11a 1702 24a 36a 94a 21a 97a 14.4322 86a 108a 76a 20a 69a (1 a 1702 6a 242 36a 1042 21 a 14.43223 86a 79a 108a 762 20a 69a 1 a 70a 1262 242 104a 21 a 14.50549 86a 79a 1082 203 69a 1 a 70a 26a 24a 94a 21a 97a 14.50549 86a 79a 13a 108a 202 l a 702 24a 36a 94a 21a. 97a 14.57875 86a,13a 108a 76a 20a 1a 70a 26a 24a 36a 212 97a 14.57875 792 13a 1692 1 a 70a 26a 24a 362 942 104a 2l a 197a ~3~F.~e d. x rte, `n7.
14.578751793108a176a 20a 169a 1a 70a 126a 241104a 21a 197a 14.6520186a 1088 768 208 69a 1 a 708 24a 368 1048 21 a 197a 14.6520186a13a 10831763 20a la 0a 243 36a 194a 21a 197a 14.72528 86a 79a 13a 10076a 120a la 26a 24a 136a 121 a 97a 14-.7252886a79a 108a176a 1208 169a 170a 124a 36a194a 121a 97a 14.72528 86a 79a 13a 108a 762 20a la 70a 24a 36a ' 1212 197a 14.79853 86a 76a 208 1698 1 a 70a 24a 36a 94a 1104a 121 a 197a 14.79853 86a 138 10821763 20a 169a la 170a 1248 363 94a 121a 14.79853 86a 79a 1132 1108a 76a 208 69a 708 26a 24a 94a 121a 14.79853 86a 79a 13a 108a 76a 1202 69a 11 a 70a 126a 24a 21 a 14,7985386a113a 108a 76a 20a 69a is 24a 1368 942 121a 97a 14.871 79 103176a 20a 69a la 70a 126a 24a 136a 194a 21a 197a 14.87179868798 108a176a 1208 169a 170a 268 24a 94a 104a 21a 14.87179 86a 79a 138 1108a176a 20a 169a 70a 26a 24a 36a 121a 14.87179 86a 79a 1138 108a176a 20a 70a J'262 24a 104a 21 a 1978 14.87179 86a 79a 1768 1208 1698 la 170a 124a 1368 94a 1104a 121 a 14.94506868138 108a176a 120a 69a la 1708 26a 24a 194a 121a 14.9450686a113a 108a 76a 20a !la 170a 26a 24a 36a 1104a 21a 14.945061138 108aj76a 208 la 70a 126a 24a 136a 194a 121 a 97a 14.94506186a 13a 1108a 76a 20a 169a la 70a 26a 24a 36a 21 a 15.01832 86a 138 10881768 208 69a la. 26a 1248 94a 21 a 97a 15.0183218631138 108a i76a 20a 169a 170a 24a 36a 94a 21 a 97a 15.09157186a 79a 1138 1108ai76a 120a la 26a 243 94a 121a 197a 15.09157108 76a 120a 1698 (1 a 170a 124a 36a 948 104a 121 a 97a 15.16483186a~79a 138 1108a176a 1208 170a 26a 1248 943 104a 21a 15.164837868 798 108a 762 120a ;698 70a 26a 1248 1048 21a 97a 15.16483186a1108a176a 20a 169a 1a 70a 26a 248 94a 104a 21a 15.16483868 79a 113a 108a 76a 20a 169a 70a 24a 36a 94a 21a 15.16483186a 798 108a 176a 1208 698 170a 26a 248 368 21a 97a 15.16483186a 138 108a 768 20a Ila 170a 24a 36a 94a 104a 121a 15.16483 86a 79a 176a 20a l a 170a 124a 36a 94a ,104a 21a 97a 15.16483 86a 798 138 1108a176a 20a 11 a 124a 368 94a 21a 97a 15.2381 86a 13a 11088 1768 120a 69a la 70a 248 94a 21a 972 15.2381 868 798 138 108a 176a 20a la 1708 26a 124a 94a 21a 15.2381 86a 79a 13a 1088 768 208 69a 170a 268 24a 1048 21a 15.2381 86a 79a 13a 108a 76a 1208 69a 708 124a 94a 104a 21a 15.2381 86a 79a 1082 76a 20a 169a 70a 26a 124a 94a 21a 97a 15.2381 86a 798 1088 76a 20a 69a 70a 1248 36a194a 104a 21a 15.2381868 798 1088 76a 20a la 708 268 248 948 21 a 97a 15.31136186a 108a 768 20a 69a la 708 24a 948 104a 21 a 97a 15.3113679a 138 1088 76a 20a 698 70a 268 248 363 94a 21a 15.31136179a 138 108a 76a 208 70a 24a 36a 948 1048 21 a 97a 15.31136186a 79a 13a 76a 208 la 708 26a (248 368 21 a 97a 15.38461868 798 1088 768 208 698 la 708 26a 248 94a 121a 15.38461 868 138 11088 76a 20a 69a 70a 126224a 948 21 a 97a 15.38461 79a 1088 202 692 1 a 70a 24a 36a 94a 104a 121 a 978 15.38461 86a 13a 1108a l76a 202 1 a 70a 26a 248 948 1048 21a SFle.ld1'x1~si 15.38461186a179a 113a 76a 120a 169a 1 a 170a 26a 1248 948 21 a 15.38461 86a1798 13a 10881768 20a 1a 708 26a 24a 36a 121a 15.38461 868108a176a 20a 698 170a ~26a 24a 36a 104a 21a 97a 15.38461 86a 798 13a 1768 1208 169a 7l a 170a 24a 36a 94a 121 a 15.38461798 76a 20a 69a h a 170a242 136a 94a 104a 21 a 97a 15.45788868 798 113a 76a 120a 11 a 170a 24a 368 1942 11048 21 a 15.45788186a79a 1108a 76a 20a 169a 1708 6a 124a 36a 1042 121a 15.45788 86al13a 1108a176a 120a 69a 1a 70a 24a 94a 104a 121a 15.4578879813a 108a1768208 69a 26a 124a 36a 94a 121a 197a 15.45788 86a 1088 76a 208 69a 1 a 1708 26a 24a 104a 212 97a 15.4578886a 13a 76a 20a 69a 11-a 70a 24a 36a 194a 21a 97a 15.457881798 1088 76a 120a 69a 118 70a 24a 368 94a 21a 97a 15.45788 86a 13a 108a 76a 20a l69a 70a 26a 124a 36a 21a 97a 15,531148681138 1108a 768 208 69a 1a 70a 26a 24a 1048 21a 15.53114186a 1088 768 20a 69a 702 24a 136a 94a h104a 121 a 197a 15.5311479a 138 108a 176a 202 11 a 1708 1262 124a 1948 21 a 97a 15.5311479a 10881768 120a 169a 1708 268 248 36a 194a 1042 ,218 15.53114 868 79a 1138 1088 768 208 la 170a 24a 194a 121 a 197a 15.53114 8681798 11088 762 120a 698 l a 170a 124a 136a 194a 1218 15.53114179a1108a176a 1208 169a 11a 1708 124a 368 1048 21a 97a 15.531147981138 1088 768 208 69a 1a 268 24a 1048 21a 97a 15.53114 798 133 1088 76a 20a 69a 1 a 708 268 24a 11048 21a 15.53114179a113a 1088 768 208 698 708 248 948 1048 21a 978 15.60448681798 1108a 76a 208 69a 1a 170a 26a 24a 21a 978 16.6044868 138 1088 208 1698 1a 170a 26a 124a 36a 1218 97a' 15.6044 86a 79a 13a 1088 76a 120a 169a 18 708 248 136a 121 a 15.604413a 108a 76a 20a 698 1 a 126a 24a 1368 94a 121 a 97a 15.604 86a179a 113a 1088 768 20a 1a 708 24a 36a 94a 21a 15.60 79a 138 76a 20a I1a 170a 24a 136a 194a 104a 21a 97a 15.604486a 798 13a 108a 20a 169a la 248 J36394a 21a 97a 15.604413a1108a 768 208 69a 1la 170a 248 948 1048 218 97a 15.6044 86a1792 (108a I76a 120a 169a 1 a 70a 124a 36a 121 a 97a 15.677661868 798 138 1088 768 203 698 la 12681248 104a 21 a 15.67766868 138 768 1203 69a 11a 70a 26a 124a194a 21a 97a 15.67766868 798 113a 176a 120a 169a la 708 26a 24a 1048 21a 15.67766186a 798 76a 208 698 1a 708 268 248 948 21a 97a 15.67766 868 798 138 11088 20a 169a la 70a 268 248 21 a 97a 15.6776686a79a 108a 76a 20a 1698 70a 26a 124a 136a 94a 21a 15,6776686a79a 13a 108a 208 1a 708 26a 248 36a 121a 97a 15.7509286a 13a 108a 20a 69a 1a 70a 24a 36a 94a 21a 97a 15.75092 868 79a 113a 108a 20a 69a 1 a 70a 248 94a 21a 97a 15.750921381088 76a 20a 1a 170a 24a 36a 94a1104a 21a 97a 15.75092798 138 1088 208 1a 70a 248 36a 948 104a 218 97a 15.75092798 138 108a 768 208 70a 268 I24a 948 1048 218 978 15.75092 86a 79a 76a 20a 692 70a 124a 36a 948 1048 21 a 197a 15.75092 868138 1088 76a 120a 1698 1 a 170a 24a 36a 21 a 97a 15.7509286a 13a 10821208 169a 11 a 1708 268 243 942 121 a 197a wF...ieldwa;" :~a x~=`al 4~6'w ,7. '~ 9 0< *~?i~K
15,75092 86a 13a 1108a 176a 120a 169a la 170a 26a 24a 21 a 197a 15.75092 86a179a 113a 1108a 20a 169a la 70a 24a 36a 21 a 97a 15.7509279a113a 76a 120a Ila 70a 26a 24a 136a 94a 21a 97a 15.75092179a 13a 176a 20a 69a la 708 24a 368 94a 21a 97a 15.82418 86a 79a 108a 76a 20a 1 a 170a 26a 248104a 21a 97a 15.82418179a 13a ~108a 76a 120a 69a 70324a 136a 194a 21a 97a 15.8241813a108a176a 20a 1a 70a 126a 24a 94a 104a 21a 97a 15.8 2418 86a 79a 20a 69a 1 a 70a 124a 36a 94a 104a 121a 97a 15.82418,79a 13a 1108a 76a 20a Il a 124a 36a 94a 104a 21a 97a 15.82418j86a79a 13a 108a 76a 120a 70a 26a 24a 36a 104a 21a 1 5 8 2 4 1 8 1 0 8 7 6 8 2 0 2 692 1 a 70a 26a 24a 94a 104a 21 a 97a 15.82418186a 132- 76a 20a 69a 1 a 70a ~26a 24a f36a 121a 97a 15.82418 86a 792 76a 120a 69a 1 a 70a 24a 36a 94a 21 a 97a 15.8241886a79a 76a 20a 1692 1a 70a 126a 24a 94a 104a 21a 15.82418 86a179a 108a 762 120a 1 a 70a 124a 136a 94a 21a 97a 15.82418 86a179a 113a 108af 20a 169a 170a 24a 36894a 21a 97a 15.82418186al79a 113a 1108a120a la 170a 26a 124a 104a 21a 97a 15.82418179a 13a 76a 20a I1 a 70a 26a 24a 194a 1104a 121 a 197a 15.89744186a,79a 76a 20a 69a 70a 26a 24a 36a 1104a 21a 197a 15.89744486ai79a 13a 108a 20a 169a 1 a 126a 24a 194a 21a 97a 15.89744868 79a 1138 1088 76a 120a 1708 262 24a 36a 94a 21a 15.89744186a 79a 113a 108a120a 69a 1 a 170a 6a 24a 94a 1212 15.89744113a 108a1769 20a 169a l a 70a 126a 24a 136a ~94a 21a 15.8974418621798 108a 176a 20a 1 a 70a 26a 24a 36a 21a 97a 15.89744 79a 108a176a 20a 69a 1 a 170a 26a 24a 94a 21a 97a 15.9707798 1088 76a 208 169a 170a 26a 24a 94a 11048 21a 97a 15.970779a113a 108a 76a 69a la 26a 124a 36a 194a 104a j21 a 15.9707 79aJ76a 20a 69a 70a +26a 24a 136a 94a 1104a 21a 97a 15.9707868 798 13a 110821208698 I1 a 170a 24a 36a 94a 21a 15.9707798 138 108a 120a 169a 1 a 70a 24a 36a 94a 21a 97a 15.9707186a 108a 76a 1208 69a a 70a 26a 124a 1,36a 94a 21a 15.97071868 79a 1088 76a 1208 19a la 708 124811042 I21 a 197a 15.9707 868 79a 138 76a 208 1 a 70a 26a 24394a 1048 21a 15.970 86a 79a 113a 1088 76a 20a (70a 24a 36a 94a 104a j21a 15.970779a 13a 108a 76a 120a 1 a 70a 24a 36a 94a 21 a 97a 15.970779a 13a 76a 20a 69a 1 a 708 24a 94a 104a 21 a 978 16.04396 79a 138 1088 76a 208 69a la 170a 24a 36a 21a 978 16.0439679a 13a 1088 76a 202169a Ala 24a 36a 104a 21a 97a 16.0439679a 13a 108a 4768 0a 708 263 24a 36a 94a 104a 121a 16.0439686a79a 13a 108a1 76a 208 69a (1a 708 243 104a 21a 16.04396 86a 108a 76a 120a 69a 1 1 a 24a 36a 94a 104a 21 a 197a 16.04396179a 13a 108a 76a 20a 1 a 70a 24a 36a .104a 21 a 197a 16.04396186a 79a 138 108a 20a 69a 70a 26a 24a 1948 21a 97a 16.1172286a 10821208 69a hla 708 24a 36a 94a 1048 21a 97a 16,11722108 76a. 1208 69a 1a 70a 126a 248 36a 94a 104a 21a 16.1172286a 1088 768 20a 1a 708 24a 36a 94a 104a 21a 97a 16.11722186a 79a 13a 108a 76a 208 126a ,24a 36a 94a 21a 97a +'is>F.edd_>4?y2a,a.3:.
16.117221862179a 133 108a176a 120a 1la 126a 124a 36a 1104a121a 16.1 9048 793 13a 108a 176a 1203 69a 1 a 170a 24a 104a 21 a 197a 16.19048 79a 13a 1083 1203 69a 1 a 70a 126a 24a 943 21 a 197a 16.1904886a 1083 76a 120a 169a 70a 26a 24a 36a 94a 21a 97a 16.19048 79a 76a 1203 169a 11 a 70a 126a 24a 194a 104a 21 a 97a 16.19 048863 79a 13a 108a 176a 120a 11 a 70a 24a 104a 21 a 97a 16.19048179a 133 108a 1763 120a 69a 24a 36a 94a 104a 21a 97a 16.19048179a 13a 1762 20a '69a la 170a 26a 24a 104a 121 a 97a 16.2637 86a 79a 1108a 203 69a 1 a 170a 26a 24a 104a 121 a 197a 16.2637486a 133 1083 76a 1203 69a 70a 24a 36a 94a 1043 21a 16.26374 86a 79a 133 76a 1203 1703 26a 24a 36a 104a 21 a 97a 16.26374 86a 13a 11083 768 20a 169a 70a 26a 24a 36a 11043 21 a 16.26374 863 13a 1083 76a 1203 69a la 26a 1243 36a 1104a 21 a 16.26374793 133 76a 20a 69a 1a 1703 26a 1243 94a 21a 972 16.26374179a 13a 1108a 120a 69a la 703 24a 94a 1104a 121 a 97a 16.263741 al 132 108a1763 20a ila 703 1243 94a 11043 21a 16.2637479a 13a 11083 1763 1203 169a 70a 126a 1243 94a 121 a 197a 16.26374 86a179a 110831763 120a 703 26a 24a !94a 104a 21 a 97a 16.26374 86a 79a 133 1083 76a 20a 1693 1 a 124a 36a 21a 197a 16.26374,86a 79a 1133 1083203 69a 1a 703 262 24a 1043 216.26374793 133 1108a76a 203 169a 70a 1243 36a 94a 1043 21a 16.263741793,133 76a 120a 169a 1703 26a 24a 136a 94a 121a 197a 16.26374 79a113a 176a 120a 1693 11 a 124a 1363 942 104a 2197a 16.3371863 76a 1203 69a 11 a 170a 126a 24a _36a 11043 21a 197a 16.337793138 11083176a 1203 69a 703 26a 24a 1043 213 97a 16.337863 79a 113a 1203 _Ia 703 242 36a 94a 1043 21a 97a 16.337793 132 11083 76a 20a 1a 26a 24a 94a 104a 121a 97a 16.3371863 13a 1083 76a 20a 1a 26a 24a 136a 94a 121a 97a 16.337 86a 79a 13a 1108a'76a 203 724a _94a 104a 21a 97a 16.337 86a 79a 13a 176a 120a 1 a 70a 24a 997a 16.337 86ai 13a 1108a 76a _20a 169a 11 a 24a 362 194a 1043 21 a 16.33786a 79a 13a 108a176a 1203 169a 24a 362942 _104a 21a 16.41026186a 799 133 1083 203 69a 703 26a 24a 36a 21a 97a 16.41026 79a 1083 76a = 21692 1 a 70a 24a 363 94a 11042 21 a 16.41026179a 133 1083 76a 1203 1 a 70a 24a 94a 1104a 121a 97a 16.410261793 133 1083 763 203 693 263 243 94a 11043 213 97a 16.41026186a 79a 133 108a120a 12 70a 26a 24a 94a 1043 21a 16.4102679a13a 108a120a 1a 703 26a 24a 36a 94a (213 97a 16.41026 862 793 1:33 1083 20a la 703 24a 194a 104a 212 _97a 16.41026176a 20a 1693 1 a 70a _26a 24a 363 94a 104a 21a _97a 16.41026 793 133 1083 76a 203 1 a 170a 1263 24a 36a 21a 97a 16.41026 8631793 13a 76a 20a 693 1 a 70a 24a 94a 1043 _21a 16.41026 793 1083 763 203 693 1 a 70a 24a 94a 104a 21 a 97a 16.41026 79a 1083 76a 20a 693 709 26a 1243 136a 1043 21a 97a 16.41026862799 133 76a 203 _Ia 70a 1263 124a 363 11043121 a 16.41026 86a 793 133 1083 76a 203 _69a 263 2431943 1043 21a 16.4102679a1108a1762 ~202 693 263 243 36a 1942 104a 121a 197a 16.41026186a179a 13a 176a 120a Ila 1248 I36a 194a11048 21a 197a 16.41026186a79a 113a 76a 120a 70a 248 36a 94a 104a 21a 197a 16.4102613a 1088 762 20a 169a 70a 26a 24a 36a 94a 21a 97a 16.4102686a179a 1138 108a176a 1208 69a 1248 136a 94a 21a 97a 16.41026186all 08a1768 208 698 1a 268 124a 368 948 218 978 16.4835286a179a 13a 1088 76a 120a 69a 26a 24a 36a 121a 197a 16.48352 86al798 768 202 69a 11 a 70a 24a 94a 104a 21 a 197a 16.4835213a 108aJ768 208 698 1a 248 368 94a 104a 121a 197a 16.48352 86a 138 108a176a 120a 708 26a 248 36a 94a 21a 97a 16,48352~79a1108a 76a 208 69a 1a 24a 1368 94a 104a 21a 97a 16.48352186a 79a 108a 76a 120a 70a 26a 24a 1368 94a 121 a 978 16.48352 79a 13a 76a 208 170a 126a 124a 368 194a 1048 121 a 97a 16.4835286a 79a 132 108a 768 208 1a 26a 242 104a 21a 97a 16.4835286a79a 138 1088768 208 698 1a 126a 24a 21a 97a 16.48352186a 798 138 1088 76a 120a 169a 26a I24a 1948 21a 978 16.483521868 798 138 76a 20a 708 26a 24a 368 948 21 a 978 16.4835 86a79a 138 108a20a 69a 1a 170a 24a1104a 21a 97a 16.4835286a 79a 113a 120a 698 1 a 708 1248 3681948 121 a 197a 16.4835286a 79a 1088 208 698 a 1708 248 948 1048 218 97a 16.4835279a 13a 11082176a 20a 1702 268 124a 136a 104a 21a 197a 16.5567886a 798 13a 108a176a 208 I1 a 243 36a 104a 21a 97a 16.5567813a 76a 208 69a 1la 1708 268 24a 36a 948 21a 97a 16.556781868 798 1088 76a 20a 69a 1 a 70a 24a 94a ~ 104a 21a 16.55678 86a 79a 13a 108a 76a 20a 69a 1 a 248 36a 94a 21 a 16.55678186a 79a 13a 108a120a 69a la 708 24a 94a 104a 21 a 16.5567879a 108a 76a. 120a h1a 70a 24a 36a 942 104a 21a 97a 16.55678 86a 79a 13a 76a 1208 169a 1708 24a 36a 94a 1048 21a 16.55678 79a 138 108a =20a la 70a 26a 24a 94a 104a 21a 979 16.5567886a 798 768 20a 69a la 70a 1248 36a 104a 21 a 97a 16.5567813a108a176a 120a 69a Ia 708 248 36a 948 21a 97a 16.55678 79a 138 76a 120a h69a 708 248 36a 94a 104a 121 a 97a 16.55678 86a 79a 108a 1208 692 1 a 70a 24a 136a 1048 21 a 973 16.63004 86a 13a 1088 768 20a 169a 1 a 126a 124a 94a 11048 21 a 16.63004 86a 13a 1088 768 20a 692 708 1268 24a 1948 1048 21a 16.6300486a79a 132 1088768 208 69a 26a 248 36a 104a 21a 16.6300479a 138 1088 76a ~20a 169a la 708 248 36a 94a 21a 16.6300486a79a 138 176a 20a 69a 70a 24a 36a 94a 21a 97a 16.63004 86a 79a 108a 1208 69a 1 a 708 268 24a 94a 104a 21 a 16,7033 868 798 108a 176a 20a 1698 708 248 948 1048 21a 97a 16.7033 79a 13a 1768 20a 69a 1a 6a 24a 94a 104a 21a 97a 16.7033 79a 138 1088 76a 20a 698 1 a 268 24a 948 21a 97a-16.703311 Sa 76a 20a 11 a 708 26a 24a 36a 94a 104a 212 97a 16.7033186a 79a 13a 1088 20a 69a 70a 26a 242 104a 21a 97a 16.7033 86a 79a 13a 108a 208 1 a 24a 36a 94a 104a 21a 97a 16.7033 86a 76a 20a 69a la 170a 26a 24a 36a 94a 21a 97a 16.703379a 13a 108a 76a 20a 69a 1a 24a 36a 94a 21a 197a 16.7033 868 798 10881208 1698 1 2 708 24a 388 94a 104a 121 a tf r ^ tv ~+, K;e= ' , 4" ~ }~.t INfi'~',S F:'; Yr,: 11 'm:'..F(eld=:1:1:~,2 s 47k4:n7. ~_ 7 2t~j0 v''~~ S+~~ n .33 16.703318681798 '13a 11082 76a 120a 692 70a 242 942 21a 197a 16.70331862 792 113a 10821762 1202 1 a 242 62 94a 104a 121 a 16.7033792 132 1108a 76a 202 169aI70a 6a 24a 36a 1042 21a 16.7033 862 79a 1108a 1762 202 1 a 70a 24a 36a 1042 21 a 197a 16.7033862 79a 113a 176a 120a 69a 70a 26a 124a 94a 104a 21a 16.7033186a179a 13a 76a 20a 169a 70a 126a 124a 36a 104a 121a 16.77656,132 108a 76a 202 698 11 a 702 262 24a 104a 121 a 1972 16.77656186a1108a176a 202 69a 170a !26a 24a 94a 104a 21a 97a 16.776561132 1082 76a 20a 1692 11 a 1702 24a 36a 1942 104a 121 a 16.77656 86a 79a 11082 76a 208 70a 124a 36a 94a 104a 21 a 97a 16.7765679a113a 108a176a 202 69a la 70a 26a 24a 942 121a 16..77656 792 132 1082 76a 2208 '69a 702 126a 24a 362 21 a 97a 16.77656179a 132 1082 76a 20a 69a la 24a 9421104a 121 a (97a 16.77656'862 13a 108a 1762 20a 1 a 70a 262 24a 1104a 121 a 972 16.77656179a 13a 1082 76a 120a 169a 1a 170a 262 242 212 972 16.77656186a179a 113a 1082 762 20a 169a la 24a;36a 104a 21a 16.77656179a1108a 76a 202 1702 126a 248 36a 94aI104a 21a 197a 16.776561792132 108a 176a 1202 I1 a 126a 1242 362 942 21 a 197a 16.84982179a113a1082 76a i20a 1la 70a l24a 136a'94a 1104a 121a 16.849821862 79a 1108a 76a 20a. 70a 26a 242 362 104a 121 a 1972 16.84982792 13a 108a 76a 202 262 24a 362 94a 104a 21a 97a 16.849821862 792 11082176a 120a 169a 1 a 70a 26a 242 36a 21a 16.849821862 79a 176a 20a 69a la 24a 36a 94004a ~21 a 97a 16.8498286a 79a 1088 762 202 69a 1a 170a 24a 36a 11042 21a 16.84982179a 13a 1082 762 120a h1a 170a 1262 24a 36a 1042 21a 16.84982113a 10821762 120a 1la 170a 126a 24a 36a 942 1042 21a 16.84982179a 13a 1082 20a 169a 1 a 124a 36a 94a ~104a 21 a 972 16.923081862 79a 13a 76a 120a 70a 26a 242 942 1048 21 a 97a 16.92308186a 792 13a 208 692 11 a 70a 126a 2421942 121 a 197a 16.9230886a 792 13a 108a176a 208 262 24a 1362 1042 21a 1972 16.9230 86a 79a 1108a176a 1202 692 112 124a 1362 94a 11042 21a 16.9230813a 1082 762 120a la 26a 242 36a 942 1042 21 a 97a 16.92308179a 13a 1082 762 20a ,69a h1 a 70a 24a 94a 21 a 197a 16.9230879a 13a 11082 20a 69a la 170a 26a 124a 104a 21 a 97a 16.92308 86a 132 108a 762 120a 1 a 702 24a 94a 11042 21 a 97a 16.92308 86a 792 1108a 76a 120a 69a la 24a 36a 104a 21a 97a 16.92308186a 13a 108a 76a 203 70a 26a 24a 36a 104a 21a 97a 16.9963486a 79a 132 1082 76a 20a 69a 70a 24a 36a 212 197a 16.99634 108 762 20a 69a 1 a 702 26a 24a 36a 104a 21a 97a 16.9963413a 1082 762 20a 1a 70a 26a 24a 36a 1042 212 197a 16.9963413a 108a 76a 120a 692 1 a 70a 262 24a 94a 212 97a 16.9963486a 108a 76a 20a 69a 1a 26a 24a 362 104a 21a 97a 16.9963479a108a20a 69a h1a 702 26a 24a 94a 1042 21a 97a 16.9963486a108a120a 69a 1a 70a 126a 24a 136a 94a 21a 97a 16.9963413a 108a 76a 20a 69a f 702 24a 362 942 104a 21 a 97a 16.99634 86a 79a 1082 762 20a 692 26a 242 36a 11042 212 972 16.99634 862 132 76a 20a Ila 1702 126a 24a 362 942 21 a 978 ., cicr k': R s 11201,01074 'i i MOOD P j.. ~, 16.9963479a 13a 76a 20a 1a 170a 26a 24a !36a 104a. 21a 197a 16.9963486213a 1108a 20a 69a 1a 170a 26a 24a 36a 1042121a 16.99634 6a79a 13a 176a 120a 69a 1a 24a 136a 94a 121a 97a 16.99634179a 13a 108a 76a 20a 169a 702 124a 136a 104a 121a 97a 16.9963479a13a 108a 20a 69a 1a 126a 24a 94a 104a 21a 97a 16.9963479a 13a 1768 20a 69a -]-l a 170a 26a 24a 94a 104a 21a 16.9963 86aI79a 76a 120a 69a 70a 1262 24a 94a 104a 21a 97a 16.99634792 132 10Ba120a 69a 170a 26a 24a 36a 94a 21a 97a 16.9963 862(798 13a 11082 202 la 70a 124a 36a194a 104a 21a 16.99634(86a 132 108a 76a 120a 169a Ia 702 242 1042 21a 197a 17.06961108 76a 208 698 1 a 26a 24a 36a 94a (104a 21a 97a 17.06961862 132 ~108a 202 169a h1a 70a 24a 36a 94a 1042 212 17.0696186a 1082 76a 208 Ila 70a 26a 24a 36a 94a 1212 97a 17.0696179a 1 132 108a176a 120a 1692 70a 26a 24a 94a 1104a 21a 17.06961862 792 1132 108a176a 20a 69a 1a 70a 24a 94a 21a 17.0696(86a792 113a 108a120a 69a la 24a 36a 104a 21a 97a 17.0696;862 79a 1132 108a120a 1 a 70a 24a 36a 104a 21a 97a 17.06961862132 1082 76a 20a la 702 26a 124a 36a 94a 121a 17.069613a~1082h76a 20a 169a la 262124a 94a(104a 21a 97a 17.0696186a 79a 132 76a 120a 1 a 702 6a 24a 1042 I21 a 97a 17.14286186a 79a 13a 1082 76a 120a 692 la . 70a 24a 121 a 97a 17.142861792 132 108a 20a 69a 1 a 70a 24a 36a 94a 104a 21a 17.142861862 79a 13a 20a 169a la 702 24a 94a 1042 21 a 97a 17.14286I79a 13a 176a 20a 169a 1a 70a 24a 36a 94a 1042 21a 17.21612113a 1082 76fi- 20a 169a 1 a J70a 26a 24a 94a 104a 21a 17.21612,186a 79s 762 202 la 70a 26a 24a 94a 104a 21a 97a 17.2161286a 79a 13a 1082 76a 202 26a 24a 94a 1042 21a 97a 17.21612 79s 13a 1082 76a 1202 169a 1a 70a 24294a 104a (21a 17.2161279a 13a 76a 1202 169a 70a 26a 24a 136a 104a 21a 97a 17.2161286al79a 1108a'1202 169a la 24a 36a 94a 104a 21a 97a 17.21612862 76a 120a 69a 1a 70a 1262 24a 94a 1042 21a 197a 17.2161286a)79a 113a 76a 202 169a la 70a 24a 36a 21a 97a 17.21612862792 76a 20a 69a 1a 1702 26a 24a 104a 21a 97a 17.21612108 76a 20a 69a 70a 26a 124a 36a 94a 104a 121a 197a 11.2161286a 13a 176a 120a 69a 1a 70a 26a 24a 94a 104a 21a 17.2893886aj79a 13a 1108a76a 20a 69a 1a 26a 24a 94a 21a 17.28938862 79a 13a 1082 76a 1202 24a 36a 948 104a 21a 97a 17.2893886a 108a76a 20a la 70a 26a 24a 36a 104a 21a 97a 17.2893813a 1082202 69a la 70a 26a 24a 36a 94a 21a 97a 17.2893879a 108a 76a 20a 69a 18 26a 24a 94a 104a 21a 97a 17.2893879a13a 76a 20a 1a 26a 24a 36a 94a1048 21a 97a 17.2893886ah13a 1082 76a 20a 1a 70a 24a 36a 104a 21a 97a 17.28938862 13a 76a 20a 1a 70a 24a 136a 94a 104a 21a 97a 17.2893886a79a 1082 76a 120a, 69a 24a 36a 94a 104a 21a 97a 17.2893886a 79a 1132 176a 120a 69a 70a 26a 24a 36a 21a 97a 17.2893813a 1082 76a 209 69a la 702 26a 124a 36a 1042 1212 70a 124a 36a 104a 21 a 97a 17.28938,86a!79 T13a 76a 120a la %Fielci'1,i'.; ..' :Y':1 u ` 2' 3 f a. Sl 7`r `a, ~., ; . =~ ; o-`
t.~v... K. 4 v Ak Al.
R
17.289381798 13a 1108a176a 20a 1a 126a 124a 36a 104a 21a 197a 17.28938186a179a 1088 1768 208 1698 11 a 708 24a 1948 21a 197a 17.28938 868 13a 1108a 120a 169a i a 70a 24a 94a 104a 121 a 97a 17.2893818681798 108a 1208 159a 170a 26a 24a 36a 948 21 a 97a 17.28938 86a113a 108a 20a 1 a 170a 1248 36a 94a 104a 121 a 97a 17.2893813a 108a 76a 20a 169a 118 170a /2-,602---24a 36a 121a 97a 17.36264 79a 13a 176a 20a 69a 1la 170a 24a l36a 1048 21a 97a 17.3626486a79a 13a 76a 1208 1698 1a 26a 124a 94a 121a 97a 17.3626486a79a 13a 76a 20a 698 1a 170a 126a 124a 21a 197a 17.36264186a 13a 11088 20a 169a 1 a 170a 24a 368 104a 21a 197a 17.36264179813a 1108a, 76a 208 1698 1 a 70a 12481368 1048 21a 17.36264868 798 1138 1088 76a 120a 18 126a 1248 94a 1048121a 17.435979a 10881768 1208 is 70a 26a 124a 1368 94a 21a 97a 17.435986a179a 13a 108a120a 69a 1a 126a 124a104a 121a 97a 17.4359 8681138 108a 76a 20a 1169a _70a 126a 12421104a X21 a 1978 17.435986a179a 132 76a 120a 169a ~1a 170a 24a 94a 121a 197a 17.4359179a113a 110881768 20a la 170a 126a 124a136a 194a 218 17.435 8681798 13a 176a 1208 698 is 242 1368 948 10481218 i7.4359186a113a 768 208 69a Ila 70a 126a 1248 368 1048 _21a 17.4359186a 79a 108a 768 208 69a 126a 124a 36a 1948 21 a 97a 17.4359 86a179a 138 1082120a.169a 70a 124a 1942 1048 218 97a 17.435986a179a ~13a 1108a120a 70a 126a 124a 136a 948 219 97a 17.4359869113a 76a j20a *69a 1a 70a 1248 948 _104a 21a 1978 17.435986813a 108a!20a Ila 708 26a J24a 36a 94a 21a 97a 17,4359108176a 208 1 a 708 268 248 36a 194a 11048 21 a 97a 17.50916 8479a 13a 1088 20a 698 1 a 248 94a 104a 121 a 97a 17.50916868798 13a 1768 1208 69a 708 26a _24a 368 194a 21a 17.50916 86a 79a 108a 176a 20a 69a 708 ~24a 36a 104a 1218 97a 17.5091686a11 3a 1088 76a 20a 69a 70a 126a 248 368 _942 21a 17.509161798138 1088 768 120a 1698 1 a 124a 368 948 104a 121a 17.50916186a 13a 108a 1208 _69a 1 a 70a 1268 24a 94a 1042121a 17.58242 868138 108a 1768 208 70a 24a 36a 194a 1104a _21 a 97a 17.58242 798 13a 76a 2698 268 248 36a 948 1048 218 _97a 17.58242 868 138 1088 76a 1208 1698 i s 126a 248 368 948 21a 17.5824286a1108a 20a 1698 1a 70a 1268 124a 368 104a 121a 97a 17.58242113a(108a 76a 208 70a 268 248 _36a 948 104a (218 97a 17.5824286a79a 108a 76a 20a 69a IIs 224a 948 218 972 17.58242 86a179a 13a 108a 76a 20a 11 a 70a 24a 136a 1048 21a 17.58242 86a 79a 76a 20a 69a 1 s 708 26a 24a 36a 1048 21 a 17.5824286a 13a 76a 20a ;69a 1a 268 24a 36a 94a 21a 97a 17.58242 86a 79a 108a 76a 1208 1 a 708 248 948 104a 21a 97a 17.58242 86a 138 1088 768 120a 1 a 248 368 94a 104a 21a 97a 17.6556879a 138 108a 768 202 69a 26a 24a 368 948 104a 21a 17.65568 86a 79a 138 108a 76a 20a _69a 26a 24a '362 948 21 a 17.6556879a 108a 768 208 _la 70a 126a 248 948 1048 _21a 978 17.6556813a 108a 768 _20a 69a 1 a 170a 24a 368 104a 21 a 197a 17.65568 868 79a 11088 20a 69@170a 248 36a 948 104a 121a 1978 F~e~d,;1 Ail "NOMI. 04.0 l i.
17.65568792 132 108a120a 69a 702 242 36a 1948 1104a 121a 197a 17.72894186a179a 113a 1108a120a l69a Ila 24a 36a 942 104a 21a 17.7289479a 132 108212Da 69a la 702 124a 36a 1104a 21 a 197a 17.72894 86a179a 108a 120a 169a la 702 26a 242 36a 21 a 97a 17,7289486a1792 108a 76a 20a 69a 26a 24a 3621948 104a 21a 17.7289486a1108a 76a 120a 169a 70a 26a 24a 362 199-42 1104a 121 a 17.72894862 792 132 11082 20a 170a 26a 24a 1948 1042 21a 972 17.72894 86a179a 1082 76a 120a 69a 1 a 262 24a 11042 21 a 197a 17,7289413211082762 20a 692 170a !26a 248 362 94a 104a 21 a 17.72894 79a 76a 20a la 702 1262 1242 362 942 104a 21 a 97a 17.72894 792 762 20a 69a la 70a 26a 248 362 94a 21a 97a 17.8022,86a 13a 1082120a 69a la 70a 26a 24a 104a 21a 97a 17.802286a 79a 1088 76a 208 69a (la 262 1242 36a 1104a 21a 17.8022186a 79a 13a 202 692 170a 242 36a 94a 104a 121a 1972 17.8022186a 79a 13a 1762 120a 169a 1 a 702 24a 36a 11042121 a 17.80221862 132 1082 762 120a 692 la 702 242 36a 1042 21a 17.802213a 76a 202 169a la 262 124a 362 19421104a 21 a 97a 17.8022113a 76a 120a 1692 la 170a 124a 362 942 1042 212 97a 17.80221132 76a 20a 1692 11 a 70a 262 24a 942 104a 121 a 972 17.8022132 76a 202 169 1 a 70a 26a 24a 36a 1104a 121 a 97a 17.8022132 108a 208 69a 1 a 170a 24a 36a 942 104a 21 a 97a 17.80228621132 1082 76a 202 1692 1 a 24a 36a 104a 21 a 197a 17.80228621792 113a 1762 120a 699 la 170a 262 24a 36a 121a 17.80228621798 1082 202 169a 1702 262 124a 94a 104a 212 97a 17.8022792 108aI76a 202 1692 12 170a 26a 124a 94a 104a 21a 17.8022799 13a 76a 1203 698 702 26a 24a 36a 94a 1042 21a 17.8022179a 13a 1108a 76a 20a 1a 70a 26a 24a 94a 1104a 21a 17.80221862 13a 108a 20a la 70a 26a 124a 36a 104a 121 a 97a 17.80 862 792 132 108a 76a 20a 69a l a 1249 94a 11042 21a 17.87546 8621798 762 20a la 1702 26a 24a 36a 1104a 21a 197a 17,87546186a 13a 76a 20a 69a la 70a 26a 24a 36a 94a 21 a 17.87546668179a 108a 76a 20a 69a 26a 24a 94a 104a 21a 97a 17.8754679a,13a 108a 20a 692 18 170a 26a 24a 94a 1042 21a 17.875461862 792 13a 1088176a 202 69a 1a 262 24a 36a 21a 17.87546 86a179a 1082 76a 202 69a 1 a 24a 136a 194a 21a 97a 17,87546 79all 3a 1202 692 1la 170a 24a 36a 9421042 212 972 17.87546 86a 13a 108a 76a 202 692 la 1242 948 104a 21a 97a 17.87546 86a 792 13a 1082 76a 20a 708 24a 36a 1104a 21a 97a 17.8754686a79a 13a 76a 20a 69a 70a 26a 124a 94a 21a 97a 17.87546 86a 79a 113a 76a 208169a 1a 26a 24a 94a 104a 21a 17.87546 86079a 11082 76a 20a 69a 1a 26a 24a 94a 104a 21a 17.94872862 13a 76a 20a 69a 70a 26a 124a 36a 94a 212 97a 17.94872 86a 13a 108a 76a 20a 70a 126a 24a 94a 104a 21a 97a 17.94872862 79a 76a 20a 69a 702 262 24a 36a 94a 1042 21a 17.94872 86a 13a 762 20a 69a 1 a 70a 24a 36a 94a 104a 121 a 17.94872 86a 792 13a 108a 20a 69a 70a 26a 24a 94a 1042121 a 1082 120a 6 92 la 70a 1262 24a 362 942 21 a m V, 17.94872 86aj13a 176a 1209 69a 1la 124a j36a 94a j104a 21a 973 17.9487286a79a 113a 108a 76a 120a 169a 70a 26a 24a 21a 97a 17.94872113a 108a 76a 20a 692 1703 126a j24a 943 1104a 21a 1973 18.0219886a113a 1083 76a 20a 69a 11a 269 24aj104a 21a 97a 18.0219886a13a J108a176a 202 69a 26a 24a 36394a 213 97a 18,02198 86a 79a 11083 20a la 709 24a 36a 94a 104a 21a 97a 18.0219886a79a 13a 11083203 169a 1a 26a 24a 94a 1043 213 18.02198 8691133 76a 120a 69a 70a 24a 36a 94a j104a 21a 97a 18.021981391108a 762 20a 1692 1a 26a 24a 36a 104a 213 97a 18.02198133 1083 76a 20a 69a 11 a 26a 24a 36a 94a 104a 21 a 18.0219818631793 1133 11082203 69a 1a 26a 243 36a 21a 197a 18.02198186a 79a 133 203 69a 1 a 24a 36a 94a 104a 21 a 97a 18.02198j86a 76a 20a 69a 70a 262 242 36a 94a 104a 21 a 97a 18.0952 79a 13a 1083 76a 203 j692 262 24a 36a 104a 21a 97a 18.09524 86aj798 j13a 11083 203 11 a 1703 26a 24a 36a 104a 121a 18.0952479a,108a1762 120a 12 170a 126a 24a 36a 104a 21a 97a 18.095241863793 13a 203 693 j1a 170a 24a 36a 104a 21a 97a 18.09524186a79a 113a 1763 0a 12 1268 24a 136a 94a 21a 972 18.0952417931133 76a 20a 1 69a 1703 126a 24a 194a 104a 121 a 197a 18.095241863 79a j108a 76a 20a 69a 1 a 26a 124a 36a 121a 972 18.16851863 793 13a 1203 69a 70a 26a 24a 136a 104a 21a 197a 18,16851863 793 108a 763 1202 112 24a 363 194a 104a 21a 197a 18,16851793 1083 203 169a 1a 70a 26a 24a 136a 194a 121a 97a 18.168518621133 1083 76a 20a 69a 703 243 363 104a 21 a 97a 18.1685186a179a 1108a1202 169a 703 263 243 136a 104a 121 a 97a 18.1685~86a,108a 763 120a 1a 703 26a 124a 943 104a 21a 97a-18.1685 86a179a 13a 11083 76a 120a 263 24a 36a 94a 104a 21a 18.168586aj79a 13a 108817621208 693 1263 243 104a 21a ~97a 18.1685 863 793 76a 120a 169a 703 26a 124a 363 94a 21a 97a 18.168579a 13a 1083 763 203 693 la 126a 243 36a 213 97a 18.241 76 1 08 203 ,69a h1 a 70a j26a 24a 36a 94a 104a 21a 1973 18.24176 8631083 l76a 203 1693 la 1262124a 36a 943 104a 21 a 18.241761863132 20a 693 I1a 70a 1243 36a 94a 104a 21a 97a 18.2417679a 133 1083 763 20a 693 1a 126a 243 9.43 104a 21a 18,2417613a 1083 20a 69a la 70a 263 242 943 1043 21a 97a 18.24176 6681798 133 1083 203 j69a 263 1243 363 94a 21a 97a 18.2417686a 133 108a 76a 20a 69a 70a 24a 1943 104a 21a 97a 18.31502793 1083 763 20a 69a 1 a 70a 26a 243 36a 21a 97a 18.315021863 13a 108a 76a 20a 1 a 126a 24a 136a 1104a 21a 97a 18.3150213a .108a 20a 693 1 a 26a 24a 136a 94a 21a 97a 18.31502179a 13a 76a 20a la 70a 26a 243 36a 94a 104a 21 a 18.3882886a 79a 13a 20a 1a 70a 26a 24a 948 104a 21a 97a 18.3882886a 13a 108a 76a 20a 70a 26a 24a 136a 94a 104a 21a 18.3882813a 763 20a 69a 703 26a 24a 362 943 1043 21a 97a 18.3882879a1083762 20a 69a 1a 26a 1243 36a 94a 213 97a 18.46154862 793 1133 1083 203 69a 24a 36a 943 1043 213 97a 18.4615479313a 120a 69a 113 703 126a 124a 943 104a 1212 97a 3 õF elrl k: i {a r N 0: ii 'n4 5!ti{i003G
18.461541861132 176a 120a la 170a 126a 124a 36a 1104a 21a 979 18.461541792 1089'20a 69a 1702 26a 24a 36a 942 104a 21a 97a 18.4615486@79a 132 76a 120a T a 126a 24a 94a 104a 21a 97a 18.46154179a 1082 76a j20a 169a 1a 70a 26a 24a 36a 104a 21a 18.5348186a 79a 13a 1082 20a 69a 26a 24a 949 104a 21a 97a 18.5348186a 769 20a j69a la 170a 26a 24a 36a 94a 104a 21a 18.5348 86a179a 176a 120a la 70a 126a 24a 136a 94a 21a 97a 18.5348 8621792 76a 1202 70a 26a 24a 36a 94a 1042 21 a 97a 18.534818621792 11082 176a 20a la 702 26a 24a 94a 1104a 21a _ 18.53481862 79a 113a 1082 202 la 170a 26a 24a 36a 1942 21 a 18.534886a179a 132 20a 69a 70a 26a 24a 94a 104a 21a 197a 18.60806186210881762 120a 69a la 26a 24a 949 104a 21a 197a 18.6080679a 132 1082 20a 69a 70a 126a 124a 94a 1042 21a 197a 18.60806 86a 79a 13a 1082 202 702 126a 1243 36a 104a 21a 97a 18.608061792 76a 1202 69a 112 702 126a 24a 136a 1042 21 a 197a 18.60806 86a 132 106a 20a 698 170a 126a 248 136a 94a 121 a 97a 18,60806186a 132 762 20a 11 a 170a 126a 124a 194a 1042 21 a 197a 18,608061862 79a 113a 110821208 la 262 124a 194a 104a 121a 97a 18.60806 86a 79a 108a 76a 20a 1 a 170a 26a 24a 1362 104a 21 a 18.60806 862 798 13a 20a 69a 11 a 70a 124a 36a 94a 104a 21 a 18.60806 86a 79a 13a 76a 20a 702 26a 24a 36a 94a 1042 21 a 18.68132 86a 79a 132 20a 169a 1 a 1702 26a 242 104a 21a 197a 18.68132132 76a 20a 69a la 70a 26a 24a 36a 942 104a 21 a 18.6813213a 108a 20a la' 70a 26a 24a 36a 94a 104a 21a 97a 18.68132186a 13a 76a 20a 169a 170a 126a 24a 38a 104a 21a 972 18.681321862 798 13a 76a 1202 69a 702 248 194a 104a 21a 197a 18.68132 86a 79a 132 1082 76a 20a 69a 70a 1242 1042 21a 97a 18.68132186a 79a 13a 1108a 202 1 a 126a 24a 369948 21a 97a 18.68132186a 79a 1132 108a 20a 692 70a 26a 24a 36a 94a 21a 18,68132186a179a 20a 69a la 1702 126a 24a 194a1104a 21a 97a 18.68132 86a .79a 13a 1108a 120a 1692 1 a 170a 26a 243 36a 121 a 18.75458 79a 132 108a 20a 1 a 170a 26a 24a 36a 94a 104a 21 a 18.75458 862 1082 202 .69a 1 a 70a 262 24a 362 942 104a 21a 18,75458179a 108aj76a 20a 69a 1a 70a 126a 242 362 194a 21a 18.75458 86a 792 13a 76a 20a la 70a 126a 242 36a 94a 21a 187545879a 132 108a 20a 1 a 70a 26a 24a 36a 104a 21a 972 18.75458186a 13a 1082 202 692 j1 a 24a 136a 94a 104a 21a 97a 18.75458 86a 132 762 20a 69a 702 262 242 942 104a 121 a 97a 18.7545879a 76a 20a 692 la 26a 24a T6-al-947004a 21 a 97a 18.75458 862 792 13a 158a 75a 20a 698 1 a 24a 104a 121 a 97a 18.8278486a79a 13a 108a76a 20a j1a 24a 94a 104a 21a 97a 18.8278486a79a 13a 20a la 1702 126a 24a 136a 104a 21a 97a 18.9011186a 79a 13a 1108a 202 70a 24a 369 94a 104a 21a 97a 18.9011 86a 13a 11082 202 692 70a 242 36a 942 104a 21a 197a 18.901186a 13a 108a 20a 69a 70a 26a 24a 36a 104a 21a 97a 248 94a 1042 121a 97a 18.9011868,1082 202 692 1 a 70a 26a 18.90111862 132 1108a 176a 1202 la 1262 242 136a 1949 1042 21 a s ti .Fief.ci:1 '; Cj >r2:.aa9i3> `? % 5 6 1 V '$ Wig" ~0 SAM-1 am 18.901117931133 176a 120a 1693 la 126a 24a 136al94a 21a l97a 18.97436186a 79a 113a 76a 20a 169a 26a l24a 362 (94a 21a 197a 18.9.7436186a179a 113a 108a 20a 1,69a 1262 242 36a 104a 18.97436186a 79a 133 108a 20a I1 a 26a 24a (362 11042 21a 197a 18,9743686a79a 76a 20a 69a 1a 70a 26a 124a 36a 212 97a 18,97436186a 79a 132 76a 202 69a 1 a 70a 24a 1042 21 a 973 18.97436`79a 13a ~76a 20a 69a la 70a 26a 24a 36a 94a 21a 18.9743686a 79a 132 202 69a I13 170a 26a 24a 94a 1042 212 18.9743618631792 132 176a 20a 692 12 24a 94a 104a 21 a 97a 19.04762 86a179a 13a 20a 69a 702. 26a 24a 36a 94a 21 a 97a 19.04762186a 79a 13a 76a 20a 1 a 26a 24a 136a 104a 21a ~97a 19.04762,86a 79a 1082 76a 20a Is 70a 24a 136a 94a 1104a ~21 a 19.04762186a 13a 11082 120a Is h70a 26a 124a 194a 104a J21 a 97a 19.04762 86a 79a 1082 76a 20a 1 a 126a 124a 136a 104a 121 a 197a 19.04762 86a 79a 1762 120a 69a 1 a 1262 24a 194a 104a 121 a 97a 19.04762 86a 79a 13a 108a 76a 20a J69a 1 a 124a 194a 21 a 97a 19.04762!79a 13a 202 I1 a 170a 126a 124a 360 194a 1042 21a 97a 19.12088186a 79a 108a j2Oa 1 a 170a 26a 124a 36a 94a 21a 197a 19.12088113a1108a 76a 20a 169a I70a 26a 1242 36a ~104a 1212 97a 19.1208886a113a 763 20a 69a 13 70a 26a 24a 104a 21a 97a 19.12088 79a 13a 11082 10a 69a 1 a 26a 24a 36a 94a 21a 97a 19.12088113a11082 202 169a 1 a 70a 26a 124a 136a 1104a 21a 97a 19.12088 79a 132 10821202 11 a 126a 24a 136a 194a 1042 21a 97a 19,120881792 132 1082 76a 120a .69a Is 702 262 24a 36a 21a 19.1208886213a 20a 69a 12 170a 126a 24a 36a 94a 21a 97a 19.12088113a 108a120a 169a 1 a 70a 26a 24a 362 942 104a 121 a 19.19414 792108aI76a 20a 69a 1 a 26a 24a 36a 104a 121a 197a 19.194141862 792 1082 202 1 a 170a 126a 24a 94a 104a 1212 97a 19.19414186a 1082 76a 1202 1 a 170a 126a 24a 136a 942 1104a 21 a 19.1941486a 13a 1108@176a 20a Ila 126a +24a 94a 104a 21a 97a 19.2674 86a 792 13a I1080762 202 169a 70a 24a 36a 104a 21 a 19.2674 862 132 76a 20a 1693 1 a 26a 24a 36a 104a 21 a 97a 19.267479a113a 1108a 762 20a 1a 26a 24a 362 942 104a,21 a 19.2674 862 790 76a 202 69a 26a 24a 36a 942 1042 21 a 97a 19.34066 862 792 13a 108a 762 20a 69a 24a 94a 11042 21a 97a 19.34066;862 792 13a 202 69a 1a 702 26a 242 36a 21a 97a 19.34066792 132 1082 20a 70a 26a 24a 136a 94a 104a 21a 97a 19.41392 79a 76a 120a 169a Is 702 262 242 362 942 104a 21a 19.41392 86a 79a 108a 20a 69a I@ 26a 242 942 1042 21 a 97a 19.4139286a 133 1082 76a 20a 69a 26a 24a 94a 104a 1212 97a 19.41392186a 79a 1132 20a I a 70a 26a 24a 36a 94a 212 97a 19.487181793 132 108a 120a 69a 70a 26a 24a 36a 94a 104a 21a 19.487181863 79a 20a 69a 70a 26a 24a 36a 94a 1042 21a 97a 19.48718j79a 108a20a Is 70a 26a 124a 36a 94a 104a 21a 97a 19.4871879a 132 106a 202 69a Is 170a 26a 242 36a 94a 21a 19.48718 867a 79a 132 1082 20a 69a 70a 24a 36a 1104a 21a 972 24a 19,487181860 132 762 20a 69a 1 a 262 94a 1104a 21a 197a Field i ' , ?b1 1 2;r . 3 ~ IN 4,' ;; rs i6 7 Y1.
19.4871886a13a 1108a120a 11a 170a 126a 24a 136a 94a 1042 21a 19.56044862 13a 108a 20a 69a 70a 126a 24a 942 104a 121a 97a 19.56044862 13a 20a 69a 11a 170a 1262 124a 136a 1042 21a 972 19.5604 86aI79a 132 1762 202 169a 1246 36a 94a 1042 21 a 97a 19,633786a79a 13a 76a 120a 1698 70a 126a 242 104a 21a [97a 19.633779a113a 108a 20a 69a 702 26a 24a 36a 104a 21a 1972 19.6337862 792 108a 20a 692 la 1702 26a 24a 36a 1042 21a 19.6337186a1138 1082 76a 120a 69a 126a 24a 36a 1104a 21a 197a 19,6337 862 792 76a 120a 69a 1 a 702 26a 242 36a 94a 21 a 19.63 37 86a 179a 1132 176a 20a 169a 12 26a 242 36a 21a 972 19.633779al13a 20a 69a 70a 1262 24a 362 94a 11042 21 a 97a 19.70696 792 13a 76a 20a 169a la j26a 124a 362 1042 21 a 97a 19.70696186a179a 113a 76a 20a 69a j26a I24a 94a 104a 121 a 97a 19.7802211321082 762 20a 692 26a 124a 36a 94a 104a 121 a 97a 19,78022 86a 79a 1082 76a 202 la 26a 242 36a 194a 21 a= 97a 19.78022,86a1132 20a 169a 1l a 170a 1268 24a 942 11042 21 a 97a 19.78022186a179a 13a 1108a120a 169a 70a 242 362 94a 11042 212 19.7802217921132 768 20a 692 l a 702 262 242 362 21 a 97a 19.8534886a 132 1082 202 69a 112 262 124a 1362 104a 21a 97a 19.85348179a 132 1082 762 202 692 1 a j2 6a 242 362 1042 212 19.853481862 792 13a 1088 76a 120a 69a 1242 3621104a 21 a 1972 19.853481862 79a 13a 20a 169a 1 a 26a 124a 948 104a 21a 972 19.85348 86a 132 108a 176a 120a 169a 24a 368 94a 1042 21a 97a 19.9267479a 1082 202 169a la 70a 1262 24a 362 942 1046 21 a 19.926747921138 1082 202 69a 1a 702 262 2421362 21a 97a 19.92674 862 79a 1108a 120a 1692 la 708 26a 24a 136a 94a 21a 201868 79a 132 76a 120a 69a I1 a 124a 36a 104a 21a 972 20186a 79a 1083 76a 20a 70a 26a 24a 136a 94a . 104a 21a 20179a 13a 11082120a 69a 26a 24a 36a 194a 1042 21a 97a 2079210821762 120a Ila 26a 1242 36a 942 104a 121a 97a 20132 202 692 la 170a 126a 242 362 942 104a 21 a 197a 20 86a 79a 132 1082 762 120a 1 a 26a 242 36a 94a 121a 201863 79a 13a 762 20a 26a 24a 36a 94a 104a 21 a 197a 20 86a 79a 13a 20a ~70a 26a 124a 368 94a 104a 21 a 97a 20 862 13a 176a 202 69a 1 a 702 242 36a 11042 21 a 972 20 86a 762 20a 1692 1 a 26a 24a 136a 94a 11 04a 21 a 97a 20.073261862 792 113a 1082 208 69a 70a 26a 242 362 104a 21a 20.07326186a 79a 13a 76a 20a 1692 la 26a 242 104a 21a 97a 20.0732686a 13a 76a 20a la 702 26a 24a 1362 94a 1042 21a 20.0732686a79a 138 108a 202 69a l1a 702 124a 36a 1048 21a 20.1465279a 132 762 20a 69a 1a 70a 26a 24a 368 104a 21a 20,1465286a 79a 13a 76a 20a 69a 26a 24a 36a 1042 21a 97a 20.14652186a 792 108a 76a 20a 26a 24a 36a 94a 1042 212 97a 20.14652 862 76a 20a la 70a 126a 24a 36a 94a 104a 21a 97a 20.14652 868138 11082 20a 692 1 a 26a 24a 94a 104a 21a 97a 20.21978 86a1792 13a 76a 202 69a 70a 242 362 104a 2l a 197a 20.21978 862 792 20a 69a I@ 70a 26a 243 36211048 121 a 197a `F,-..eld 1..~ -f, ? r3 6rtIlk, 112ta 20.29304186a179a 1108a120a 169a la 26a 24a 136a194a 1218 978 20,29304 86a 13a 1769 20a 70a 26a 24a 36a 94811048 218 97a 20.3663113a 108a20a 69a 1a 26a (24a 36a 194a 104a 21a 197a 20.3663 868 798 1088 768 20a 1 a 170a 26a 24a 36a 948 21 a 20.3663 798138 1088 (768 209 69a la 126a 1248 (36a 94a 121 a 20.4395686a1108a(76a 120a 702 26a 24a 36a 948 1048 218 97a 20.43956 868 798 113a (768 120a 169a la 268 ~24a 136a 10421218 20.51282798 13a 120a 169a 1a 170a 26a 24a 368 94a 121a 97a 20.51282,868 798 108a 176a 120a I1 a 126a 1248 194a 104a 21 a 97a 20.58606179a 1088 76a 20a la 170a (26a 1248 36a 94a 1048 21a 20.58608798 1Q8a 20a 169a la 26a (24a 36a 94a 104a 121a 97a 20.58608868 79a 1108a 20a (69a 70a 126a 24a 36a 948 104a 121a 20.58608186a113a 176a 20a 169a 170a 126a 24a (368 94a 1042 21a 20.6593479a 10840a 69a 112 708 126a 248 6a 104a 21a 978 20.6593479a 20a (69a (1 a 1708 268 1248 368 '948 ~104a 121 a 197a 20.6593479a 10881768 20a 1692 11a 126a 24a 1363 94a 1104a 121a 20,7326186a79a 1132 1088 20a J69a la, 26a j24a 36a 104a 21a 20.7326 868 79a 1108a 1208 la 170a 26a 24a 136a 104a 1212 978 20.7326 86a 798 768 20a 698 la 268 24a 136a 1104a 21a ~97a 20.7326 86a 798 1088 76a 208 (69a 11 a 24a 94a 11 04a 21 a 97a 20.732679a 13a 11088 20a 698 1a 70a 26a 248 36a 11048 218 20,9523886a{798 1088 208 169a 118 268 24a 36a 1048 121a 97a 21.0256 8681138 11088176a 20a 69a 268 24a 36a,94a 1048 21a 21.0256 868 79a 110881208 69a 268 248 368 948 1048 218 97a 21.0989186a20a. 69a 11a 170a 126a 24a 136a 94a1104a 121a 197a 21.2454 863 108a 76a 208 69a 126a 124a 1368 948 104a 21a 197a 21.24542 868 798 1088763 20a 1698 11 a 26a 24a 136a 94a 21 a 21.318681862179a 138 76a 20a 1la 1268 1248 36a 1948 104a 121a 21.31868 86a 79a 13a 108a,20a 118 268 248 368 94a 11048 21 a 21.39194 868 798 176a 20a 11 a 70a ,26a 1248 363 94a 1104a 121 a 21.4652138 1088 20a 1698 170a 126a 24136a 94a 104a 21 a 197a 21.465 868 798 20a 169a 11 a 170a 26024a 36a 948 21a 97a 21.465 868798 13a 768 20a 1698 268 24a 36a 94a 11048 21a 21.5384686a1108a 208 69a 170a 268 24a 36a 948 104a 218 197a 21.61172 868 798 13a 1088 208 26a 24a 36a 94a 1048 21a 97a 21.61172 868 798 76a 208 692 1 a 26a 24a 368 948 121a 97a 21.61172868798 13a 20a 69a la 70a 26a 24a136a .11048 218 21.61172 862179a 13a 108a 20a 70a 26a I24a 36a 948 1048 21a 21:68498 868 13a 20a 1 a 70a 26a 248 36a 94a 104a 21 a 97a 21.68498868139 108a 20a 69a 70a 268 24a 36a 94a 104a 21a 21,6849 79a113a 20a 69a 1a 70a 126a 248 36a 104a 21a 97a 21.7582 868 798 76a 208 1 a 26a 248 368 94a 1048 21 a 97a 21.75824 868 13a 176a 20a 69a 1 a 26a 24a 36a 194a 104a 21a 21.75824 868138 20a 69a 70a 26a 24a 36a 948 104a 121 a 97a 21.75824868798 13a 108a20a 69a 26a 24a 368 948 1104a 21a 21.8311 79a 13a 1088 20a 69a la 26a 248 36a 104a 21a 197a 21.90476 868 138 108a 120a 698 1 a )268 24a 1363 94a 1048 121 a

Claims (27)

1. A method for producing a mass-coded set of compounds of the general formula X(Y)n, wherein X is a scaffold, n is from 2 to about 6, and each Y is, independently, a peripheral moiety, comprising the steps of:

(a) choosing every set of two different peripheral moiety precursors from a peripheral moiety precursor set, said choosing performed in a manner such that for each set of two, if the two peripheral moiety precursors have equal molecular masses, then one of the two is removed, forming a remaining set;

(b) from the remaining set, choosing every set of four peripheral moiety precursors, including for a given set of four, removing one of the four peripheral moiety precursors if a sum of the molecular masses of a first two precursors in the given set of four equals a sum of the molecular masses of a second two precursors in the given set of four peripheral moiety precursors, said choosing forming a remainder set;

(c) from the remainder set, choosing every set of six different peripheral moiety precursors, including for a given set of six, removing one of the six peripheral moiety precursors if a sum of the molecular masses of a first three precursors in the given set of six equals a sum of the molecular masses of a second three precursors in the given set of six, said choosing forming a working selection set of peripheral moiety precursors;

(d) from the working selection set of peripheral moiety precursors (i) choosing all peripheral moiety precursor subsets, said subsets comprising a sufficient number of peripheral moiety precursors that there exist at least about 250 distinct combinations of n peripheral moieties derived from said subsets;
(ii) from the chosen subsets, generating all possible combinations of n peripheral moiety precursors; and (iii) determining whether at least about 90% of the generated combinations have molecular mass sums which are distinct from the molecular mass sums of all other combinations of n peripheral moieties derived from said possible subset, and if so, selecting the chosen possible subset as the peripheral moiety precursor subset, and if not, repeating step (ii), and if no further possible combinations remain, then repeat steps (a) through (d)(ii);

and (e) contacting said peripheral moiety precursor subset with a scaffold precursor, said scaffold precursor having n reactive groups, wherein each reactive group is capable of reacting with at least one peripheral moiety precursor to form a covalent bond, under conditions sufficient for the reaction of each reactive group with a peripheral moiety precursor, thereby producing a mass-coded set of compounds of the general formula X (Y)n.

2. The method according to claim 1 wherein the scaffold precursor comprises one or more saturated, partially unsaturated or aromatic cyclic groups.

3. The method according to claim 2 wherein at least one cyclic group is substituted by one or more reactive groups.

4. The method according to claim 3 wherein the reactive groups are attached to the cyclic group directly or via an intervening C1-6-alkylene group.

5. The method according to claim 4 wherein each reactive group is independently selected from the group consisting of: reactive carbonyl groups, reactive sulfonyl groups, reactive phosphonyl groups, terminal epoxide group and the isocyanate group.

6. The method according to claim 5 wherein the reactive group is selected from the group consisting of:
carbonyl chloride, carbonyl pentafluorophenyl ester and sulfonyl chloride.

7. The method according to claim 5 wherein at least one peripheral moiety precursor comprises a primary amino group, a secondary amino group or a hydroxyl group.

8. The method according to claim 4 wherein each reactive group is independently selected from the group consisting of: primary amino, secondary amino and hydroxyl.

9. The method according to claim 8 wherein at least one peripheral moiety precursor comprises a reactive carbonyl group, reactive sulfonyl group, reactive phosphonyl group, terminal epoxide group or an isocyanate group.

10. The method according to claim 9 wherein at least one peripheral moiety precursor comprises a carbonyl chloride, a carbonyl pentafluorophenyl ester or a sulfonyl chloride group.

11. The method according to claim 1 wherein steps (a) through (d) are performed by a digital processor assembly.

12. The method according to claim 1 wherein all members of the peripheral moiety precursor subset are contacted with and can react with all n reactive groups of the scaffold precursor.

13. The method according to claim 1 wherein the scaffold precursor is contacted with all members of the peripheral moiety precursor subset simultaneously.

14. Apparatus for producing a mass-coded set of compounds of the general formula X(Y)n, wherein X is a scaffold, n is from 2 to about 6, and each Y is, independently, a peripheral moiety, the apparatus comprising:
storage for storing a peripheral moiety precursor set;
and a digital processor assembly for selecting a peripheral moiety precursor subset from the peripheral moiety precursor set, wherein the digital processor assembly employs a routine executed by a digital processor for:
(a) choosing every set of two different peripheral moiety precursors from the peripheral moiety precursor set, said choosing performed in a manner such that for each set of two, if the two peripheral moiety precursors have equal molecular masses then one of the two is removed forming a remaining set;

(b) from the remaining set, choosing every set of four peripheral moiety precursors, including for a given set of four, removing one of the four peripheral moiety precursors if a sum of the molecular masses of a first two precursors in the given set of four equals a sum of the molecular masses of a second two precursors in the given set of four peripheral moiety precursors, said choosing forming a remainder set;

(c) from the remainder set, choosing every set of six different peripheral moiety precursors, including for a given set of six, removing one of the six peripheral moiety precursors if a sum of the molecular masses of a first three precursors in the given set of six equals a sum of the molecular masses of a second three precursors in the given set of six, said choosing forming a working selection set of peripheral moiety precursors from which to select a desired subset; and (d) from the working selection set, choosing a desired subset so as to provide the selected subset by (i) choosing all possible subsets from the working selection set, (ii) from the chosen possible subsets, generating all possible combinations of n peripheral moiety precursors, and (iii)determining whether at least about 90% of said combinations of n peripheral moieties derived from said chosen possible subsets have molecular mass sums which are distinct from the molecular mass sums of all other combinations of n peripheral moieties derived from said chosen possible subsets, and, if so, selecting the chosen possible subset as the selected subset, and if not, repeating step (ii), and if no further possible combinations remain, then repeat steps (a) through (d) (ii) ;

wherein the selected subset comprises a sufficient number of peripheral moiety precursors that there exist at least about 250 distinct combinations of n peripheral moieties derived from said selected subset.

15. The apparatus of claim 14 wherein the scaffold precursor comprises one or more saturated, partially unsaturated or aromatic cyclic groups.

16. The apparatus of claim 15 wherein at least one cyclic group is substituted by one or more reactive groups.

17. The apparatus of claim 16 wherein the reactive groups are attached to the cyclic group directly or via an intervening C1-6-alkylene group.

18. The apparatus of claim 17 wherein each reactive group is independently selected from the group consisting of:
reactive carbonyl groups, reactive sulfonyl groups, reactive phosphonyl groups, terminal epoxide group and the isocyanate group.

19. The apparatus of claim 18 wherein the reactive group is selected from the group consisting of: carbonyl chloride, carbonyl pentafluorophenyl ester and sulfonyl chloride.

20. The apparatus of claim 18 wherein at least one peripheral moiety precursor comprises a primary amino group, a secondary amino group or a hydroxyl group.

21. The apparatus of claim 17 wherein each reactive group is independently selected from the group consisting of:
primary amino, secondary amino and hydroxyl.

22. The apparatus of claim 21 wherein at least one peripheral moiety precursor comprises a reactive carbonyl group, reactive sulfonyl group, reactive phosphonyl group, terminal epoxide group or an isocyanate group.

23. The apparatus of claim 22 wherein at least one peripheral moiety precursor comprises a carbonyl chloride, a carbonyl pentafluorophenyl ester or a sulfonyl chloride group.

24. The apparatus of claim 14 wherein all members of the peripheral moiety precursor subset are contacted with and can react with all n reactive groups of the scaffold precursor.

25. The apparatus of claim 14 wherein the scaffold precursor is contacted with all members of the peripheral moiety precursor subset simultaneously.

26. Apparatus for producing a mass-coded set of compounds of the general formula X(Y)n, wherein X is a scaffold, n is from 2 to about 6, and each Y is, independently, a peripheral moiety, the apparatus comprising:

storage for a peripheral moiety precursor set; and a digital processor assembly for selecting a peripheral moiety precursor subset from the peripheral moiety precursor set, wherein the digital processor assembly employs a routine executed by a digital processor for:
(a) choosing every set of two different peripheral moiety precursors from the peripheral moiety precursor set, said choosing performed in a manner such that for each set of two, if the two peripheral moiety precursors have equal molecular masses then one of the two is removed forming a remaining set;
(b) from the remaining set, choosing every set of four peripheral moiety precursors, including for a given set of four, removing one of the four peripheral moiety precursors if a sum of the molecular masses of a first two precursors in the given set of four equals a sum of the molecular masses of a second two precursors in the given set of four peripheral moiety precursors, said choosing forming a remainder set; and (c) from the remainder set, choosing a desired subset so as to provide the selected subset by (i) choosing all possible subsets from the working selection set, (ii) from the chosen possible subsets, generating all possible combinations of n peripheral moiety precursors, and (iii)determining whether at least about 90% of said combinations of n peripheral moieties derived from said chosen possible subset have molecular mass sums which are distinct from the molecular mass sums of all other combinations of n peripheral moieties derived from said chosen possible subset, and, if so, selecting the chosen possible subset as the selected subset, and if not, repeating step (ii), and if no further possible combinations remain, then repeat steps (a) through (c)(ii) wherein the selected subset comprises a sufficient number of peripheral moiety precursors that there exist at least about 250 distinct combinations of n peripheral moieties derived from said selected subset.

27. Apparatus for producing a mass-coded set of compounds of the general formula X(Y)n, wherein X is a scaffold, n is from 2 to about 6, and each Y is, independently, a peripheral moiety, the apparatus comprising:
storage for storing a peripheral moiety precursor set;
and a digital processor assembly for selecting a peripheral moiety precursor subset from the peripheral moiety precursor set, wherein the digital processor assembly employs a routine executed by a digital processor for:
(a) choosing every set of two different peripheral moiety precursors from the peripheral moiety precursor set, said choosing performed in a manner such that for each set of two, if the two peripheral moiety precursors have equal molecular masses then one of the two is removed forming a remaining set; and (b) from the remaining set, choosing a desired subset so as to provide the selected subset by (i) choosing all possible subsets from the working selection set, (ii) from the chosen possible subsets, generating all possible combinations of n peripheral moiety precursors, and (iii) determining whether at least about 90% of said combinations of n peripheral moieties derived from said chosen possible subsets have molecular mass sums which are distinct from the molecular mass sums of all other combinations of n peripheral moieties derived from said chosen possible subsets, and, if so, selecting the chosen possible subset as the selected subset, and if not, repeating step (ii), and if no further possible combinations remain, then repeat steps (a) through (b)(ii) wherein the selected subset comprises a sufficient number of peripheral moiety precursors that there exist at least about 250 distinct combinations of n peripheral moieties derived from said selected subset.