CA2303323A1 - Compounds containing six-membered rings, processes for their preparation, and their use as medicaments - Google Patents

Abstract

Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidase activity are also described.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DE
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets THiS SECTION Oi= THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
THtS IS VOLUME _ J O!=
_~__ NOT>': For additional volumes.pl~ase contact the Canadian Patent Office . ,' COMPOUNDS CONTAINING SIX-MEMBERED RINGS, PROCESSES FOR THEIR PREPARATION, AND
THEIR USE
AS MEDICAMENTS
Cross Referenced to Related Applica+~~rs This application is based upon United States Provisional Application IO Serial Number 60/060,195, filed September 26, 1997, United States Patent Application Serial Number 08/938,644, filed September 26, 1997, and United States Provisional Application Serial Number 60/059,308, filed September 17, 1997.
This application is also related to United States Patent Application Serial Number 08/653,034, filed March 24, 1996, which was a conHnuation-in-part application of United States Patent Application Serial Number 08/606,624, filed February 26, 1996, which was a continuation-in-part application of United States Patent Application Serial Number 08/580,567, filed December 29, 1995, which was a continuation-in-part application of United States Patent Application Serial Number 08/476,946, filed June 6, 1995, which was a continuation-in-part application of United States Patent Application Serial Number 08/395,245, filed February 27, 1995, all of which are incorporated herein by reference in their entirety. This application is related to United States Patent Application Serial Number 08/917,640, filed August 22, 1997, which describes methods of making carbocyclic compounds in particular methods of making GS 4104, phosphate salt, and is incorporated by reference in its entirety.
Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alpha-ketosidically linked sialic acids from glycoproteins, glycolipids and oligiosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. These pathogenic organisms include influenza virus.
Neuraminidase has been implicated in the pathogenicity of influenza viruses. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
von Itzstein, M. et al.; "Nature", 363(6428):418-423 (1993), discloses the rational design of sialidase-based inhibitors of influenza virus replication.
Colman, P. M. et al.; International Patent Publication No. WO
92/06691 (Int. App. No. PCT/AU90/00501, publication date April 30, 1992), von Itzstein, L. M. et al.; European Patent Publication No. 0 539 204 A1 (EP
App. No. 92309684.6, publication date April 28, 1993), and von Itzstein, L. M.
et al.; International Publication No. WO 91/16320 (Int. App. No.
PCT/AU91/00161, publication date October 31, 1991) disclose compounds that bind neuraminidase and are asserted to exhibited antiviral activity in vivo.
Objects of the Invention A principal object of the invention is inhibition of viruses, in particular influenza viruses. In particular, an object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases.
An additional object of the invention is to provide neuraminidase inhibitors that have a retarded rate of urinary excretion, that enter into nasal or pulmonary secretions from the systemic circulation, that have sufficient oral bioavailability to be therapeutically effective, that possess elevated potency, that exhibit clinically acceptable toxicity profiles and have other desirable pharmacologic properties.
Another object is to provide improved and less costly methods for synthesis of neuraminidase inhibitors.
A still further object is to provide improved methods for administration of known and novel neuraminidase inhibitors.
An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles These and other objects will be readily apparent to the ordinary artisan from consideration of the invention as a whole.
Summar;~r of the Invent_i ,~
Compounds, or compositions having formula (I) or (II) are provided herein:
Ji U~ A~. E~ J~ U~ A Ei Tt Jta T~
Jta J2 J~ JZ
G~ J2a ~'-'t J2a (~) (~~) wherein A1 is -C(Jl)=,.-N= or -N(O)=;
to A2 is -C(Jl)2-, -N(Jl>-, -N(O)(h)-, -s-, -s(o)-, -s(o)2- or -o-;
E1 is -(CR1R1)mlWl;
G1 is N3, -CN, -OH, -OlZ6a, -N02, or -(CR1R1)mlW2;
Tl is -NR1W3, H, -I~, -R5, a heterocycle, or is taken together with Ul or G1 to form a group having the structure Rsb-N
U1 is H, -I~ or -X1W6;
Jl and Jla are independently Rl, Br, Cl, F, I, CN, N02 or N3;
J2 and J2a are independently H or Rl;
Rl is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OR6a, -ORi, -N(Ri)2, -N(Rl)(R6b), -N(R6b)2, -SRl, -SRE,a, -S(O)RT, -S(O)2R1, -S(O)ORl, -S(O)ORE,a, -S(O)20R1, -S(O)20RE,a, -C(O)ORl, -C(O)R6c, -C(O)O~a, -~(O)Rl, -N(Rl)(C(O)R1), -N(~b)(C(O)Rl), -N(Rl)(C(O)ORO, -N(~b)(C(O)ORl), -C(O)N(R1)2, -C(O)N(~b)(R1), -C(O)N(~b)2, -C(NRl)(N(R1)2), -C(N(R6b))(N(Rl)2), -C(N(Rl))(N(Rl)(R6b)), -C(N(R6b))(N(Rl)(REb)), -C(N(Rl))(N(RCb)2), -C(N(R6b))(N(R6b)2), -N(Rl)C(N(Rl))(N(Rl)2), -N(Rl)C(N(R1))(N(R1)(~b)), -N(Rl)C(N(R6b))(N(Rl)2), N(R6b)C(N{R1)){N{Rl)2), -N{~b)C{N{R6b))(N(Rl)2), -N{R6b)C{N{Ri)){N(R1)(R6b)), -N(R1)C{N{R66)){N{Rl)(R6b)).
-N{R1)C{N{R1)){N{R6b)2), -N{R6b)C(N{R6b))(N(Rl)(R6b)), -N{R(,b)C{N{Rl)){N{R6b)2), -N{Rl)C{N{R6b)){N{REb)2), -N{R6b)C{N{R6b)){N{~b)2), =O, =S, =N{R1), =N{fib) or W5;
R4 is independently alkyl of 1 to I2 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkyiene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
R6a is independently H or an ether- or ester-forming group;
R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R~,~ is independently H or the residue of an amino-containing compound;
Wl is a group comprising an acidic hydrogen, a protected acidic group, or an Rbc amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom or a group derivatizable to a basic heteroatom;
W3 is W4 or W5;
W4 is R5 or -C(O)R5, -C(O)WS, -S02R5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -~5, -W5, -R5aW5, -C(O)OR6a, -C(O)R6c, -C(O)N{R6b)2, -C{NR6b)(N{R6b)2), -C(NR6b)(N{H){R6b)), -C{N(H)(N(R6b)2), -C{S)N{R6b)2, or -C(O)R2;
XI is a bond, -O-, -N(H)-, -N{W6)-, -N(OH}-, -N(OW6)-, -N(NH2)-, -N{N{H){W6))-, -N{N{W6)2)-, -N(H)N{W6)-, -S-, -SO-, or -S02-; and each mI is independently an integer from 0 to 2;
provided, however, that compounds are excluded that are described in WO
91 / 16320 at page 3, line 23 to page 5, line 6, which appear to include compounds wherein:
{a) A1 is -CH= or -N= and A2 is -CH2-;

(b) E1 is COOH, P(O)(OH)2, SOOH, S03H, or tetrazol;
(c) G1 is CN, N(H)R2p, N3, SR2p, OR2p, guanidino, -N(H)CN
N-R2o ~ NR2o ~ N--~O ~ -NH~1-R2o ORzo R2o RZOR2o N ~ _ or _ N/-'1, CH2 ~-N ~ , N
(d) T1 is -NHR20;
(e) R2p is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an N02 group, an NH2 group or a COOH group;
(f) Jl is H and Jl a is H, F Cl, Br or CN;
(g) J2 is H and J2a is H, CN or N3;
(h) U1 is CH2YR2pa, CHYR20aCH2YR20a or CHYR2paCHYR2paCH2YR20a:
(i) R20a is H or acyl having 1 to 4 carbon atoms;
(j) YisO,S,HorNH;
(k) 0 to 2 YR2pa are H, and (1) successive Y moieties in a U1 group are the same or different, and when Y is H then R2pa is a covalent bond, and provided that if G1 is N3 then U1 is not -CH20CH2Ph.
and the pharmaceutically acceptable salts and solvates thereof;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Also excluded herein are compounds described in WO 92/06691 at Page 9, Line 26, to Page 11, Line 5, which appear to include compounds of the formula II wherein:
(a) A2 is O;
(b) E1 is COOH, P(O)(OH)2, N02, SOOH, S03H, tetrazole, CHzCHO, CHO, CH(CHO)2 or where E1 is COOH, P(O)(OH)2, SOOH or SO~H, an ethyl, methyl or pivaloyl ester thereof;
(c) G1 is hydrogen, N(R2oa)2, SR2oa or OR2oa;
{d) Tl is -NHC(O)R2ob, where R2ob is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR2oa, OR2oa, COOH or alkyl/aryl ester thereof, N02, C(RZOa)3, CH2COOH or alkyl/aryl ester thereof, CH2N02 or CH2NHR2ob;
(e) R2oa is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an N02 group, an NHZ group or a COOH group;
(f) J1 is H and Jla is H, OR2oa, F, Cl, Br, CN, NHR2oa, SR2oa or CHZX wherein X is NHR2oa, halogen or OR2oa;
(g) J2 is H or J2a is hydrogen, N(R2oa)Z, SR2oa or ORZOa;
(h) U1 is CH2YR2oa, CHYR2oCH2YR2oa or CHYR2oaCHYR2oaCH2YRz«a where Y is O, S or H, and successive Y moieties in U1 are the same or different and R2oa represents a covalent bond when Y is hydrogen and and pharmacologically acceptable salts or derivatives thereof.
Another embodiment of the invention is directed to compounds of the formula:
U1 Ji i J ~ ~.. E~ J
J~a J2 G J J~ T~ J2 ~~a 1 2a G ~ J2a (I11) wherein E1 is -(CR1R1)mlWl:
G1 is N3, -CN, -OH, -OR6a, -N02, or -(CR1R1)mlW2;
T1 is -NR1W3, a heterocycle, or is taken together with Ul or G1 to form a group having the structure Rsb-N
U1 is H or -X1W6 and, if -X1W6, then Ul is a branched chain;
J1 and Jla are independently Rl, Br, Cl, F, I, CN, N02 or N3;
J2 and J2a are independently H or Rl;
Rl is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently R,3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -NOz, -OIt6a, -ORi, -N{Rl)2, -N{Rl){R6b). -N(R6b)z. -SRi, -SRE,a, -S(O)Ri, -c~'(O)2R1, -S{O)ORl, -S(O)ORba.
-S(O)zORi, -S(O)20R~,a, -C(O)ORi, -C(O)RD, -C(O)OR~,a, -OC(O)Ri.
-N(Ri)(C(O)R1), -N(~b)(C(O)Ri), -N(Ri)(C(O)OR1), -N(~b)(C(O)ORi), -C(~)N(R1)2, -C(~)N(R6b)(R1), -C(O)N(Rfb)z. -C(NRi)(N(Rl)z).
-C(N(R6b))(N(R1)2), -C(N(Rl))(N(R1)(R6b)), -C(N(R6b))(N(R1)(RE,b)).
-C(N(R1))(N{~b)2), -C(N{R6b))(N(Rbb)2), -N(R1)C(N(Ri))(N(R1)2), -N(Ri)C(N(Ri))(N(R1)(R6b)). -N(Ri)C(N(R6b)){N(Ri)z).
-N{R6b)C(N{R1))(N(R1)2), -N(R6b)C(N(R6b)){N(R1)2), -N(R6b)C{N(R1))(N{Rl)(R6b)), -N(R1)C(N(R6b))(N(Rl)(R6b)).
-N(Rl)C(N(R1))(N(R6b)z). -N(R6b)C(N(R6b))(N(Rt)(RGb)), -N(~b)C(N{R1))(N(R6b)2), -N(Rl)C(N(R6b))(N(Rfb)2).
-N(~b)C(N(R6b))(N(~b)2), =O, =S, =N(Rl) or =N(R6b):
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
R(a is independently H or an ether- or ester-forming group;
R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6~ is independently H or the residue of an amino-containing compound;
Wl is a group comprising an acidic hydrogen, a protected acidic group, or an It6c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an It6b amide of the basic heteroatom;
W3 is W4 or WS;
W4 is R5 or -C(O)RS, -C(O)WS, -S02RS, or -S02WS:
WS is carbocycle or heterocycle wherein WS is independently substituted with 0 to 3 R2 groups;
W6 is -RS, -WS, -RSaWS, -C{O)ORba, -C(O)R6c, -C(O)N(R6b)2, -C(NR6b)(N(R6b)2)~ -C(S)N(R6b)2, or -C{O)R2:
Xl is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-, -N(N(H)(W6))-, -N{N(Wb)2)-, -N{H)N{W6)-, -S-, -SO-, or -S02-; and each ml is independently an integer from 0 to 2;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of the formula:
Jt , ~ Et Tt Jta J2 /~ ;Jt C't J2a wherein E1 is -(CR1R1)mlWl:
G1 is N3, -CN, -OH, -OR6a, -N02, or -{CR1R1)mlW2:
Tl is -NR1W3, a heterocycle, or is taken together with Ul or G1 to form a group having the structure Rsb-N
U1 is H or -X1W6;
Jl and Jla are independently Rl, Br, Cl, F, I, CN, N02 or N3;
J2 and J2a are independently H or Rl;
Rl is independently H or alkyl of 1 to 12 carbon atoms;
- g_ R2 is independently R,3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OR6a, -0Rl, -N(Rl)2.
-N(Rl){R6b). -N(R6b)2. -SRl, -SR~,a. -S{O)R1, -S{O)2R1. -S{O)ORI, -S(O)ORba.
-S(O)20R1, -S(O)ZORE,a, -C(O)ORZ, -C{O)R~, -C(O)ORS, -OC(O)Rl, -N(Rl)(C{O)Rl). -N{R6b){C{O)R1). -N(R1)(C(O)ORl), -N(Rbb)(C{O)OR1).
-C{O)N(R1)2. -C(O)N(~b)(R1). -C(O)N(R6b)2, -C(NRl)(N{RI)2).
-C(N(R6b))(N(R1)2), -C(N{Rl)){N(R1){R6b)). -C(N(R6b))(N(R1){R6b)).
-C{N{R1)){N{REb)2). -C(N{R6b)){N(R6b)2), -N(R1)C(N{Rl))(N{Rl)2).
-N(Rl)C(N(R1))(N{R1){R6b)). -N{Rl)C(N(R6b)){N{Rl)2).
-N{R6b)C(N(Rl)){N{Rl)2). -N(R6b)C(N(~b))(N(R1)2), -N(R6b)C(N(R1))(N{R1)(R6b)), -N(Rl)C(N{~b))(N(R1){~b)).
-N{Rl)C{N(Rl)){N(Ffib)2). -N(Rfb)C(N{~b))~N(Rl){R6b)).
-N(R6b)C{N{R1))(N{~b)2), -N(R~)C{N{R6b))(N(~b)2)~
-N(Rfb)C(N(Rfib))(N{R6b)2), =O. =S. =N{Rl) or =N(R(,b):
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyi of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkyiene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
R6a is independently H or an ether- or ester-forming group;
Rib is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6~ is independently H or the residue of an amino-containing compound;
W1 is a group comprising an acidic hydrogen, a protected acidic group, or an RE,c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom;
W3 is W4 or W5;
W4 is R5 or -C(O)R5, -C(O)WS, -S02R5, or -S02W5:
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5. -C(O)OR6a, -C(O)R6c. -C(O)N{R6b)2, wo 99/iais5 -C(NR6b)(N(IZ6b)2). -C(S)N(It6b)2, or -C(O)R2;
X1 is -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-, -N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -S02-; and each ml is independently an integer from 0 to 2;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of the formula:
E~
Ti v w herein:
E1 is -C02R1;
G1 is -NH2, -N(H)(I~5) or -N(H)(C(N(H))(NH2));
Tl is -N(H)(C(O)CH3);
U1 is -OI~p;
Rl is H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms;
and Rip is a branched alkyl of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of formulas (VII) or (VIII):
U~\N \ E~ Ui\ Et T~ Jia Tt '~~a Gy J G
2a 1 ~2a {VII) {VIII) wherein E1 is -(CR1R1)mlWl;
G1 is N3, -CN, -OH, -OItda, -N02, or -(CR1R1)mlW2;
Tl is -NR1W3, a heterocycle, or is taken together with G1 to form a group having the structure Rsb-N
U1 is -X1W(;

Jl and Jla are independently Rl, Br, Cl, F, I, CN, N02 or N3;
J2 arid J2a are independently H or Rl;
Rl is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently I~3 or R4 wherein each R~ is independently substituted with 0 to 3 I~ groups;
R3 is independently F, Cl, Br, I, -CN, N3, -NO2, -OTt6a, -ORl, -N(Rl)2, -N(Rl)(R6b). -N(R(,b)2. -SRl, -SR~,a. -S(O)RT, -S{O)2R1. -S(O)ORl, -S(O)OR~,a.
-S(O)20R1. -S(O)20RE,a. -C(O)ORI, -C(O)~c. -C(O)OR6a. -OC{O)R;.
-N(Rl)(C(O)Rl), -N(~b)(C(O)R1), -N(Rl)(C(O)OR1). -N(~b)(C(O)ORl).
-C(~)N(Rl)2, -C(~)N(~b)(Rt). -C{~)N(Rfib)2, -C(NRl)(N(Rl)2).
-C(N(R(,b))(N(R1)2), -C(N(Rl))(N(Rt)(R6b)), -C(N(R(,b))(N(R1)(~b)), -C(N(Rl))(N(R6b)2). -C(N(REb))(N(R6b)2). -N{RI)C(N{Rl))(N{RI)2).
-N(R1)C(N(R1))(N(Ri)(R6b)), -N(Rl)C(N(Rbb))(N(Rl)2), -N(R6b)C(N(Rl))(N(Rl)2). -N(Rfib)C(N(Rfib))(N(R1)2), -N(R6b)C(N(R1))(N(R1)(Rsb)). -N(R1)C(N(R6b))(N(R1)(R(b)).
-N(R1)C(N(Rl)HN(~b)2), -N(Rlb)C(N(R6b))(N(R1){R6b)).
-N(R6b)C(N(R1))(N(~b)2), -N(Ri)C(N(Rsb)){N(~b)2).
-N(R6b)C(N(~b))(N{REb)2), =O. =S. =N(Rl) or =N(~b):
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 I~ groups;
R6a is independently H or an ether- or ester-forming group;
Itbb is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6~ is independently H or the residue of an amino-containing compound;

W1 is a group comprising an acidic hydrogen, a protected acidic group, or an RE,c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom;
W3 is W4 or W5;
W4 is R5 or -C(O)R5, -C(O)WS, -S02R5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -I~5, -W5, -R5aW5, -C(O)OIt6a, -C(O)R6c, -C(O)N(R6b)2, -C(NRF,b)(N(R6b)2), -C(~6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2.
or -C(O)R2;
Xl is a bond, -O-, -N(H)-, -N(W6)-, -S-, -SO-, or -S02-; and each ml is independently an integer from 0 to 2;
provided, however, that compounds are excluded wherein U1 is H or -CH2CH(OH~H2(OH);
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
In another embodiment of the invention a compound or composition of the invention is provided that further comprises a pharmaceutically-acceptable carrier.
In another embodiment of the invention the activity of neuraminidase is inhibited by a method comprising the step of treating a sample suspected of containing neuraminidase with a compound or composition of the invention.
Another embodiment of the invention provides a method for inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuramirudase with the composition embodiments of the invention.
Another embodiment of this invention is a method for the treatment or prophylaxis of viruses, particularly influenza virus infection in a host comprising administration to the host, by a route other than topically to the respiratory tract, of a therapeutically effective dose of an antivirally active compound described in WO 91/16320, WO 92/06691 or US patent 5,360,817.
In other embodiments, novel methods for synthesis of the compounds of this invention are provided. In one such embodiment, a method is provided for using a compound of the formula 281 wherein the method comprises treating compound 281 with a compound of the formula R5-Xl-H to form a compound of the formula 281.1 R5-Xyn..... CO2R51 ~ C02R5~
Rsa N ~N

281 281.1 wherein:
Xl and R5 are as described above;
R51 is an acid stable protecting group for a carboxylic acid; and R54 aziridine activating group.
In another embodiment, a method is provided for using a compound of the formula:
HO~HS

4 i, HO~~~~ 3 2 OH
Quinic Acid wherein the method comprises treating Quinic acid with a geminal dialkoxyalkane or geminal dialkoxy cycloalkane and acid to form a compound of the formula:
OH
R /pu.» = O
so.0~,,.
O

treating compound 274 with a metal alkoxide and an alkanol to form a compound of the formula:

OH
,O
~ C02Rs1 Rso.O.,,.
OH

treating compound 275 with a suifonic acid halide and an amine to form a compound of the formula:
OH
/QIH..
C02R5~
Rso~ Ow~

and treating compound 276 with a dehydrating agent followed by an acid and an alkanol to form a compound of the formula:
HO.,,. \ C02R51 HO~

wherein:
Rsp is a 1,2 diol protecting group;
R51 is an acid stable carboxylic acid protecting group; and R52 is a hydroxy activating group.
Figs. 1 and 2 depict the arterial oxygen saturation (Sa02) levels of influenza-A infected mice treated with varying i.p. doses of GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid), a known anti-influenza compound (Fig. 1) and compound 203 of this invention (Fig. 2):
50, 10, 2 and 0.5 mpk (mg/kg/day) of test compounds and saline control are designated, respectively, by squares, solid circles, triangles, diamonds and open circles. In all Figures, *P<0.05, **P<0.01 compared to the saline controls.
Figs. 3-5 compare the Sa02 levels achieved in influenza A infected mice treated with p.o. doses of ribavirin {triangles), compound 203 (squares) and GG167 (solid circles); saline controls are open circles: Fig. 3: 150 mpk of each of compound 203 and GG167, 100 mpk ribavirin; Fig. 4: 50 mpk of each of compound 203 and GG167, 32 mpk of ribavirin; Fig. 5: 10 mpk of each of compound 203 and GG167, 10 mpk of ribavirin.
Figs. 6-8 depict the SaO2 levels in influenza A infected mice treated with low p.o. doses of compounds 262 (circles) and 260 {solid squares) and GG167 (triangles); saline controls are open circles and uninfected controls are open squares: Fig. 6: mpk of each of the test compounds; Fig. 7: 1 mpk of each test compound; Fig. 8: 0.1 mpk of each test compound.
Detailed Desc~;ption Compssitions of the Invention.
The compounds of this invention exclude compounds heretofore known. However, as will be further apparent below in other embodiments it is within the invention to use for antiviral purposes known compounds heretofore only produced and used as intermediates in the preparation of antiviral compounds. With respect to the United States, the compounds or compositions herein exclude compounds that are anticipated under 35 USC
~102 or obvious under 35 USC ~103. In particular, the claims herein shall be construed as excluding the compounds which are anticipated by or not possessing novelty over WO 91 / 16320, WO 92 / 06691, US Patent 5,360,817 or Chandler, M. et al., "J. Chem. Soc. Perkin Trans. 1", 1189-1197 (1995).
The foregoing notwithstanding, in an embodiment of the invention one identifies compounds that may fall within the generic scope of WO
91/16320, WO 92/06691, or US Patent 5,360,817 but which have (a) formula Ia of the '320 application, (b) carbon for group "A" in the '320 application, and (c) R5 of the '320 and '691 applications being "-CH2YR6, -CHYR6CH2YR6 or -CHYR6CHYR6CH2YR6~~ where YR6 cannot be either OH or protected OH in which the protecting group is capable of hydrolysis to yield the free OH
under conditions of the human gastrointestinal tract, i.e. the compounds are stable to hydrolysis in the gastrointestinal tract. Thus, typically excluded from this embodiment are compounds of the '320 or '691 applications where R5 therein is acetyl or other carbacyl having 1-4 carbon atoms.
Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Such compounds are suitable for use in this embodiment. Note that simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydroyzed in vivo. Prodrugs typically will be stable in the digestive system but are substantially hydroyzed to the parental drug in the digestive lunem, liver or other metabolic organ, or within cells in general.
It should be understood, however, that other embodiments of this invention more fully described below contemplate the use of compounds that are in fact specifically disclosed in WO 91/16320, WO 92/06691, or US
Patent 5,360,817, including those in which YR6 is free hydroxyl, or hydroxyl protected by a readily hydrolyzable group such as acetyl. In this instance, however, the compounds are delivered by novel routes of administration.
In another embodiment, the compounds herein exclude those in which (a) El is -C02H, -P(O)(OH)2, -N02, -S02H, -S03H, tetrazolyl, -CH2CH0, -CHO, or -CH(CHO)2;
(b) G1 is -CN, N3,-NHR20, NR20, -OR2p, guanidino, SR20.
-N(R2p)-~O, -N(R20)(OR20), -N(H)(R20)N(R20)2, unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl)methyl;
(c) Tl is -NHR20, -N02; and R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an N02 group, an NH2 group or a COOH group;
(d) each J1 is H; and (e) Xl is a bond, -CH2- or -CH2CH2-;
in which case W6 is not H, W7 or -CH2W7 wherein W7 is H, -OR(a, -ORl, -N(Rl)2, -N(Rl)(R6b), -N(R6b)2, -SR1, or -SR6a.
Also excluded herein are compounds described in WO 92/06691 at Page 9, Line 26, to Page 11, Line 5, which appear to include compounds of the formula II wherein:
(a) A2 is O;
(b) E1 is COOH, P(O)(OH)2, N02, SOOH, S03H, tetrazole, CH2CH0, CHO, CH(CHO)2 or where El is COOH, P(O)(OH)2, SOOH or S03H, an ethyl, methyl or pivaloyl ester thereof;
(c) G1 is hydrogen, N(R2oa)2, SR2~a or ORZ~a;
(d) Tl is -NHC(O)R2~b, where R2~b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR2~a, OR2«a, COOH or alkyl/aryl ester thereof, N02, C(R2oa)3, CH2COOH or alkyl/aryl ester thereof, CH2N02 or CH2NHRZ~b;
(e) R2~a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an N02 group, an NHZ group or a COOH group;
(f) Ji is H and Jla is H, OR2«a, F, Cl, Br, CN, NHRZ~a, SR2~a or CH2X wherein X is NHRZ«a, halogen or OR2~a;
(g) J2 is H or J2a is hydrogen, N(R2«a)Z, SR2«a or OR2~a;
(h) U1 is CH2YR2~a, CHYR2«CH2YR2«a or CHYR2~aCHYR2t~aCH2YRz«a where Y is O, S or H, and successive Y moieties in U1 are the same or different and R2~a represents a covalent bond when Y is hydrogen and and pharmacologically acceptable salts or derivatives thereof.
In a further embodiment, the compounds of this invention are those in which U1 is not -CH20H, -CH20Ac, or -CH20CH2Ph.
In a further embodiment, the compounds of this invention are those in which E1 is not -CH20H, -CH20TMS, or -CHO.
In a further embodiment, the compounds of this invention are those in which U1 is not bonded directly to the nuclear ring by a carbon atom or U1 is not substituted with hydroxyl or hydroxyester, in particular U1 is not polyhydroxyalkane, especially -CH(OH)CH(OH)CH20H. In a further embodiment, U1 is a branched chain group R5 as described below or a carbocycle which is substituted with at least one group R5, In a further embodiments, excluded from the invention are compounds of the formula:

U~..,,.. Az Ei Ui~.,.. A E~
T~ T~
G~ G~
(V) (Vi}
wherein:
1. In formula (V):
A2 is -O- or -CH2-;
El is -C02H;
G1 is -N(H){C(NH)(NH2)):
Tl is -N(H)(Ac); and U 1 is of the formula:
OH
or ~- S
OH OH HO
2. In formula (V):
A2 is -O- or -CH2-;
El is -C02H;
G1 is -NH2;
T1 is -N(H)(Ac); and Ul is -CH20H;
3. In formula (V):
A2 -CH2-;
E1 is -CH20H or -CH20TMS;
G1 is -N3;
T1 is -N(H)(Ac); and Ul is -CH20CH2Ph;
4. In formula (V):
A2 -CH2-;
El is -C02H or -C02CH3;
G1 is -N3;
Tl is -N{H)(Ac); and U1 is -CH20H;
5. In formula (V):
A2 -CH2-;
El is -CO2H, -CHO, or -CH20H;

Gl is -N3;
Tl is -N(H)(Ac); and Ul is -CH20CH2Ph;
6. In formula (VI):
A2 -CH2-;
El is -CC~H;
Gl is -OCH3;
Tl is -NH2; and Ul is -CH20H; and 7. In formula (VI):
A2 -CH2-;
El is -C02H;
Gl is -OCH3;
T1 is -N(H)(Ac); and Ul is -CH20Ac.
Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "Rl" or "RE,a", then it will be understood that the groups may be the same or different, i.e., each group is independently selected.
"Heterocycle" as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem.
Soc.", 82:5566 (1960).
Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, (3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or (i-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
"Alkyl" as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3),1-propyl (n-Pr, n propyl, -CH2CH2CH3), 2-propyl (~-Pr, ~-propyl, -CH(CH3)2), 1-butyl (n-Bu, ~-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, ~-butyl, -CH2CH(CH3)2), 2-butyl (~ Bu, ~-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (~-Bu, f-butyl, -C(CH3)3),1-pentyl (~ pentyl, -CH2CH2CH2CH2CI~3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH{CH2CH3)2), 2-methyl-2-butyl {-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl {-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CI-1,3),1-hexyl {-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CI-~)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3~H2CH(CH3)2), 3-methyl-3-pentyl (-C(CI~)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Examples of alkyl groups appear in Table 2 as groups 2-5, 7, 9, and 100-399.
The compositions of the invention comprise compounds of either formula:
3t Ut At~ Et ~ Ut A Et t Tt Vita Tt 1a J2 Gt ~2a Jt J Gt ~2a In the typical embodiment, the compounds of Formula I are chosen.
J1 and J1a are independently R1, Br, Cl, F, I, CN, N02 or N3, typically R1 or F, more typically H or F, more typically yet H.
J2 and J2a are independently H or R1, typically H.
A1 is -C(J1)=, or -N=, typically -C(J1)=, more typically -CH=.
A2 is -C(J1)2-, -N(11)-, -N{O)Ul)-, -N(O)=, -S-, -S(O)-, -S(O)2- or -0-, typically -C(jl)2-, -NUl)-, -S-, or -O-, more typically -C(J1)2-, or -O-, more typically yet -CH2- or -O-, still more typically -CH2-.
E1 is -(CR1R1)mlWl.
Typically, R1 is H or alkyl of 1 to 12 carbon atoms, usually H or an alkyl of 1 to 4 or 5 to 10 carbon atoms, still more typically, H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more typically yet, H or an alkyl of 1 to 3 carbon atoms selected from methyl, ethyl, ~-propyi, and i-propyl.
Most typically R1 is H.
m1 is an integer of 0 to 2, typically 0 or 1, most typically 0.
m2 is an integer of 0 to 1.
m3 is an integer of 1 to 3.
W1 is a group comprising an acidic hydrogen, a protected acidic group or an R6c amide of the group comprising an acidic hydrogen which, within the context of the invention, means a group having a hydrogen atom that can be removed by a base yielding an anion or its corresponding salt or solvate. The general principles of acidity and basicity of organic materials are well understood and are to be understood as defining Wl. They will not be detailed here. However, a description appears in Streitwieser, A.; and Heathcock, C. H.; "Introduction to Organic Chemistry, Second Edition"
(Macmillan, New York, 1981), pages 60-64. Generally, acidic groups of the invention have pK values less than that of water, usually less than pK = 10, typically less than pK = 8, and frequently less than pK = 6. They include tetrazoles and the acids of carbon, sulfur, phosphorous and nitrogen, typically the carboxylic, sulfuric, sulfonic, sulfinic, phosphoric and phosphonic acids, together with the R6c amides and R~,b esters of those acids (R6c and R6b are defined below). Exemplary Wl are -C02H, -C02RE,a.
-OS03H, -S03H, -S02H, -0P03H2, -P03(R6a)2, -P03H2, -P03(H)(IZ6a), and -OP03(R6a)2~ El typically is Wl, and Wl typically is -C02H, -C02R~,a, -C02R4 or C02R1, and most typically is C02R14 wherein R14 is normal or terminally secondary C1_C6 alkyl.
W1 may also be a protected acidic group, which, within the context of the invention means an acidic group as described above that has been protected by one of the groups commonly used in the art for such groups and are described below under R~,a. More typically, protected Wl is -C02R1;
S03R1, -S(O)ORl, -P(O)(OR1)2, -C(O)NHS02R4, or -S02NHC(O)-R4, wherein Rl and R4 are defined above.
Most typically, El is selected from -C(O)O(CH2)bCH((CH2)cCI-~)2 where b = 0 to 4, c = 0 to 4, and b + c = 1 to 4, or from the group of O O
~ Hs O-CH , ~ , OH a O

CH3 ~ CH3 ~ CH3 O ~ O-O CH3 Ow Ys~oH , , H
O~ /OH O~ /O-CH3 N~N~N
YP~OH ~ ~P~O-CH , and ~ N

Exemplary El groups are listed in Tables 3a through 3b.
G1 is N3, -CN, -OH, ORga, -N02 or -(CR1R1)mlW2, wherein Rl and m1 are defined above. Ordinarily, Gl is -(CR1R1)mlW2~
W2 is a group comprising a basic heteroatom, a protected basic heteroatom or an Rbb amide of the basic heteroatom. W2 generally comprises a basic heteroatom, which, within the context of the invention means an atom other than carbon which is capable of protonation, typically by an acidic hydrogen having an acidity in the range described above for Wl.
The basic principles of basicity are described in Streitwieser and Heathcock (op. cit.) and provide meaning for the term basic heteroatom as will be understood by those ordinarily skilled in the art. Generally, the basic heteroatoms employed in the compounds of the invention have pK values for the corresponding protonated form that are in the range of values described above for Wl. Basic heteroatoms include the heteroatoms common in organic compounds which have an un-shared, non-bonding, n-type, or the like, electron pair. By way of example and not limitation, typical basic heteroatoms include the oxygen, nitrogen, and sulfur atoms of groups such as alcohols, amines, amidines, guanidines, sulfides, and the like, frequently, amines, amidines and guanidines. Ordinarily, W2 is amino or an amino alkyl (generally lower alkyl C1 to C6) group such as aminomethyl, aminoethyl or aminopropyl; an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl; or guanidinyl, or a guanidinoalkyl group such as guanidinomethyi, guanidinoethyl, or guanidinopropyl (in each instance wherein the alkyl group serves to bridge the basic substituent to the carbocyclic ring). More typically, W2 is amino, amidino, guarudino, heterocycle, heterocycle substituted with 1 or 2 amino or guanidino groups (usually 1), or an alkyl of 2 to 3 carbon atoms substituted with amino or guanidino, or such alkyl substituted with an amino and a second group selected from the group consisting of hydroxy and amino. The heterocycles useful as W2 include typically N or S-containing 5 or 6 membered rings, wherein the ring contains 1 or 2 heteroatoms. Such heterocycles generally are substituted at ring carbon atoms. They may be saturated or unsaturated and may be linked to the core cyclohexene by lower alkyl (ml=1 or 2) or by -NRl-. Still more typically, W2 is -NHRl, -C(NH)(NH2), -NRl-C(NRl)(NR1I~3), -NH-C(NH)(NHR3), -~-C{~)(~R1). -NH-C{~)~2, -CH(CH2NHR1)(CH20H).
-CH(CH2NHR1){CH2NHR1), -CH(NHRl), -(CR1R1)m2-CH(NHRl)Rl, -CH(OH)-(CR1R1)m2-CH(NHRl)Rl, or -CH(NHRl)-(CR1R1)m2-CH(OH)Rl, -{CR1R1)m2-S-C(NH)NH2, -N=C(NHRl)(R3), -N=C(SRl)N(Rl)2, -N(Rl)C(NH)N(Rl)C=N, or -N=C(NHRl)(Rl); wherein each m2 is ordinarly 0, and ordinarily Rl is H and R3 is C(O)N(Rl)2.
W2 optionally is a protected basic heteroatom which within the context of the invention means a basic heteroatom as described above that has been protected by Rfb such as one of the groups common in the art.
Such groups are described in detail in Greene (op. cit.) as set forth below.
Such groups include by way of example and not limitation, amides, carbamates, amino acetals, imines, enamines, N-alkyl or N-aryl phosphinyls, N-alkyl or N-aryl sulfenyls or sulfonyls, N-alkyl or N-aryl silyls, thioethers, thioesters, disulfides, sulfenyls, and the like. In some embodiments, the protecting group R fb will be cleavable under physiological conditions, typically it will be cleavable in vivo where, for example, the basic heteroatom forms an amide with an organic acid or an amino acid such as a naturally occurring amino acid or a polypeptide as described below for the R6a group.
Typically G1 is selected from the group consisting of:

YNH2 ~NH2 NH2 NH2 , ~' ~ , ~ N H ' '~C~ N H , H H
~~N~NH ~NH2 ,/C~N~NH
NH2 ' ~ NrH2 , YN~NH2 YNYNH2 YNYNH2 H C' H3 SI CH3 H CH3 H ~CH3 H CH3 YN i N YN i N ~ N I N
H ~ NH2 , r ~r N ~,, HN N, N~H
I /~--NH2 S ~ H ,N
C N ~ N, H
N ~ , H~ CN
' NH2 ' H H H
N
CH3 ~iNuCH3 ~,N~/w.CH3 H H H
i i ~~N~CH3 ~~N~OH ~~N~ NH2 CH3 ~ ' , ~~N~CH3 and ~~~CH3 .
Further exemplary G1 groups are listed in Table 4.
T1 is -NR1W3, -R3, -R5 or heterocycle, or is taken together with Ul or G1 to form a group having the structure Rsb-N
where R6b is defined below, and Rl and W3 are defined above. Typically Tl is -NRl, W3 or heterocycle. Generally Tl is selected from the group consisting of:
O
H3C N FH2C~N~ HF2C N
H , H ~ H , O O
O
N
F3C N ' ~N~ N~ ~N
H , , , and .
O
Exemplary TI groups are listed in Table 5.
W3 is W4 or W5, wherein W4 is R5 or -C{O)R5, -C(O)WS, -S02R5, or -S02W5. Typically, W3 is -C(O)R5 or W5.
R2 is independently R3 or R4 as defined below, with the proviso that each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OIt6a, -ORl, -N{Rl)2, -N{Rl)(Rbb), -N(R6b)2, -SRI, -SRE,a, -S(O)Rl, -S(O)2R1, -S{O)ORI, -S(O)OR~.
-S{O)20R1, -S(O)20R6a. -C(O)ORl, -C(O)R6c. -C(O)OR6a, -OC(O)Rl, -N(RI)(C(O)Rl), -N{~b)(C(O)Rl), -N(R1)(C(O)OR1), -N(R6b)(C(O)OR1), -C(O)N(Rl)z, -C(O)N(~b)(RI), -C(O)N(~b)z, -C(NRl)(N(Rl)z), "'C(N{R6b))(N(RI)2), -C(N(Rl))(N(R1){R6b)), -C(N(R6b)){N(R1)(R6b)), -C(N(Ri)){N(Rbb)2), -C(N(R6b))(N{Rbb)2), -N{R1)C(N(R1))(N(RI)2), -N(R1)C(N{R1))(N(R1)(R6b)), -N(R1)C(N(Rbb))(N(R1)2), -N(Rbb)C(N(R1))(N(R1)2), -N(R6b)C(N(R6b))(N(Rl)2), -N(R6b)C(N(R1))(N(R1)(R6b)), -N(RI)C(N(R6b)){N(R1)(R6b)), -N(R1)C(N(Rl))(N{R6b)2), -N(R6b)C(N(R6b))(N(R1){R6b)).
-N{R6b)C(N(R1))(N(Rbb)2), -N(R1)C(N(R6b))(N(R6b)2), -N(RE,b)C(N(R6b))(N{R6b)2), =O, =S, =N{RI), =N(IZbb) or W5. Typically R3 is F, Cl, -CN, N3, N02, -OItda, -ORl, -N(Rl)2, -N(R1)(R6b), -N(R6b)2; -SRl, -SRba, -C(OX~R1, -C(O)R6c, -C(O)ORba, -OC(O)Rl, -NR1C(O)Rl, -N(Rgb)C(O)Rl, -C(O)N(R1)2, -C(O)N(Itdb)(R1), -C(O)N(R6b)2. or =O. More typical R3 groups comprising R6b include -C(O)N(R6b)2 or -C(O)N(R6b)(Rl).
More typically yet R3 is F, Cl, -CN, N3, -0Rl, -N(Rl)2, -SRl, -C(O)ORl, -OC(O)R1, or =O. More typically still, R3 is F, -OR1, -N(R1)2, or =O. In the context of the present application, "=O" denotes a double bonded oxygen atom (oxo), and "=S" =N{RE,b) and "=N(Rl)" denote the sulfur and nitrogen analogs.
R4 is alkyl of 1 to 12 carbon atoms, and alkynyl or alkenyl of 2 to 12 carbon atoms. The alkyl R4's are typically of 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 carbon atoms and the alkenyl and alkynyl R4's are typically of 2, 3, 4, 5, 6, .7, 8, 9, 10, 11, or 12 carbon atoms. R4 ordinarily is alkyl (as defined above). When R4 is alkenyl it is typically ethenyl (-CH=CH2), 1-prop-1-enyl (-CH=CHCH3), 1-prop-2-enyl (-CH2CH=CH2), 2-prop-1-enyl (-C(=CH2)(CH3)), 1-but-1-enyl (-CH=CHCH2CH3),1-but-2-enyl (-CH2CH=CHCH3),1-but-3-enyl (-CH2CH2CH=CH2), 2-methyl-1-prop-1-enyl (-CH=C(CH3)2), 2-methyl-1-prop-2-enyl (-CH2C{=CH2)(CH3)), 2-but-1-enyl (-C(=CH2)CH2CI~), 2-but-2-enyl (-C(CH3)=CHCH3), 2 but-3-enyl (-CH(CH3)CH=CH2), 1-pent-1-enyl (-C=CHCH2CH2CH3),1-pent-2-enyl {-CHCH=CHCH2CH3), 1-pent-3-enyl (-CHCH2CH=CHCH3),1-pent-4-enyl (-CHCH2CH2CH=CH2), 2-pent-1-enyl (-C(=CH2)CH2CH2CH3), 2-pent-2-enyl (-C(CH3)=CH2CH2CH3), 2-pent-3-enyl (-CH(CH3)CH=CHCH3), 2-pent-4-enyl (-CH(CH3)CH2CH=CH2) or 3-methyl-1-but-2-enyl (-CH2CH=C(CH3)2). More typically, R4 alkenyl groups are of 2, 3 or 4 carbon atoms. When R4 is alkynyl it is typically ethynyl (-C-CH),1-prop-1-ynyl (-C~CH3),1-prop-2-ynyl (-CH2C~H), lbut-1-ynyl (-C~CH2CH3),1-but-2-ynyl (-CH2C-CCH3),1-but-3-ynyl (-CH2CH2C---CH), 2-but-3-ynyl (CH(CI-1'3)C=CH),1-pent-1-ynyl (-C~CH2CH2CH3),1-pent-2-ynyl {-CH2C=CCH2CH3),1-pent-3-ynyl (-CH2CH2C~CH3) or 1-pent-4-ynyl (-CH2CH2CH2C~H). More typically, R4 alkynyl groups are of 2, 3 or 4 carbon atoms.
R5 is R4, as defined above, or R4 substituted with 0 to 3 R3 groups.
Typically R5 is an alkyl of 1 to 4 carbon atoms substituted with 0 to 3 fluorine atoms.
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups. As defined above for R4, Rya's are of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkylene and of 2, 3, 4, 5, 6, 7, 8, 9, 10, lI, or 12 carbon atoms when alkenylene or alkynylene. Each of the typical R4 groups is a typical R5a group with the proviso that one of the hydrogen atoms of the described R4 group is removed to form the open valence to a carbon atom through which the second bond to the R5a is attached.
R14 is normal or terminally secondary C1-C6 alkyl.
W5 is a carbocycle or heterocycle, with the proviso that each W5 is independently substituted with 0 to 3 R2 groups. W5 carbocycles and TI and W5 heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from -78°C to 200°C. Each W5 is independently substituted with 0 to 3 R2 groups. Typically, Tl and W5 are a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, TI or W5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms. The Tl and W5 rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms. Unsaturation of the W5 rings include internal and external unsaturation wherein the external incorporates a ring atom.
When W5 is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W5 monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W5 bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo (4,5], [5,5], (5,6] or [6,6]
system, still more typically, 9 or 10 ring atoms arranged as a bicyclo [5,6) or [6,6] system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, I-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
A Tl or W5 heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and I to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, T1 and W5 heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), still more typically, 5 or b ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
T1 and W5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
Typically Tl and W5 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
More typically, the heterocycle of T1 and W5 is bonded through a carbon atom or nitrogen atom thereof. Still more typically T1 heterocycles are bonded by a stable covalent bond through a nitrogen atom thereof to the cyclohexene ring of the compositions of the invention and W5 heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof to the cyclohexene ring of the compositions of the invention. Stable covalent bonds are chemically stable structures as described above.
W5 optionally is selected from the group consisting of:
/ ~ ~ ~N ~ Nw \ ~ / , / f , N \ H N
I / N
~N , N H
SY~ ~ N N
~N , S / , and ~S
U1 is H or -X1W6, but typically the latter.
X1 is a bond, -O-, -N(H)-, -N(W6)-, -N(OH}-, -N(OW6)-, -N(NH2)-, -N{N{H){W6))-, -N{N(W6}2)-, -N(H)N(W6)-, -S-, -SO-, or -S02-; typically, Xl is a bond, -O-, -N(H)-, -N(R5)-, -N(OH)-, -N(OR5)-, -N(NH2)-, -N(N(H)(R5))-, -N(N{R5)2)-, -N(H)N(R5)-, -S-, -SO-, or -S02-, more typically X1 is a bond, -O-, -NR1-, -N(OR1)-, -N(NR1R1)-, -S-, -SO-, or -S02-. Ordinarily X1 is -0-, -NH-, -S-, -SO-, or -S02-.;
W6 is -R5, -W5, -R5aW5, -C(O)OR6a. -C(O)R6c, -C(O)N(R6b)2.
-C(NR6b)(N(R6b)2), -C(~6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2.
or -C(O)R2, typically W6 is -R5, -W5, or -I~5aW5; in some embodiments, W6 is Rl, -C(O)-Rl, -CHR1W~, -CH(Rl)aW~, -CH(W7)2, (where, W~ is monovalent a is 0 or 1, but is 0 when W~ is divalent} or -C(O)WS. In some embodiments, W6 is -CHR1W~ or -C(O)WS, or W6 is -(CH2)mlCH((CH2)m3~)2, -(CH2)m1C((CH2)m3~)3:
-(CH2)mlCH((CH2)m3R5aW5)2:
-(CH2}mlCH((CH2)m3~)((CH2)m3R5aW5):
-(CH2)m1C((CH2)m3~3)2(CH2)m3R5aW5), (CH2)m1C((CH2)m3R5aW5)3 or -(CH2}m1C((CH2)m3R3)((CH2)m3R5aW5)2: and wherein m3 is an integer from 1 to 3.
W2 is I~3 or R5, but typically is alkyl of 1 to 12 carbons substituted with 0 to 3 I~ groups, the latter typically selected from the group consisting of -NRl(It6b), -N(It6b)2. -OR6a, or SR6a. More typically, W~ is -0Rl or an alkyl of 3 to 12 carbon atoms substituted with ORl.
In general, Ul is R10-, -OCHR1W~, HO~O~ HO~O~ HO~O~
' OH ' OH ' H3C~0~0~ ~O ~O

H3C-~/O~ H3C~0~ H3C O~ H3C O
CHs CH3 , and H3C
Exemplary U1 groups are listed in Table 2.
An embodiment of the invention comprises a compound of the formula:
~ E2 O

wherein E2 is El, but is typically selected from the group consisting of:
,-O
~~~ i0 OH ~ O-Rsa , S~S~OH , H
O\ /OH O~ /O_Rsa ~N~
S~P~OH ' ~P O_Rsa , and N~
and wherein G2 is Gl, but is typically selected from the group consisting of:
Y NH2 ,/'~ NH2 NH2 NH2 N H , ~~C~ N H , H H
YN~NH ~NH2 ,~C~N~NH
NH2 ' ~ ~NH2 , YN~NH2 ~~N~NH2 ~~N~NH2 H CH3 H ~CH3 H CH3 YN~N YN~N ,/~N~N
N' H2 ' INH2 ' NH2 N ~ S HN~N'H ~N~H
,~ H .JN
C ~~NH2 N 1 ,N, N , NH2 , H CN , and and wherein T2 is It4 or IBS. Generally, T2 is alkyl of 1 to 2 carbon atoms substituted with 0 to 3 fluorine atoms.
U2 is one of:

R~O~ R~~O~ R~~O~
' R~ ' R~ , and R~ ~ ;
wherein R~ is H, -CH3, -CH2CH3, -CH2CH2CH3, -0CH3, -0Ac (-O-C(O)CH3), -0H, -NH2, or -SH, typically H, -CH3 or -CH2CH3.
Groups It6a and Rbb are not critical functionalities and may vary widely. When not H, their function is to serve as intermediates for the parental drug substance. This does not mean that they are biologically inactive. On the contrary, a , principal function of these groups is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs are absorbed more effectively than the parental drug they in fact often possess greater potency in vivo than the parental drug. When not hydrogen, Rga and R6b are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting pro-functionality products, e.g.
alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
RE,a is H or an ether- or ester-forming group. "Ether-forming group"
means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
Va(V1)3 , ~-~-Va(V1)(V2) , S-~-Va(V3) Vb(V1)2 ~ ~ ~ Vb(V2) , Of S-~_-Vc~VI~
Wherein Va is a tetravalent atom typically selected from C and Si; Vb is a trivalent atom typically selected from B, Al, N, and P, more typically N and P; Vc is a divalent atom typically selected from O, S, and Se, more typically S;
Vl is a group bonded to Va, Vb or Vc by a stable, single covalent bond, typically Vl is W6 groups, more typically Vl is H, R2, W5, or -R5aW5, still more typically H or R2; V2 is a group bonded to Va or Vb by a stable, double covalent bond, provided that V2 is not =O, =S or =N-, typically V2 is =C(Vl}2 wherein Vl is as described above; and V3 is a group bonded to Va by a stable, triple covalent bond, typically V3 is --_C(Vl) wherein Vl is as described above.
"Ester-forming group" means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
Va{V1)(V4) ~ ~'-~'ub{V4) , ~ ~'ud{V1)2(V4) S ~ udU4)2~ ~ ~ Ve~Vl~3~V4~ ~ Of ~ ~ Ve(V1)(V4~2 Wherein Va, Vb, and V1, are as described above; Vd is a pentavalent atom typically selected from P and N; Ve is a hexavalent atom typically S; and V4 is a group bonded to Va, Vb, Vd or Ve by a stable, double covalent bond, provided that at least one V4 is =O, =S or =N-V1, typically V4, when other than =O, =S or =N-, is =C(Vl)2 wherein Vl is as described above.
Protecting groups for -OH functions (whether hydroxy, acid or other functions) are embodiments of "ether- or ester-forming groups".
Particularly of interest are ether- or ester-forming groups that are capable of functioning as protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed under R6c below. It6c is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
In its ester-forming role, RE,a typically is bound to any acidic group such as, by way of example and not limitation, a -C02H or -C(S)OH group, thereby resulting in -C02R~a. lZba for example is deduced from the enumerated ester groups of WO 95/07920.
Examples of R~,a include C3-C12 heterocyle {described above) or C6-C12 aryl. These aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4-and 5-pyrimidinyl, C3-C12 heterocycle or C6-C12 aryl substituted with halo, Rl, R1-~1-C12 alkylene, Ci-C12 alkoxy, CN, N02, OH, carboxy, carboxyester, thiol, thioester, Ci-C12 haloalkyl (1-6 halogen atoms), C2-C12 alkenyl or C2-C12 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (Ci-C12 alkyl), 2-, S-and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-0-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, Cl-C12 alkyl including 4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, Cl-C12 alkyl including 4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (Cl-C4 alkyl, including 2-, 3- and 4-ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-CloH6-OH) and aryloxy ethyl [C6-C9 aryl (including phenoxy ethyl)], 2,2'-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -C6H4CH2-N(CH3)2, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (Clue alkyl);
Rl O(O)C
N ~ -Cl..i2_O-C(p) I N I
O H ; ; ~ ; C4 - Cg esters of 2-carboxyphenyl; and C1-C4 alkylene-Cg-C6 aryl (including benzyl, -CH2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH2-isotMazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2-pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, Cl-C12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, Cl-C12 haloalkyl (1 to 6 halogen atoms;
including -CH2-CC13), Cl-C12 alkyl (including methyl and ethyl), C2-C12 alkenyl or C2-C12 alkynyl;
alkoxy ethyl [Cl-C6 alkyl including -CH2-CH2-O-CH3 (methoxy ethyl)];
alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH3, -CH(CH3)2, -C(CI-~)3.
-CH2CH3, -(CH2)2CH3. -(CH2)3CH3. -(CH2)4C~, -(CHz)5CH3, -CHZCH2F, -CH2CH2C1, -CH2CF3, and -CH2CC13);

~N O
-N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -CHZ-C(O)-N(Rl)2, -CH2-S(O}(Rl), -CH2-S(O)2(Rl), -CH2-CH(OC(O)CH2R1)-CH2(OC(O)CH2R1), cholesteryl, enolpyruvate (HOOC-C(=CH2)-), glycerol;
a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues);
triglycerides such as a-D-(3-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6_26, C6-1s or C6_1o fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linoleruc and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride;
phospholipids linked to the carboxyl group through the phosphate of the phospholipid;
phthalidyl (shown in Fig. 1 of Clayton et al., "Antimicrob. Agents Chemo." 5(6):670-671 [1974]);
cyclic carbonates such as (5-ltd-2-oxo-1,3-dioxolen-4-yl) methyl esters (Sakamoto et al., "Chem. Pharm. Bull." 32(6}2241-2248 [1984]) where Rd is Rl, R4 or aryl; and n -CH2C(O) The hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in W094/21604, or with isopropyl.
As further embodiments, Table A lists examples of R6,, ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(O)(O-)2 groups.
Several lt6c amidates also are shown, which are bound directly to -C(O)- or -P(O)2. Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like} and N ,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsC03, N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone}. When Wl is phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
TABI,,~A

1. -CH2-C(O)-N(Ri)2 10.-CHZ-O-C(O~C(CH3)3 2. -CH2-S(O)(Ri) 11.-CHZ-CC13 3. -CH2-S(O)2(Ri) 12.-C6H5 -CH2-0-C(O)-CH2-Cf,HS13.-NH-CH2-C(O)O-CH2CH3 4.

5. 3-cholesteryl 14.-N(CH3)-CH2-C(O)O-CH2CH3 6. 3-pyridyl 15.-NHRi 7. N-ethylmorpholino 16.-CH2-0-C(O)-CipHi5 8. -CH2-O-C(O)-C~-i5 17.-CHz-0-C(O)-~H(CH3)2 -CH2-O-C(O)-CH2CI-~318.-CH2-C#H(OC(O)CH2Ri)-CH2-9.

-(OC(O)CH2Ri ) / HO
OH HO
-CH2C(O)N O N
19. '--~ 20. O H 21. HO
CH30(O~
N N
-CHZ-0-C(O) I ~ -CH2CH2 22. 23. 24.

CH3CH20(O)C -CH2 I ~ OCH3 25. 26. ~H3 # - chiral center is (R), (S) or racemate.
Other esters that are suitable for use herein are described in EP 632,048.
R6a also includes "double ester" forming profunctionalities such as -C~i20C(O)OCH3, o , -CH2~OC~~ ..CH2pCON(CH3)2, or alkyl- or aryl-acyloxyalkyl groups of the structure -CH(R1 or W5)O((CO)R37) or -CH(Rl or W5)((CO)OR3g) (linked to oxygen of the acidic group) wherein R37 and R3g are alkyl, aryl, or alkylaryl groups (see U.S. patent 4,968,788).
Frequently R37 and R3g are bulky groups such as branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethyl group. These are of particular use with prodrugs for oral administration. Examples of such useful It6a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH2CH20CI~3~7C(O)C(CH3)3, ~O
O ; -CH20C(O~IOHlS. ..CH20C(O)C(CH3)3.
-CH(CH20CH3)OC(O)C(CI~)3, -CH(CH(CH3)2~C(O)C(CH3)3, -CH20C(O)CH2CH(CH,3)2. -CH20C{O)C~hl. -CH20C(O)C6H5.
-CHZOC(O)C1pH15. -CH20C(O)CH2CH3. -CH20C(O)CH(CH3)2 .
-CH20C(O)C(CH3)3 and -CH20C(O)CH2CE,H5~
For prodrug purposes, the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
As noted, It6a, It6c and It6b groups optionally are used to prevent side reactions with the protected group during synthetic procedures, so they function as protecting groups {PRT) during synthesis. For the most part the decision as to which groups to protect, when to do so, and the nature of the PRT will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect carboxyl, hydroxyl or amino groups. The order of deprotection to yield free groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
A very large number of R~,a hydroxy protecting groups and R6c amide-forming groups and corresponding chemical cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W.
Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; "Protecting Groups" (Georg Thieme Veriag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups:
An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For R6a carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for Wl acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.
In some embodiments the lt6a protected acidic group is an ester of the acidic group and R fa is the residue of a hydroxyl-containing functionality.
In other embodiments, an Rdc amino compound is used to protect the acid functionality. The residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920. Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on pages 11-18 and related text of WO 95/07920 as groups L1 or L2. WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
Typical It6a esters for protecting Wl acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication. Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R31 or R35), the table on page 105, and pages 21-23 (as R). Of particular interest are esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or Cl-C4 alkylestercarboxyphenyl (salicylate C1-C12 alkylesters).
The protected acidic groups Wl, particularly when using the esters or amides of WO 95/07920, are useful as prodrugs for oral administration.
However, it is not essential that the Wl acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route. When the compounds of the invention having protected groups, in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
Typical R~ hydroxy protecting groups described in Greene (pages 14-118) include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2-{Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyi, 4-Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl S,S-Dioxido, 1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 35, 1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)); Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido, Diphenylmethyl, p,p'-Dirutrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, a-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di{p-methoxyphenyl)phenylmethyl, Trip-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-{Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-Bis{4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9 Phenyl-10-oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S

Dioxido); Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate, 4-0xopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Niotro-4-methylpentanoate, a-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate);
Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, a-Naphthoate, Nitrate, Alkyl N,N,N',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
More typically, R~ hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
Typical 1,2-diol protecting groups (thus, generally where two OH
groups are taken together with the Rba protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, a-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative, a-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene Group, 1,3-(1,1,3,3 Tetraisopropyldisiloxanylidene), and Tetra-t-butoxydisiloxane-I,3-diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
More typically, 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
Table B
~r r~ r 0 0 0 0 0 0~~ o r ~c r ~c r ~c r ~c r o R90~N O y R9p-N O
R O-N~ ,O
9 ~P,, S
R O O O ~~ '~O R9p~P~~O
wherein R9 is C1-C6 alkyl.
Tt~,b is H, a protecting group for amino or the residue of a carboxyl-contairung compound, in particular H, -C(O)R4, an amino acid, a polypeptide or a protecting group not -C(O)R4, amino acid or polypeptide.
Amide-forming RE,b are found for instance in group Gl. When lt6b is an amino acid or polypeptide it has the structure R15NHCH(R16)C(O)-, where R15 is H, an amino acid or polypeptide residue, or R5, and R16 is defined below.
R16 is lower alkyl or lower alkyl (Cl-C,~) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C6-C~ aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R16 also is taken together with the amino acid a N to form a proline residue (Rlb = -CH2)3-) However, Rlb is generally the side group of a naturally-occurring amino acid such as H, -CH3, -CH(CHg)2 -CH2-CH(CH3)2, -CHCH3-CH2-CHg, -CH2-C6H5, -CHZCH2-S-CHg, -CH20H, -CH(OH~CH3, -CHz-SH, -CH2-C~OH, -CH2-CO-NHZ -CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH, -(CH2)4-NH2 and -(CH2)3-NH-C(NH2}-NH2. R16 also includes 1-guanidinoprop-3-yl, benzyl, 4 hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
R6b are residues of carboxylic acids for the most part, but any of the typical amino protecting groups described by Greene at pages 315-385 are useful. They include Carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl);
Substituted Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-{2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups With Assisted Cleavage (2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o-nitrophenyl)methyl);
Urea-Type Derivatives (phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl);
Miscellaneous Carbamates (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyciobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dirnethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methyicyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl~thyl, 1-methyl-1-{p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, 2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides With Assisted Cleavage (N-o-nitrophenylacetyl, N-o-rutrophenoxyacetyl, N-acetoacetyl, {N'-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(0-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-rutro-2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-{4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N'-oxide), Irvine Derivatives (N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N,(N',N'-dimethylaminomethylene, N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene); Enamine Derivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N-copper or N-zinc chelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-P
Derivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N
diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-Sulfenyl Derivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-(i-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl).
More typically, protected amino groups include carbamates and amides, still more typically, -NHC(O)Rl or -N=CR1N(Ri)2. Another protecting group, also usefull as a prodrug at the Gl site, particularly for amino or -NH(R5), is:
S
see for example Alexander, J. et al., "J. Med. Chem." 39:480-486 (1996).
Itb~ is H or the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHS02R4, NHC(O)R4, -N(R4)2, NH2 or -NH(R4)(H), whereby for example the carboxyl or phosphoric acid groups of Wl are reacted with the amine to form an amide, as in -C{O)R~, -P(O)(R6~)2 or -P(O)(OH)(R~). In general, It6c has the structure R1~C(O)CH(R16)NH-, where Rl~ is OH, ORfa, ORS, an amino acid or a polypeptide residue.
Amino acids are low molecular weight compounds, on the order of less than about 1,000 MW, that contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single WO 99/14185 PCT/tJS98/19355 substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug.
Typically, the residue does not contain a sulfhydryl or guanidino substituent.
Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof.
Polypepddes most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
When R6b and IZ6c are single amino acid residues or polypeptides they usually are substituted at R3, W6, Wl and/or W2, but typically only Wl or W2. These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example) and W2. Similarly, conjugates are formed between Wl and an amino group of an amino acid or polypeptide. Generally, only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site. Usually, a carboxyl group of Wl is amidated with an amino acid. In general, the a-amino or a-carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
With respect to the carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by Rfa, esterified with Rg or amidated with R6c. Similarly, the amino side chains R16 optionally will be blocked with It6b or substituted with R5.
Such ester or amide bonds with side chain amino or carboxyl groups, like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments. The esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups. The free acid or base of the parental compound, for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
When an amino acid residue contains one or more chiral centers, any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used. In general, if the intermediates are to be hydrolyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines), D isomers are useful. On the other hand, L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
Examples of suitable amino acids whose residues are represented by Rbb and R~ include the following:
Glycine;
Aminopolycarboxylic acids, e.g., aspartic acid, (3-hydroxyaspartic acid, glutamic acid, (3-hydroxyglutamic acid, (3-methylaspartic acid, [3-methylglutamic acid, ~i,(i-dimethylaspartic acid, 'y hydroxyglutamic acid, p,~
dihydroxyglutamic acid, ~i-phenylglutamic acid, y-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ~i-aminoalanine, y-aminobutyrine, orruthine, citruline, homoargirune, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
Other basic amino acid residues such as histidine;
Diaminodicarboxylic acids such as a,a'-diaminosuccinic acid, a,a'-diaminoglutaric acid, a,a'-diaminoadipic acid, a,a'-diaminopimelic acid, a,a'-diamino-(3-hydroxypimelic acid, a,a'-diaminosuberic acid, a,a'-diaminoazelaic acid, and a,a'-diaminosebacic acid;
Imino acids such as proline, hydroxyproline, allohydroxyproline, y methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;
A mono- or di-alkyl (typically C1 - Cg branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, a-methylserine, a-amino-a-methyl-'y hydroxyvaleric acid, a-amino-a-methyl-8-hydroxyvaleric acid, a-amino-a-methyl-E-hydroxycaproic acid, isovaline, a-methylglutamic acid, a-aminoisobutyric acid, a-aminodiethylacetic acid, a-aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, a-aminodiisobutylacetic acid, a-aminodi-n-butylacetic acid, a-aminoethylisopropylacetic acid, a-amino-n-propylacetic acid, a-aminodiisoamyacetic acid, a-methylaspartic acid, a-methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, ~3-methyltryptophan and a-amino-~i-ethyl-(3-phenylpropionic acid;
(3-phenylserinyl;
Aliphatic a-amino-~i-hydroxy acids such as serine, ~i-hydroxyleucine, ~3-hydroxynorleucine, ~i-hydroxynorvaline, and a-amino-(3-hydroxystearic acid;
a-Amino, a-, ~-, 8- or e-hydroxy acids such as homoserine, 'y hydroxynorvaline, S-hydroxynorvaline and epsilon-hydroxynorleucine residues; canavine and canaline; 'y hydroxyornithine;
2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid;
a-Amino-(3-thiols such as penicillamine, (3-thiolnorvaline or (3- , thiolbutyrine;
Other sulfur containing amino acid residues including cysteine;
homocystine, (i-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
Phenylalanine, tryptophan and ring-substituted a amino acids such as the phenyl- or cyclohexylamino acids a-aminophenylacetic acid, a-aminocyciohexylacetic acid and a-amino-(3-cyclohexylpropionic acid;
phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, vitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dicloro, o-, m-or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-vitro-, 2-hydroxy-5-vitro- and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophan analogues and derivatives including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;
a-Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline; and a-Hydroxy and substituted a-hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000MW) and proteins.
Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
The polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not imrnunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound. The conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it.
Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals. The polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues - 48_ recognized by a peptidolytic enzyme.
Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences. Such enzymes and their substrate requirements in general are well known. For example, a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its a-amino group to the phosphorus or carbon atoms of the compounds herein. In embodiments where Wl is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, iL, IIC, IIvI, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, Si, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.

Tripeptide residues are also useful as R6b or R6c. When Wl is phosphonate, the sequence -X4-pro-X5- (where X4 is any amino acid residue and. X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond. The carboxy group of X5 optionally is esterified with benzyl.
Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an a-amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., "Pharm Res." 9:969-978 (1992). Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds. Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N (EC
3.4.11.2). In addition, di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A (EC 3.4.11.7), di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) are poor substrates for endopeptidase 24.11 (EC
3.4.24.11), and peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P (EC 3.4.17).
Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
Another embodiment of the invention relates to compositions of the formula (VII) or (VIII):

Ui\N \ Ei Ui\ E~
T~ ~~a T~ J
~ 1a Gt ~2a G~~2a (VII) (VIII) wherein E1, G1, T1, Ul, J1. JIa. J2 and J2a are as defined above except:
T1 is -NR1W3, a heterocycle, or is taken together with G1 to form a group having the structure Rsb-N
and X1 is a bond, -O-, -N(H)-, -N(R,5)-, -S-, -SO-, or -S02-; and provided, however, that compounds are excluded wherein U1 is H or -CH2CH(OH)CH2(OH);
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Each of the typical or ordinary embodiments of formula (I)-(VI) detailed above are also typical embodiments of formula (VII) and (VIII).
The synthesis of a number of compounds of the formula (VII) and (VIII) wherein Ul is H or -CH2CH(OH)CH2(OH) are provided in Nishimura, Y. et al., "J. Antibiotics" 46(2):300; 46(12):1883 (1993); and "Nat. Prod.
Lett.", 1(1):39 (I992). Attachment of U1 groups of the present invention proceed as described therein.
The compounds of the invention are enriched or resolved optical isomers at any or all asymmetric atoms. For example, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diasteromeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
One or more of the following enumerated methods are used to prepare the enantiomerically enriched or pure isomers herein. The methods are listed in approximately their order of preference, i.e., one ordinarily should employ stereospecific synthesis from chiral precursors before chromatographic resolution before spontaneous crystallization.
Stereospecific synthesis is described in the examples. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites. One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield. In general, those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis. If an unexpected racemization occurs in a method thought to be stereospecific then one needs only to use one of the following separation methods to obtain the desired product.
If a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods. One method of general utility is chromotographic resolution of enantiomers on chiral chromatography resins. These resins are packed in columns, commonly called Pirkle columns, and are commercially available. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept. 3-4, 1987. Examples of chiral columns that could be used to screen for the optimal separation technique would include Diacel Chriacel OD, Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil I00, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Not all of these columns are likely to be effective with every racemic mixture. However, those skilled in the art understand that a certain amount of routine screening may be required to identify the most effective stationary phase. When using such columns it is desireable to employ embodiments of the compounds of this invention in which the charges are not neutralized, e.g., where acidic functionalities such as carboxyl are not esterified or amidated.
Another method entails converting the enantiomers in the mixture to diasteriomers with chiral auxiliaries and then separting the conjugates by ordinary column chromatography. This is a very suitable method, particularly when the embodiment contains free carboxyl, amino or hydroxyl that will form a salt or covalent bond to a chiral auxiliary.
Chirally pure amino acids, organic acids or organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all of which are well known in the art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group. For example, pure D or L amino acids can be used to amidate the carboxyl group of embodiments of this invention and then separated by chromatography.
Enzymatic resolution is another method of potential value. In such methods one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis. For this method to be successful an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and lipases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
If the enatiomeric mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiomerically-pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation. This method, however, is not practical for large scale preparations and is of no value for true racemic compounds.
Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
Further guidance in the separation of enantiomeric mixtures can be found, by way of example and not limitation, in "Enantiomers, Racemates, and resolutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4). In particular, Part 2, Resolution of Enantiomer Mixture, pages 217-435; more particularly, section 4, Resolution by Direct Crystallization, pages 217-251, section 5, Formation and Separation of Diastereomers, pages 251-369, section 6, Crystallization-Induced Asymmetric Transformations, pages 369-378, and section 7, Experimental Aspects and Art of Resolutions, pages 378-435; still more particularly, section 5.1.4, Resolution of Alcohols, Transformation of Alcohols into Salt-Forming Derivatives, pages 263-266, section 5.2.3, Covalent Derivatives of Alcohols, Thiols, and Phenols, pages 332-335, section 5.1.1, Resolution of Acids, pages 257-259, section 5.1.2, Resolution of Bases, pages 259-260, section 5.1.3, Resolution of Amino Acids, page 261-263, section 5.2.1, Covalent Derivatives of Acids, page 329, section 5.2.2, Covalent derivatives of Amines, pages 330-331, section 5.2.4, Covalent Derivatives of Aldehydes, Ketones, and Sulfoxides, pages 335-339, and section 5.2.7, Chromatographic Behavior of Covalent Diastereomers, pages 348-354, are cited as examples of the skill of the art.
Exemplary stereochemistry of the compounds of this invention is set forth below in Table C.
Table C
~~a J~a J
J
\ E~ 2 Ei Ui 3 2 6 1 Ui 4 3 ~ 1 Tt 4 5 Ti 5 6 2 G~ Gi -WO 99/14185 ~ PCT/US98/19355 Formula (I) -.., E1 11a 11b U1 Tl G1 a a a a a a a a a a a a a a a Formula (I) El 11a 11b 32 Ul Tl Gl a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a The compounds of the invention can also exist as tautomeric isomers in certain cases. For example, ene-amine tautomers can exist for imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.

Exemplary FnLmerated ComT ounds.
By way of example and not limitation, embodiment compounds are named below in tabular format (Table 6). Generally, each compound is depicted as a substituted nucleus in which the nucleus is designated by capital letter and each substituent is designated in order by lower case letter or number. Tables la and lb are a schedule of nuclei which differ principally by the position of ring unsaturation and the nature of ring substituents.
Each nucleus is given a alphabetical designation from Tables 1a and lb, and this designation appears first in each compound name. Similarly, Tables 2a-av, 3a-b, 4a-c, and 5a-d list the selected Ql, Q2. Q3 and Q4 substituents, again by letter or number designation. Accordingly, each named compound will be depicted by a capital letter designating the nucleus from Table la-lb, followed by a number designating the Q1 subsdtuent, a lower case letter designating the Q2 substituent, a number designating the Q3 substituent, and a lower case letter or letters designating the Q4 substituent. Thus, structure 8, scheme 1, is represented by A.49.a.4.i. Ql-Q4, it should be understood, do not represent groups or atoms but are simply connectivity designations.

Table 1a O
Q' 0~~,, Q2 Q; 5~.,. Q2 ~ S.,,. Q2 Q, Q4 __ Q4 = Q4 _ C
,,O H Q OH
i S'''' Q2 Q~ N~~. 2 Q . Ni.,.
Q4 = Q4 ~ Q4 Q2 Q~ O''~. ( p2 Q~ 5~...

G H
O O~~ ~O H
Q; 5~,,. Q2 Q~. S~,~, Q2 p' N~~,, Q;
p4 = p4 _ Q4 J K L

Q~ N~~~ Q2 Q .N.., Q2 Qt ~~~. Q2 i Q4 _ Q4 _ Q4 nn N o G1~..~. I Q2 Q~ 0.,. I Q2 Q; 0.,, v Q4 = 0.,. O., Q R

Table 1b Q1 iW., ~2 Q, ~0,,~ Q2 Q2 Q4 Q4 ~3 S T U

~a-N

V

Table 2a H Q~ H3C Q~ H3C~Qi H3C,~Q~

H3C Q~ ~ H C
H C Qi HsC~Q~ H C\/~
3 3 - = Q

H3C~Qi ~Q HsC~Qi O
IIi II
H$C O H3C~Q~

O HO
H C Q H3C~Q ~Q~ ~Q' y ~ O

HO~Q~ HO~Q~ H3C~(~~ HO~Q~

H C * Q Ol H HO HsC

OH H3C * Q1 H3C~. HO- v ~ _Q
* Q> >

Table 2b O O
HO~Q~ HO~Q~ H C
H3C O 3 ~Q~ HO
OH

O OH O O
H3C~~Q~ ~ H * _ OH H3C Q~ O ~ Q~ HO Q~

H2N~Q~ H2N~Q~ HsC~Q H N~Gp H3C~Q~ N~ H2N HsC
NH2 H3C * Qi H3C
* Qi H2N Qt H2N~Q~ H2N~Q~ H C * O O
HsC O s ~ Q~ ~~
NH H2N~4~

N O O O
*
H3C Q~ H3C * Q~ H2N~Qi HO' v 'Q

Table 2c HO~Q~ HO Q~ OH
OH
HO H3C~Qi OH

H3C * * Q~ ~ HO * *
HO * Q ~p OH ~ OH

HO Q~ O OH O
HO HO~Q~ H C * * Q
3 ~ 1 OH OH

O O
HO ,/ ~* OH O
Q~ HO ~~ HO Q
OH
HO

H2N~Q~ H N a~ NH2 NH2 H3C * * Q

H2N HsC
H3C * * Qi H2N * * Q~
NH2 H2N * p~ NH2 Table 2d H2N Q~ H2N~ Q~ H3C * * 4 O

* Q~ H2N Cl~
NH2 H2N Ch * * Q
HO~G1~ H2N~Q~ HO *

*
H3C~Q~ HaC . * Q~ H C
3 *

H3C * * HO * * Q~ H N * * ~~
Q
OH ~ NH2 OH

H2N * Gl~ HO * C1~ H2N

Table 2e O O OH O
HO~Qy H2N * Q~ H3C

*
H C * Q HO * Qi H2N~Q~
3 ~~ 1 88 8g 90 ~ ~ ~~ Il Qi H2N~Q~ H N' v _Q NH
z 91 g2 93 N NH O
H2N Qi H2N~ Q~ H2N
94 g5 96 H3C~O~Q~ H3C'O~ Q1 97 g8 Q~ ~ CH3 Q~ NCH Q~ ~CH3 Table 2f CH Q~~CH3 ~w/'~CH3 Q1 ~CH3 Q1 ~CH3 Q~ ~./~CH3 1~ 107 108 C~i~CH Q~,~ H3C CH3 G~i~CH3 CH CH
/~ 3 Q' Q1 3~' 3 CH
CH3 Q~ CH3 CH3 Q~ ~~CH3 Q~ ~~
CH

_ CH

Table Zg Q~~CHg ('~~~CH3 CH ~

GlyCHs Q~~CHs Cp ~ CH

I

G'~,~CH3 Q~ ~ H3 CH3 (~~ CH3 Qi~CH3 Q H3C CH3 QH3C CH3 T CH yCH

CH3 CH3 3 s Qt CH3 Q3C CH3 q1 CH3 '~CH i-~ CH

3 s Q~~CH3 H3C CH3 CH3 Qi~CHs qi~'CH3 Table Zh 4 ~H3 CH Q~ '~CH3 CHs H3C CHs G~~.~CH3 CHs CH ~i CHs CHs Q~ CHs CHs CHs Q~ CHs G~~ CHs CHs G~~~~CH3 CHs Q~ CHs CHs Qy CHs CHs D CHs CH ~~ ~/~/'YCH3 CHs - b6-Table 2i CH3 Q»'/~/''CHs Q~~CH3 s H3C CH3 4~~~~CH3 4~~~CH3 Q~~~CHs (~~~j~/'~ n~\~~CH C,~~CH3 CH3 CH3 CH3 3 CHa CH3 n~~'~CH3 4~~CHs C~~~CH3 '~ 3 CH3 ~CH3 CH Q~ C~~CH
CHg 3 Q H3C CH3 CH3 ~H3 i~.,~CH3 ~~~~CH3 Q~~~CH3 Table 2j CH3 C~H3 CH3 CH3 p~'~~CH3 Q~~CH3 Qi~~CH

p~ CH3 Q~~~~CH3 p~~./~CH
H C CH
CHg 3 3 CH3 CH3 Cl~ CH3 p~ CH3 pW~CHs Qy.~~ CH3 Qi~CH3 H3C~CH3 H3C CH3 H3C ~'=CH3 Q~ CH3 p~~CH3 Qi ~ CH3 CH3 s Qi~CH3 Q~ CH3 Q~~"~CH3 i S
~~~H s ~ ~H
~CH3 Ctl3 3 Cflg 185 1g6 187 Table 2k H3C CHs H3C.~CH3 H3C'/~ CHs ~~ ~.,~CHs CI~~~CH3 Q CH
1'~/~ 3 CHs CHs CHs CHs Q~.~CH3 Q~ CHs CHs CHs H3C CHs Qi CH3 Q CH Hs CHs 1~ 3 Q~ CH3 H3C CHs H3C~CHs CH

194 195 19fi CH CHs ~CH3 Q' s CH3 41 ~CH3 3 /~CH3CI H3 CH3 CHs CHs CHs CHs CHs CIi~CHs 4~~CH3 C1 H3 CI H3 CHs CHs HsC (~~ Q~
CHs H C CHs H C

Table 2Z

Q~

3 CHg H3C CHs H3C ,,,.CH3 H C

q 1 '~~~
Qt Q~
CH3 NCH HsC CH3 n~~
~

CH3 CH3 CH3 CH3 l Q

Table 2m H3C HsC H3C
Q' ~~~ Q' CH
CHs CHs CHs CHs CHs s H3C HsC H3C
Q w ~i~~w CHs ~ CHs ~ CHs CHs CHs CHs H3C CHs H3C CHs CHs Q' Qr,/',~ Qi CHs CHs CHs ,CHs CHs Q H3C CHs CZ~
CHs CHs CHs CHs ~H3 CHs CHs G1~ Cp Q' CHs CHs CHs CHs CHs CHs CH3 CHs CHs CHs Q1 CHs CHs Qi CHs CHs CHs Table 2n Q" CH3 CH3 Q~

Qi~~ Q
CH3 ~CH H3C CH3 H3C HsC H3C
CH Q~ G~~ w 1 3 : CH3 'Y CH3 C>>.,~.~ D
CH3 1 G~i 4i Qi Qi 3~ /~ 3 3 D
H C w ~ CH3 q~~CH

~CH3 Table 20 Q' CHs Q~~CHs C'',~' CHs w. H3C CHs HaC CHs H3C CHs CH3CHs CH3CHs 4~~CH3 C~ AW
HgC'~ CHs CHs ~CH3 CHs CHs CH3 CHs CHs Ci qi~
CHs ~CH3 HsC CHs CHs CHs CHs Ai~ C~ aW
HsCi CHs HsC CHs HsCi CHs CHs CHs ~CH3 Q' CHs Q'~CHs C' CHs ~CH3 H3C

H3C CHs H3C~CH3 CHs Qi Q~ C~~
CHs HsC HsC CHs Table 2p CHs = CHs ,CHs 4i 1~ Q
CH3 l ~
CHs ' CHs CH
CHs 3 CHs 4 H3C,~ CHs Q H3 ~ CHs CHs Q~ CHs H3C H3C HsC
280 281 2$2 ~ CHs CHs ~ CHs Q~ CHs ~~ .,,.CHs Q~ ~,CH3 HC HC

CHs ,CHs Q~ CHs 4~ Q~
H3C CHs H3C CHs H3C CHs Q~~CH3 ~~ CHs ~~ ~ CHs i~ C\~~ CHs H3C CHs s CHs CHs CHs CHs CHs Q~ CHs Q~ CHs H~ C:/~CH

Table 2q HsC CHs Hs ~-CHs CHs Qi CHs Gl~ CHs p~ CHs CHs CHs CHs CHs CHs ~CH3 ~ CHs f~~ CHs pi~CHs pi~.%~.CHs CH CH
CHs CHs 3 3 CHs CHs H3C CHs CHs CHs p CH a~ CHs p~~CH3 s HsC CHs H Cj~ CTHs CHs CHs p~ CHs Gl~ CHs 4~~CH3 l CHs ~ CHs HsC CH~H3 p~~CH3 p~ CHs p~~CH3 1 ' H C CH %~Hs ~ CHs s CHs s HsC CHs HsC CHs pi CHs (~~~CH3 p' CHs H3C~~,~CH3 H3C CHs ~'~~CH3 H3C CHs Table 2r CHs CHs C~H3 CHs CHs CHs p~\~~CH3 p~\'~CH3 p~'~CH

CHs CHs CHs p H C CH3(CH3 CHs CHs p~.,~~ H p~~~~CHs CHs C s CHs CHs CHs CHs CHs p~~~CHs C~~~~CHs (~~.,~CHs CHs CHs C~ H3 Ci Hs CHs CHs CHs CHs CHs CHs ~ H3 CHs p~~~~CH3 Q~~~~CHs p~~~CHs CHs CHs CHs CHs CHs CHs CHs pI~~CH3 p~'~~CH3 Q~ CHs CHs H3C CHs HsC CH~CHs p1 CHs CHs plH3C CHCHs p H3C CH CH
1'~~ 3 HsC CH3CHs CHs CHs CHs C' H3 Table Zs Q1 CHs CHs Q1 CHsCHs Q CHs CHs H \~ l -CH
CH3CHs s CHs CHs s (;I~CHs Q
CHs ~ Q~ CHs G>>.~ = CHs CHs C_H HCHs H3C CH HsC CHCHs C~~CHs H C CHs CHs CH3 HsC1_l-CHs HsC C 3 Hs GZ~ CHs ~1~./W,/CH3 337 33g 339 f,~i CHs Q~~CH3 CHs Qrt CHs H C~CH3 H TCH
3 CHs sC CHs 3 HsC CHCHs Q~~ s Q HsC CHs Q~H~3~C CHs CHs ~ ~ CH3 'C CHs HsCT"CHs CHs ~ CHs CH3 CHs CHs Q HsC CH CH Q1 CHs HsC CHs s \~CH3 C~~wi~CH3 HsC CHs H3C CH3 CHs H C/\CH

_ 77_ Table 2t CHs CH CHs HsC CHs HsC CHs H3C ~ CHs .Qi CHs Q~ = CHs 4~~CHs CHs CHs CHs CHs HsC~-CHs H3C CHs \V~CH3 Q~~CH C1~~~CH3 C~ t CH3 CH 3 CHs CHs CHs CHs CHs CHs H3C CHs C~i~~ HHs Qi~i~-CHs G~~~~,~~~CHs 3 CHs CHs H3C CHs HsC H3C
~,,~CHs Q~~~ GZi CHs CHs (~~ Q1 * Q1 * CHs CHs G~i CHs CHs CHs CHs H3C H3 C~ * * * CHs Q~ * CHs CHs CHs CHs H3C CHs _ 7g_ WO 99/14185 PCTlUS98/19355 Table Zu Q~ CHs CHs CHs CH3 ~~ * CHs ~~ * * CHs H3C CH CHs CHs H C
Q~ * * CHs HsC Q1 * s H3C * q~ CHs CHs H3C * CHs ~~ * CHs Q~ * Qi CHs CHs CHs Q CHs CH CHs CHs CHs * 3 ~~ * CHg ('~~ *
T * * Y 'CHs H3C CHs CHs CHs HsC CH H3 HsC H3C CHs CHs CHs HsC CHs HsC CH HsC CH
HsC CHs s s CHs HsC HsC Q HsC
* ~*
Qi 4~
CH3 CHs Table 2v HsC CHs 4~ .* ~~ * Qi CHs CHs CHs CHs CHs CHs CHs CHs G~~ * * * * CHs HsCQi CHs ~i CHs CHs CHs CHs HsC HsC C 3 Hs CHs HsC H3C
Qi Q~ G~i CHs CHs HsC HsC CHs 4~ Q~ Q~
CHs CH CHs CHs CHs CHs CHs CHs HsC CHs CH CHs Q~ CHs Qi H3C CH3 CHs CHs v CHs CHs H3C

Table 2w Cite C~~ ~ CH3 CH3 4~~

C~ ~CH3 H3C QWCH3 CH3 Q~
403 404 405 4~

~'~1 4~~ C'~CH3 Q' T

Q~ ~CH3 G1WCH3 Q'~'~/'~CHs Q~ _CHs 4iCHs Qi Q'~~/'~~CH3 q~~ H3 Table 2x p~~CHg p~~CH3 H3C CH3 _C' H3 '~ 'C~'H

p~ CH3 CH3 G~~~CH3 p1~ p1 CH3 CH3 Di CH3 - CHg rCH3 p lm,..~
p ~.~..a a s p~ p ~'. p 1\r Q~\~ 1\v~

Table 2y Q~ ,,~CH3 Q~.~,, CHs Q~ ,,~CH3 4~,~, CHs CHs CHs CHs CHs CHs CHs 4~~~'CH3 p''~w CHs p~ Ann"..
~4 445 446 447 CHs CHs ~,a CHs ,~ CHs ~ p1 pi~ p~~~"..4:
CHs CHs ,CHs D CH CHs p , s ' p1~ p1 CHs CH3 CHs CHs Qi~CH3 p~ p~u~...
p i"...
i pi p p~~..~~CHs p~~ CHs Table 2z Qi~ CHs CHs Q
i~~~
CHs C'~~ Qi Q~ CHs Q~~~,~.~CH3 G~~~,,,.CHs Gly~,...Q.~CH3 p Qy CHs H3C CHs CHs CHs CHs CHs CH3 Qi CHs CHs CHs CHs CHs CHs CHs .,~.CHs CH Q».
CH 3 CHs CHs .~,CH3 CHs CHs ~iW'~CH p QiW
CHs CHs _ g4_ Table Zaa Q Q
CH ~ w"

Q~",... ~CH3 Qi Q~
HsC CH3 H3C CH3 H3C CH3 H3C

CH3 Q~ Q~~ Q~
Q~n,...

Q~ CH3 Qw.,~w~CH3 Qy~~,~CH3 Q~ ....CH3 Q~.H CH3 Qi~~~"~~"~~4.~CH3 CH3 ~CH3 Q~ ,~CH3 Q~.~,. CH3 Q~ ,.~~~~CH Q~~,~ CH
3 ~ 3 ' 3 '~~~.~CHs '°~y~CH CH3 CH3 Table tab CHs CHs Q~ '"~~CH a'~'" CH
,~ 3 Q1 Q~u~,.
CHs CHs CHs CHs CHs CHs CHs CHs Q1 Q1~ Q'na.. Q'~u...
CH3 ~1~'~ CHs CH3 ~~11'~-CH

CHs ,CHs CHs H3C
Q CHs ~'CH3 .~' CHs '~' CHs HsC HsC HsC
CHs t~ CHs ~~-CHs Q, Q~n~... Q Q~m,..4 ,~
5i7 518 519 520 Q~ p~~ Qi _ Q, CHs CHs ~CH3 CHs Q"~: q Q,~J .o CHs % Q1~N'"~ 's CHs CHs WO 99/14185 PC'C/US98/19355 Table 2ac pi~ pi~W~'~ p~ . p~IN...
v HsCs HaC V

~ H3 CH3 CH3 p .mCHs p~ 1»... p 4> ; a --~ 3 p' ~CH3 p~ CH3 p~ 1~».. CH3 p~.-~CH3 p ..,ICH

CH3 CH3 C_ H3 t p~ n~...~CH3 p~ 1~,.. ..,~CH3 p~~..~.~,CH3 p~ 1"...~..~ICH3 p pi 1~»..
i _ 87_ Table tad ~ CH3 ~CH3 Q~~--~ q~n"..~ q' CH3 4i CH3 p~~.»,~~~~ q H3C H3C H3C H3~
u....
pi y CH3 CH3 ,,CH3 .,,,CH3 Q~~ Q~~"... p~ p a - ~-'a p Qi --qy _ 8g_ Table tae G~~ Q~\.w~''' CH
s CHs CHs .~CH ~ ..
Q1\a~"' 3 Q ~'~nCH3 Q1\h"' CH3 Q~ CH Qi .CHs Q .,. CHs Chi ,~,CH3 s CHs 1 .. CHs ..aCHs CHs G~~ .,,.CHs Gay.,,,. CHs p~ r'''CHs ..,.CHs CHs CHs ~CH3 Q~~,, CHs .~CH3 CH CHs \CHs s Q~ CH
3 CHs CHs WO 99/14185 PC1'/US98/19355 Table 2af p~ ~,.I p ~J ~y,~CHs ~y,..CH3 (~~
p' CH3 ~ CH3 W
596 597 5gg p' ~~b''' GZ~ 4~~/"%...

~N
p~ CH3 p' ~ ~~' CH3 4' ..,~CH3 pi Q
'~..,,CH3 Table tag CHs CHs ~CH3 pi~ CHs CHs pw CHs CHs CHs '., ..., p ...nu~

w, HC

p~~ p~~"...~ D
CHs HsC CH H3C'\CH HsC~CH3 H3C

plm... p~~.,I/ p~um..
CHs ~,J ,,~CH3 .4,~CHs p~
CHs ~,CH3 HsC CHs H C~CH

Table 2ah CHs CHs CHs Qww~~' CHs CHs CHs CHs ~~'-CH3 CHs ...pN
Qt'~..vx" L,H Qt Q~,,~.v~,..

...,", Q ~ "CHs Q~ .. ~ ~-CHs Q

~~ Q~~ Qi C~~ C~~ /
G~~

Q / CHs Q / Q / H3C
y~* i CHs Q~

Table tai CHs Q, * C~,---~* Q, CHs H3C

H CHs 3 *
Ch l G1~ l p~ ~ * CH3 HsC CHs o, l * CHs D, * Q, ~ * * CHs Q~
CHs CHs I ~ a~ I

O, o ~ I Q~ ~
CHs CHs Table 3a OH Q2~ OH ~O.CH3 O-CH
O O
a b c d O
Oo ~ ~ n GZ2 OH ~ OH p2 S'OH r OOH
G~2 f g h O ~S ~O O
Q2 N CH3 p2 ''N ~CH3 Q ~N' ~CH3 H H H
i j k O O O H H
~~ i ~ , Q ~N~S~CH3 42iS.N~CHs C~2'S.~CH3 H CIH3 O~ ~O IOI O~ ~O O
n O~ OOH ~ ~p-CH3 ~\ OOH ~\ ,O-CH3 POOH
2 POOH Q2 O-CH3 Q Q \O-CH3 o P 4 r Table 3b H
CH s H CHs N' N N'N'N Q2'S'~ Q2'S, it ~~
4 ~ N Q2~-N O O O O O O

S t U V
CHs Q2;S ~CH3 O O O O O
O O O H~~~ H C CHs 3''' C H g 3 X Y Z
Q Q
Q

O O O O O O O O
H3C--~ CH 3 CHs CHs CHs H sC
A B C D

~O ~O
O O
CHs CHs CHs E F

Table 4a Q3 OH Cl3-N3 C~3--N02 Q3 NH2 Q ~ NH2 ~3~ ~ 3 NH2 Q3 * NH2 H2N

NH H H
Q3~NH2 Q 2 Q ~N NH N NH
3~ 3 NH NH Q NH
H3CYN.,,,~NH
Q3 NH2 ~ NH2 ~ NH2 ~3 H3C NH ~3 S NH Q NH * NH
''~' NH2 ~ a z NH

NH2 * NH2 NH2 Q ~ NH2 Q3~ NH2 Q3~ NH2 Q3 * * CH3 Table 4b NH2 Os~ NH2 ~OH G~s~ NH2 Q3 Q3 * OH

* OH
Cl3~OH O Q/~ * CH3 D * NH Q * OH 3 * l ~* CH3 NH
Q -CN
OH Q3 * NH2 3 Q ~S NH2 ~3 03 N~NHZ 43 N~NH2 03 NYNH2 N
H CH3 SCH3 C ~NH2 N

~3 ~3 ~3 S HN N. H N.
_ ~ H
N~ .N. H~N

H
H , Q3 N.,~NCH3 03 N~NCH2CH3 Table 4c H
iN~ H N
CH3 p3~~,,iCH3 Qs~ ~Chl H H
H
Os~N~CH3 ~N N
H C q3 OOH Os~ ~NH2 CIs~N~CH3 G~s~N~CHa -9&

Table Sa H_Q4 H3C'Q4 H3C/1Q4 ~Q4 CH
~3 CHs H3C Q4 a b c d a O O O H
~Q4 HsC H3C N.
H3C Q4 ~Q4 Q

f 9 h i CH3 H H3C O~ CH3 H
N.Q ~ Q4 H C N,Q FH2C~N'Q4 4 CH3 3 ~ II4 O O O
J k I m F2HCuN.Q4 F3C~N'Q H3C~N~Q N'Q

O O O
n o p H
H3C N. CHs CH3 CH3 CH

t..~3C~N'Q4 FH2C N.Q F2HC N'Q
CH3 IO ~ 4 ~ 4 O O
r s t a Table 5b F3C N.Q4 H3C ~S~N.p4 ~S~N.Qa H3C~S''N.Q4 o '~ w O O
O O O O O
v w x N ' H3C.S~N.p4 ~ ,N. ~ ~N. 4 ~N,p w Q4 H3C ~ S 0 p ~N
O O O
z as ab ac H
N ' I ., N I N.. N \
~~N.
N ~ G~4 / N~Q4 / N~p4 / N~Q4 H~ H H H
ad ae of a9 H H H \
~S~N,Qa ~N N.G~ N~N.G1 ( / H
~N S~ a ~S a N.
p4 ah ai al ak CH3 CH3 I ~ N I N~
N N CN 'N, / 4 p4 N~ pa N~ 4 / N~p4 N H~ CH3 CH3 al am an ao Table Sc N ~ S CHs CH3 CH3 '7-,.N- N \ N.
N~44 ~N G~4 ~~N.Q4 N

ap aq ar as H3C. H

H3C H3C H3C_J
at au av aw H3C,O,Q4 H3C~O,Q4 H3C~S~Q4 H3C~S~Q4 ax ay az ba O O O
H C O Q ~'O~G~4 H3C O~(~o S,Q4 CH

bb be bd be S. OvS~~O ~,.N, Q4 Q4 ~~ ~4 bf b9 bh I
N
~N_ Q4 ~N_ Q4 N
O
bi bl bk Table 6 - Exemplary Enumerated Compounds A.l7.a.4.i; A.l7.a.4.v; A.l7.a.6.i; A.l7.a.6.v; A.l7.a.ll.i; A.l7.a.ll.v;
A.l7.a.14.i;
A.l7.a.14.v; A.l7.a.15.i; A.l7.a.15.v; A.l7.a.18.i; A.l7.a.18.v; A.l7.a.25.i;
A.l7.a.25.v; A.l7.e.4.i; A.l7.e.4.v; A.l7.e.6.i; A.l7.e.6.v; A.l7.e.ll.i;
A.l7.e.11.v;
A.l7.e.14.i; A.l7.e.14.v; A.l7.e.15.i; A.l7.e.15.v; A.l7.e.18.i; A.l7.e.18.v;
A.l7.e.25.i; A.l7.e.25.v; A.l7.g.4.i; A.l7.g.4.v; A.l7.g.6.i; A.l7.g.6.v;
A.l7.g.ll.i;
A.l7.g.ll.v; A.l7.g.14.i; A.l7.g.14.v; A.l7.g.15.i; A.l7.g.15.v; A.l7.g.18.i;
A.l7.g.18.v; A.l7.g.25.i; A.l7.g.25.v; A.17.1.4.i; A.17.1.4.v; A.17.1.6.i;
A.17.1.6.v;
A.l7.l.ll.i; A.l7.l.ll.v; A.17.1.14.i; A.17.1.14.v; A.17.1.15.i; A.17.1.15.v;
A.17.1.18.i; A.17.1.18.v; A.17.1.25.i; A.17.1.25.v; A.l7.m.4.i; A.l7.m.4.v;
A.l7.m.6.i; A.l7.m.6.v; A.l7.m.11.i; A.l7.m.ll.v; A.l7.m.14.i; A.l7.m.14.v;
A.l7.m.15.i; A.l7.m.15.v; A.l7.m.18.i; A.l7.m.18.v; A.l7.m.25.i; A.l7.m.25.v;
A.l7.o.4.i; A.l7.o.4.v; A.l7.o.6.i; A.l7.o.6.v; A.l7.o.11.i; A.l7.o.ll.v;
A.l7.o.14.i; A.l7.o.14.v; A.l7.o.15.i; A.l7.o.15.v; A.l7.o.18.i; A.l7.o.18.v;
A.l7.o.25.i; A.l7.o.25.v; A.33.a.4.i; A.33.a.4.v; A.33.a.6.i; A.33.a.6.v;
A.33.a.ll.i;
A.33.a.ll.v; A.33.a.14.i; A.33.a.14.v; A.33.a.15.i; A.33.a.15.v; A.33.a.18.i;
A.33.a.18.v; A.33.a.25.i; A.33.a.25.v; A.33.e.4.i; A.33.e.4.v; A.33.e.6.i;
A.33.e.6.v;
A.33.e.ll.i; A.33.e.ll.v; A.33.e.14.i; A.33.e.14.v; A.33.e.15.i; A.33.e.15.v;
A.33.e.18.i; A.33.e.18.v; A.33.e.25.i; A.33.e.25.v; A.33.g.4.i; A.33.g.4.v;
A.33.g.6.i;
A.33.g.6.v; A.33.g.ll.i; A.33.g.11.v; A.33.g.14.i; A.33.g.14.v; A.33.g.15.i;
A.33.g.15.v; A.33.g.18.i; A.33.g.18.v; A.33.g.25.i; A.33.g.25.v; A.33.1.4.i;
A.33.1.4.v; A.33.1.6.i; A.33.1.6.v; A.33.l.ll.i; A.33.l.ll.v; A.33.1.14.i;
A.33.1.14.v;
A.33.1.15.i; A.33.1.15.v; A.33.1.18.i; A.33.1.18.v; A.33.1.25.i; A.33.1.25.v;
A.33.m.4.i; A.33.m.4.v; A.33.m.6.i; A.33.m.6.v; A.33.m.ll.i; A.33.m.ll.v;
A.33.m.14.i; A.33.m.14.v; A.33.m.I5.i; A.33.m.15.v; A.33.m.18.i; A.33.m.18.v;
A.33.m.25.i; A.33.m.25.v; A.33.o.4.i; A.33.o.4.v; A.33.o.6.i; A.33.o.6.v;
A.33.o.ll.i; A.33.o.11.v; A.33.o.14.i; A.33.o.14.v; A.33.o.15.i; A.33.o.15.v;
A.33.o.18.i; A.33.o.18.v; A.33.o.25.i; A.33.o.25.v; A.49.a.4.i; A.49.a.4.v;
A.49.a.6.i; A.49.a.6.v; A.49.a.11.i; A.49.a.11.v; A.49.a.14.i; A.49.a.14.v;
A.49.a.15.i; A.49.a.15.v; A.49.a.18.i; A.49.a.18.v; A.49.a.25.i; A.49.a.25.v;
A.49.e.4.i; A.49.e.4.v; A.49.e.6.i; A.49.e.6.v; A.49.e.11.i; A.49.e.ll.v;
A.49.e.14.i;
A.49.e.14.v; A.49.e.15.i; A.49.e.15.v; A.49.e.18.i; A.49.e.18.v; A.49.e.25.i;
A.49.e.25.v; A.49.g.4.i; A.49.g.4.v; A.49.g.6.i; A.49.g.6.v; A.49.g.ll.i;
A.49.g.ll.v;
A.49.g.14.i; A.49.g.14.v; A.49.g.15.i; A.49.g.15.v; A.49.g.18.i; A.49.g.18.v;
A.49.g.25.i; A.49.g.25.v; A.49.1.4.i; A.49.1.4.v; A.49.1.6.i; A.49.1.6.v;
A.49.l.ll.i;
A.49.l.ll.v; A.49.1.14.i; A.49.1.14.v; A.49.1.15.i; A.49.1.15.v; A.49.1.18.i;
A.49.1.18.v; A.49.1.25.i; A.49.1.25.v; A.49.m.4.i; A.49.m.4.v; A.49.m.6.i;
A.49.m.6.v; A.49.m.ll.i; A.49.m.ll.v; A.49.m.14.i; A.49.m.14.v; A.49.m.15.i;
A.49.m.15.v; A.49.m.18.i; A.49.m.18.v; A.49.m.25.i; A.49.m.25.v; A.49.o.4.i;
A.49.o.4.v; A.49.o.6.i; A.49.o.6.v; A.49.o.11.i; A.49.o.11.v; A.49.o.14.i;
A.49.o.14.v; A.49.o.15.i; A.49.o.15.v; A.49.o.18.i; A.49.o.18.v; A.49.o.25.i;
A.49.o.25.v; B.l7.a.4.i; B.l7.a.4.v; B.l7.a.6.i; B.l7.a.6.v; B.l7.a.ll.i;
B.l7.a.11.v;
B.l7.a.14.i; B.l7.a.14.v; B.l7.a.15.i; B.l7.a.15.v; B.l7.a.18.i; B.l7.a.18.v;
B.l7.a.25.i; B.l7.a.25.v; B.l7.e.4.i; B.l7.e.4.v; B.l7.e.6.i; B.l7.e.6.v;
B.l7.e.11.i;
B.l7.e.11.v; B.l7.e.14.i; B.l7.e.14.v; B.l7.e.15.i; B.l7.e.15.v; 8.17.e.18.i;

B.l7.e.18.v; B.l7.e.2S.i; B.l7.e.25.v; B.l7.g.4.i; B.l7.g.4.v; B.l7.g.6.i;
B.l7.g.6.v;
B.l7.g.ll.i; B.l7.g.ll.v; B.l7.g.14.i; 8.17.g.14.v; B.l7.g.15.i; B.l7.g.15.v;
B.l7.g.18.i; B.l7.g.18.v; B.l7.g.25.i; B.l7.g.25.v; B.17.1.4.i; B.17.1.4.v;
B.17.1.6.i;
B.17:1.6.v; B.l7.l.ll.i; B.17.1.11.v; B.17.1.14.i; 8.17.1.14.v; B.17.1.15.i;
B.17.1.15.v;
B.17.1.18.i; B.17.1.18.v; B.17.1.25.i; B.17.1.25.v; B.l7.m.4.i; B.l7.rn.4.v;
B.l7.m.6.i;
B,l7.m.6.v; B.l7.m.ll.i; B.l7.m.ll.v; B.l7.m.14.i; B.l7.m.14.v; B.l7.m.15.i;
8.17.m.15.v; B.l7.m.18.i; B.l7.m.18.v; B.l7.m.25.i; B.l7.m.25.v; B.l7.o.4.i;
B.l7.o.4.v; B.l7.o.6.i; B.l7.o.6.v; B.l7.o.ll.i; B.l7.o.ll.v; B.l7.o.14.i;
B.l7.o.14.v;
B.l7.o.15.i; B.l7.o.15.v; B.l7.o.18.i; B.l7.o.18.v; B.l7.o.25.i; B.l7.o.25.v;
B.33.a.4.i; B.33.a.4.v; B.33.a.6.i; B.33.a.6.v; B.33.a.ll.i; B.33.a.11.v;
B.33.a.14.i;
B.33.a.14.v; B.33.a.15.i; B.33.a.15.v; B.33.a.18.i; B.33.a.18.v; B.33.a.25.i;
B.33.a.25.v; B.33.e.4.i; B.33.e.4.v; B.33.e.6.i; B.33.e.6.v; B.33.e.ll.i;
B.33.e.ll.v;
B.33.e.14.i; B.33.e.14.v; B.33.e.15.i; B.33.e.15.v; B.33.e.18.i; B.33.e.18.v;
B.33.e.25.i; B.33.e.25.v; B.33.g.4.i; B.33.g.4.v; 8.33.g.6.i; B.33.g.6.v;
B.33.g.11.i;
B.33.g.ll.v; B.33.g.14.i; B.33.g.14.v; B.33.g.15.i; B.33.g.15.v; B.33.g.18.i;
B.33.g.18.v; B,33.g.25.i; B.33.g.25.v; B.33.1.4.i; B.33.1.4.v; B.33.1.6.i;
B.33.1.6.v;
B.33.l.ll.i; B.33.1.11.v; B.33.1.14.i; B.33.1.14.v; B.33.1.15.i; B.33.1.15.v;
B.33.1.18.i;
B.33.1.18.v; B.33.1.25.i; B.33.1.25.v; B.33.m.4.i; B.33.m.4.v; B.33.m.6.i;
B,33.m.6.v; B.33.m.ll.i; B.33.m.11.v; B.33.m.14.i; B.33.m.14.v; B.33.m.15.i;
B.33.m.15.v; B.33.m.18.i; B.33.m.18.v; B.33.m.25.i; B.33.m.25.v; B.33.o.4.i;
B.33.o.4.v; B.33.o.6.i; B.33.o.6.v; B.33.o.ll.i; B.33.o.ll.v; B.33.o.14.i;
B.33.o.14.v;
B.33.o.15.i; B.33.o.15.v; B.33.o.18.i; B.33.o.18.v; B.33.o.25.i; B.33.o.25.v;
B.49.a.4.i; B.49.a.4.v; B.49.a.6.i; B.49.a.6.v; B.49.a.11.i; B.49.a.ll.v;
B.49.a.14.i;
B.49.a.14.v; B.49.a.15.i; B.49.a.15.v; B.49.a.18.i; B.49.a.18.v; B.49.a.25.i;
B.49.a.25.v; B.49.e.4.i; B.49.e.4.v; B.49.e.6.i; B.49.e.6.v; B.49.e.ll.i;
B.49.e.ll.v;
B.49.e.14.i; B.49.e.14.v; B.49.e.15.i; B.49.e.15.v; B.49.e.18.i; B.49.e.18.v;
B.49.e.25.i; B.49.e.25.v; B.49.g.4.i; B.49.g.4.v; B.49.g.6.i; B.49.g.6.v;
B.49.g.11.i;
B.49.g.ll.v; B.49.g.14.i; B.49.g.14.v; B.49.g.15.i; B.49.g.15.v; B.49.g.18.i;
B.49.g.18.v; B.49.g.25.i; 8.49.g.25.v; B.49.1.4.i; B.49.1.4.v; B.49.1.6.i;
8.49.1.6.v;
B.49.l.ll.i; B.49.1.11.v; B.49.1.14.i; B.49.1.14.v; 8.49.1.15.1; B.49.1.15.v;
B.49.1.18.i;
B.49.1.18.v; B.49.i.25.i; B.49.L25.v; B.49.m.4.i; B.49.m.4.v; B.49.m.6.i;
B.49.m.6.v; B.49.m.ll.i; B.49.m.ll.v; B.49.m.14.i; B.49.m.14.v; B.49.m.15.i;
B,49.m.15.v; B.49.m.18.i; B.49.m.18.v; B.49.m.25.i; B.49.m.25.v; B.49.o.4.i;
B.49.o.4.v; B.49.o.6.i; B.49.o.6.v; B.49.o.Il.i; B.49.o.ll.v; B.49.o.14.i;
B.49.o.14.v;
B.49.o.15.i; B.49.o.15.v; B.49.o.18.i; B.49.o.18.v; B.49.o.25.i; B.49.o.25.v;
E.l7.a.4.i; E.l7.a.4.v; E.l7.a.6.i; E.l7.a.6.v; E.l7.a.ll.i; E.l7.a.11.v;
E.l7.a.14.i;
E.l7.a.14.v; E.l7.a.15.i; E.l7.a.15.v; E.l7.a.18.i; E.l7.a.18.v; E.l7.a.25.i;
E.l7.a.25.v; E.l7.e.4.i; E.l7.e.4.v; E.l7.e.6.i; E.l7.e.6.v; E.l7.e.ll.i;
E.l7.e.ll.v;
E.l7.e.14.i; E.l7.e.14.v; E.l7.e.15.i; E.l7.e.15.v; E.l7.e.18.i; E.l7.e.18.v;
E.l7.e.25.i;
E.l7.e.25.v; E.l7.g.4.i; E.l7.g.4.v; E.l7.g.6.i; E.l7.g.6.v; E.l7.g.11.i;
E.l7.g.11.v;
E.l7.g.14.i; E.l7.g.14.v; E.l7.g.15.i; E.l7.g.15.v; E.l7.g.18.i; E.l7.g.18.v;
E.l7.g.25.i;
E.l7.g.25.v; E.17.1.4.i; E.17.1.4.v; E.17.1.6.i; E.17.1.6.v; E.l7.l.ll.i;
E.17.1.11.v;
E.17.1.14.i; E.17.1.14.v; E.17.1.15.i; E.17.1.15.v; E.17.1.18.i; E.17.1.18.v;
E.17.1.25.i;
E.17.1.25.v; E.l7.m.4.i; E.l7.m.4.v; E.l7.m.6.i; E.l7.m.6.v; E.l7.m.ll.i;
E.l7.m.11.v; E.l7.m.14.i; E.l7.m.14.v; E.l7.m.15.i; E.l7.m.15.v; E.l7.m.18.i;
E.l7.m.18.v; E.l7.m.25.i; E.l7.m.25.v; E.l7.o.4.i; E.l7.o.4.v; E.l7.o.6.i;
E.l7.o.6.v;
E.l7.o.ll.i; E.l7.o.ll.v; E.l7.o.14.i; E.l7.o.14.v; E.l7.o.15.i; E.l7.o.15.v;

E.l7.o.18.i; E.l7.o.18.v; E.l7.o.25.i; E.l7.o.25.v; E.33.a.4.i; E.33.a.4.v;
E.33.a.6.i;
E.33.a.6.v; E.33.a.ll.i; E.33.a.ll.v; E.33.a.14.i; E.33.a.14.v; E.33.a.15.i;
E.33.a.15.v;
E.33.a.18.i; E.33.a.I8.v; E.33.a.25.i; E.33.a.25.v; E.33.e.4.i; E.33.e.4.v;
E.33.e.6.i;
E.33.e.6.v; E.33.e.ll.i; E.33.e.11.v; E.33.e.14.i; E.33.e.14.v; E.33.e.15.i;
E.33.e.15.v;
E.33.e.18.i; E.33.e.18.v; E.33.e.25.i; E.33.e.25.v; E.33.g.4.i; E.33.g.4.v;
E.33.g.6.i;
E.33.g.6.v; E.33.g.11.i; E.33.g.11.v; E.33.g.14.i; E.33.g.14.v; E.33.g.I5.i;
E.33.g.15.v;
E.33.g.18.i; E.33.g.18.v; E.33.g.25.i; E.33.g.25.v; E.33.1.4.i; E.33.1.4.v;
E.33.1.6.i;
E.33.1.6.v; E.33.1.11.i; E.33.l.ll.v; E.33.1.14.i; E.33.1.14.v; E.33.1.15.i;
E.33.1.15.v;
E.33.1.18.i; E.33.1.18.v; E.33.1.25.i; E.33.1.25.v; E.33.m.4.i; E.33.m.4.v;
E.33.m.6.i;
E.33.m.6.v; E.33.m.11.i; E.33.m.ll.v; E.33.m.14.i; E.33.m.14.v; E.33.m.15.i;
E.33.m.15.v; E.33.m.18.i; E.33.m.18.v; E.33.m.25.i; E.33.m.25.v; E.33.o.4.i;
E.33.o.4.v; E.33.o.6.i; E.33.o.6.v; E.33.o.ll.i; E.33.o.ll.v; E.33.o.14.i;
E.33.o.14.v;
E.33.o.15.i; E.33.o.15.v; E.33.o.18.i; E.33.o.18.v; E.33.o.25.i; E.33.o.25.v;
E.49.a.4.i;
E.49.a.4.v; E.49.a.6.i; E.49.a.6.v; E.49.a.11.i; E.49.a.ll.v; E.49.a.14.i;
E.49.a.14.v;
E.49.a.15.i; E.49.a.15.v; E.49.a.18.i; E.49.a.18.v; E.49.a.25.i; E.49.a.25.v;
E.49.e.4.i;
E.49.e.4.v; E.49.e.6.i; E.49.e.6.v; E.49.e.ll.i; E.49.e.11.v; E.49.e.14.i;
E.49.e.14.v;
E.49.e.15.i; E.49.e.15.v; E.49.e.18.i; E.49.e.18.v; E.49.e.25.i; E.49.e.25.v;
E.49.g.4.i;
E.49.g.4.v; E.49.g.6.i; E.49.g.6.v; E.49.g.ll.i; E.49.g.11.v; E.49.g.14.i;
E.49.g.14.v;
E.49.g.15.i; E.49.g.15.v; E.49.g.18.i; E.49.g.18.v; E.49.g.25.i; E.49.g.25.v;
E.49.1.4.i;
E.49.1.4.v; E.49.1.6.i; E.49.1.6.v; E.49.l.ll.i; E.49.1.11.v; E.49.1.14.i;
E.49.1.14.v;
E.49.1.15.i; E.49.1.15.v; E.49.1.18.i; E.49.1.18.v; E.49.1.25.i; E.49.1.25.v;
E.49.m.4.i;
E.49.m.4.v; E.49.m.6.i; E.49.m.6.v; E.49.m.ll.i; E.49.m.ll.v; E.49.m.14.i;
E.49.m.14.v; E.49.m.15.i; E.49.m.15.v; E.49.m.18.i; E.49.m.18.v; E.49.m.25.i;
E.49.m.25.v; E.49.o.4.i; E.49.o.4.v; E.49.o.6.i; E.49.o.6.v; E.49.o.ll.i;
E.49.o.11.v;
E.49.o.14.i; E.49.o.14.v; E.49.o.15.i; E.49.o.15.v; E.49.o.18.i; E.49.o.18.v;
E.49.o.25.i; E.49.o.25.v; H.l7.a.4.i; H.l7.a.4.v; H.l7.a.6.i; H.l7.a.6.v;
H.l7.a.ll.i;
H.l7.a.ll.v; H.l7.a.14.i; H.l7.a.14.v; H.l7.a.15.i; H.l7.a.15.v; H.l7.a.18.i;
H.l7.a.18.v; H.l7.a.25.i; H.l7.a.25.v; H.l7.e.4.i; H.l7.e.4.v; H.l7.e.6.i;
H.l7.e.6.v;
H.l7.e.ll.i; H.l7.e.ll.v; H.l7.e.14.i; H.l7.e.14.v; H.l7.e.15.i; H.l7.e.15.v;
H.l7.e.18.i; H.l7.e.18.v; H.l7.e.25.i; H.l7.e.25.v; H.l7.g.4.i; H.l7.g.4.v;
H.l7.g.6.i;
H.l7.g.6.v; H.l7.g.ll.i; H.l7.g.ll.v; H.l7.g.14.i; H.l7.g.14.v; H.l7.g.15.i;
H.l7.g.15.v; H.l7.g.18.i; H.l7.g.18.v; H.l7.g.25.i; H.l7.g.25.v; H.17.1.4.i;
H.17.1.4.v; H.17.1.6.i; H.17.1.6.v; H.l7.l.ll.i; H.l7.l.ll.v; H.17.1.14.i;
H.17.1.14.v;
H.17.1.15.i; H.17.1.15.v; H.17.1.18.i; H.17.1.18.v; H.17.1.25.i; H.17.1.25.v;
H.l7.m.4.i; H.l7.m.4.v; H.l7.m.6.i; H.l7.m.6.v; H.l7.m.ll.i; H.l7.m.11.v;
H.l7.m.14.i; H.l7.m.14.v; H.l7.m.15.i; H.l7.m.15.v; H.l7.m.18.i; H.l7.m.18.v;
H.l7.m.25.i; H.l7.m.25.v; H.l7.o.4.i; H.l7.o.4.v; H.l7.o.6.i; H.l7.o.6.v;
H.l7.o.11.i; H.l7.o.ll.v; H.l7.o.14.i; H.l7.o.14.v; H.l7.o.15.i; H.l7.o.15.v;
H.l7.o.18.i; H.l7.o.18.v; H.l7.o.25.i; H.l7.o.25.v; H.33.a.4.i; H.33.a.4.v;
H.33.a.6.i; H.33.a.6.v; H.33.a.ll.i; H.33.a.ll.v; H.33.a.14.i; H.33.a.14.v;
H.33.a.15.i; H.33.a.15.v; H.33.a.18.i; H.33.a.18.v; H.33.a.25.i; H.33.a.25.v;
H.33.e.4.i; H.33.e.4.v; H.33.e.6.i; H.33.e.6.v; H.33.e.11.i; H.33.e.11.v;
H.33.e.14.i;
H.33.e.14.v; H.33.e.15.i; H.33.e.15.v; H.33.e.18.i; H.33.e.18.v; H.33.e.25.i;
H.33.e.25.v; H.33.g.4.i; H.33.g.4.v; H.33.g.6.i; H.33.g.6.v; H.33.g.11.i;
H.33.g.ll.v;
H.33.g.14.i; H.33.g.14.v; H.33.g.15.i; H.33.g.15.v; H.33.g.18.i; H.33.g.18.v;
H.33.g.25.i; H.33.g.25.v; H.33.1.4.i; H.33.1.4.v; H.33.1.6.i; H.33.1.6.v;
H.33.1.11.i;
H.33.1.11.v; H.33.1.14.i; H.33.1.14.v; H.33.1.15.i; H.33.1.15.v; H.33.1.18.i;

H.33.1.18.v; H.33.1.25.i; H.33.1.25.v; H.33.m.4.i; H.33.m.4.v; H.33.m.6.i;
H.33.m.6.v; H.33.m.11.i; H.33.m.ll.v; H.33.m.14.i; H.33.m.14.v; H.33.m.15.i;
H.33.m.15.v; H.33.m.18.i; H.33.m.18.v; H.33.m.25.i; H.33.m.25.v; H.33.o.4.i;
H.33.o.4.v; H.33.o.6.i; H.33.o.6.v; H.33.o.ll.i; H.33.o.11.v; H.33.o.14.i;
H.33.o.14.v; H.33.o.15.i; H.33.o.15.v; H.33.o.18.i; H.33.o.18.v; H.33.o.25.i;
H.33.o.25.v; H.49.a.4.i; H.49.a.4.v; H.49.a.6.i; H.49.a.6.v; H.49.a.11.i;
H.49.a.11.v;
H.49.a.14.i; H.49.a.14.v; H.49.a.15.i; H.49.a.15.v; H.49.a.18.i; H.49.a.18.v;
H.49.a.25.i; H.49.a.25.v; H.49.e.4.i; H.49.e.4.v; H.49.e.6.i; H.49.e.6.v;
H.49.e.11.i;
H.49.e.11.v; H.49.e.14.i; H.49.e.14.v; H.49.e.15.i; H.49.e.15.v; H.49.e.18.i;
H.49.e.18.v; H.49.e.25.i; H.49.e.25.v; H.49.g.4.i; H.49.g.4.v; H.49.g.6.i;
H.49.g.6.v;
H.49.g.11.i; H.49.g.11.v; H.49.g.14.i; H.49.g.14.v; H.49.g.15.i; H.49.g.15.v;
H.49.g.18.i; H.49.g.18.v; H.49.g.25.i; H.49.g.25.v; H.49.1.4.i; H.49.1.4.v;
H.49.1.6.i;
H.49.1.6.v; H.49.1.11.i; H.49.l.ll.v; H.49.1.14.i; H.49.1.14.v; H.49.1.15.i;
H.49.1.15.v; H.49.1.18.i; H.49.1.18.v; H.49.1.25.i; H.49.1.25.v; H.49.m.4.i;
H.49.m.4.v; H.49.m.6.i; H.49.m.6.v; H.49.m.ll.i; H.49.m.ll.v; H.49.m.14.i;
H.49.m.14.v; H.49.m.15.i; H.49.m.15.v; H.49.m.18.i; H.49.m.18.v; H.49.m.25.i;
H.49.m.25.v; H.49.o.4.i; H.49.o.4.v; H.49.o.6.i; H.49.o.6.v; H.49.o.ll.i;
H.49.o.ll.v; H.49.o.14.i; H.49.o.14.v; H.49.o.15.i; H.49.o.15.v; H.49.o.18.i;
H.49.o.18.v; H.49.o.25.i; H.49.o.25.v; Ll7.a.4.i; Ll7.a.4.v; Ll7.a.6.i;
Ll7.a.6.v;
Ll7.a.11.i; Ll7.a.11.v; Ll7.a.14.i; Ll7.a.14.v; Ll7.a.15.i; Ll7.a.15.v;
Ll7.a.18.i;
Ll7.a.18.v; Ll7.a.25.i; Ll7.a.25.v; Ll7.e.4.i; Ll7.e.4.v; Ll7.e.6.i;
Ll7.e.6.v;
Ll7.e.11.i; Ll7.e.ll.v; Ll7.e.14.i; Ll7.e.14.v; Ll7.e.15.i; Ll7.e.15.v;
Ll7.e.18.i;
Ll7.e.18.v; Ll7.e.25.i; Ll7.e.25.v; Ll7.g.4.i; Ll7.g.4.v; Ll7.g.6.i;
Ll7.g.6.v;
Ll7.g.11.i; Ll7.g.11.v; Ll7.g.14.i; Ll7.g.14.v; Ll7.g.15.i; Ll7.g.15.v;
Ll7.g.18.i;
Ll7.g.18.v; Ll7.g.25.i; LI7.g.25.v; L17.1.4.i; L17.1.4.v; L17.1.6.i;
L17.1.6.v;
Ll7.l.ll.i; L17.1.11.v; L17.1.14.i; L17.1.14.v; L17.1.15.i; L17.1.15.v;
L17.1.18.i;
L17.1.18.v; L17.1.25.i; L17.1.25.v; Ll7.m.4.i; Ll7.m.4.v; Ll7.m.6.i;
Ll7.m.6.v;
Ll7.m.11.i; Ll7.m.11.v; Ll7.m.14.i; Ll7.m.14.v; Ll7.m.15.i; Ll7.m.15.v;
Ll7.m.18.i; Ll7.m.18.v; Ll7.m.25.i; Ll7.m.25.v; Ll7.o.4.i; Ll7.o.4.v;
Ll7.o.6.i;
Ll7.o.6.v; Ll7.o.11.i; Ll7.o.ll.v; Ll7.o.14.i; Ll7.o.14.v; Ll7.o.15.i;
Ll7.o.15.v;
Ll7.o.18.i; Ll7.o.18.v; Ll7.o.25.i; Ll7.o.25.v; L33.a.4.i; L33.a.4.v;
L33.a.6.i;
L33.a.6.v; L33.a.11.i; L33.a.ll.v; L33.a.14.i; L33.a.14.v; L33.a.15.i;
L33.a.15.v;
L33.a.1$.i; L33.a.18.v; L33.a.25.i; L33.a.25.v; L33.e.4.i; L33.e.4.v;
L33.e.6.i;
L33.e.6.v; L33.e.ll.i; L33.e.11.v; L33.e.14.i; L33.e.14.v; L33.e.15.i;
L33.e.15.v;
L33.e.18.i; L33.e.18.v; L33.e.25.i; L33.e.25.v; L33.g.4.i; L33.g.4.v;
L33.g.6.i;
L33.g.6.v; L33.g.ll.i; L33.g.ll.v; L33.g.14.i; L33.g.14.v; L33.g.15.i;
L33.g.15.v;
L33.g.18.i; L33.g.18.v; L33.g.25.i; L33.g.25.v; L33.1.4.i; L33.1.4.v;
L33.1.6.i;
L33.1.6.v; L33.l.ll.i; L33.1.11.v; L33.1.14.i; L33.1.14.v; L33.1.15.i;
L33.1.15.v;
L33.1.18.i; L33.1.18.v; L33.1.25.i; L33.1.25.v; L33.m.4.i; L33.m.4.v;
L33.m.6.i;
L33.m.6.v; L33.m.ll.i; L33.m.ll.v; L33.m.14.i; L33.m.14.v; L33.m.15.i;
L33.m.15.v; L33.m.18.i; L33.m.18.v; L33.m.25.i; L33.m.25.v; L33.o.4.i;
L33.o.4.v;
L33.o.6.i; L33.o.6.v; L33.o.11.i; L33.o.ll.v; L33.o.14.i; L33.o.14.v;
L33.o.15.i;
L33.o.15.v; L33.o.18.i; L33.o.18.v; L33.o.25.i; L33.o.25.v; L49.a.4.i;
L49.a.4.v;
L49.a.6.i; L49.a.6.v; L49.a.11.i; L49.a.11.v; L49.a.14.i; L49.a.14.v;
L49.a.15.i;
L49.a.15.v; L49.a.18.i; L49.a.18.v; L49.a.25.i; L49.a.25.v; L49.e.4.i;
L49.e.4.v;
L49.e.6.i; L49.e.6.v; L49.e.11.i; L49.e.11.v; L49.e.14.i; L49.e.14.v;
L49.e.15.i;
L49.e.15.v; L49.e.18.i; L49.e.18.v; L49.e.25.i; L49.e.25.v; L49.g.4.i;
L49.g.4.v;

L49.g.6.i; L49.g.6.v; L49.g.11.i; L49.g.ll.v; L49.g.14.i; L49.g.14.v;
L49.g.15.i;
L49.g.15.v; L49.g.18.i; L49.g.18.v; L49.g.25.i; L49.g.25.v; L49.1.4.i;
L49.1.4.v;
L49.1.6.i; L49.1.6.v; L49.l.ll.i; L49.1.11.v; L49.1.14.i; L49.1.14.v;
L49.1.15.i;
L49:1.15.v; L49.1.18.i; L49.1.18.v; L49.1.25.i; L49.1.25.v; L49.m.4.i;
L49.m.4.v;
L49.m.6.i; L49.m.6.v; L49.m.ll.i; L49.m.11.v; L49.m.14.i; L49.m.14.v;
L49.m.15.i; L49.m.15.v; L49.m.18.i; L49.m.18.v; L49.m.25.i; L49.m.25.v;
L49.o.4.i; L49.o.4.v; L49.o.6.i; L49.o.6.v; L49.o.ll.i; L49.o.ll.v;
L49.o.14.i;
L49.o.14.v; L49.o.15.i; L49.o.15.v; L49.o.18.i; L49.o.18.v; L49.o.25.i;
L49.o.25.v;
L.l7.a.4.i; L.l7.a.4.v; L.l7.a.6.i; L.l7.a.6.v; L.l7.a.ll.i; L.l7.a.ll.v;
L.l7.a.14.i;
L.l7.a.14.v; L.l7.a.15.i; L.l7.a.15.v; L.l7.a.18.i; L.l7.a.18.v; L.l7.a.25.i;
L.l7.a.25.v; L.l7.e.4.i; L.l7.e.4.v; L.l7.e.6.i; L.l7.e.6.v; L.l7.e.11.i;
L.l7.e.ll.v;
L.l7.e.14.i; L.l7.e.14.v; L.l7.e.15.i; L.l7.e.15.v; L.l7.e.18.i; L.l7.e.18.v;
L.l7.e.25.i;
L.l7.e.25.v; L.l7.g.4.i; L.l7.g.4.v; L.l7.g.6.i; L.l7.g.6.v; L.l7.g.ll.i;
L.l7.g.ll.v;
L.l7.g.14.i; L.l7.g.14.v; L.l7.g.15.i; L.l7.g.I5.v; L.l7.g.18.i; L.l7.g.18.v;
L.l7.g.25.i;
L.l7.g.25.v; L.17.1.4.i; L.17.1.4.v; L.17.1.6.i; L.17.1.6.v; L.l7.l.ll.i;
L.l7.l.ll.v;
L.17.1.14.i; L.17.1.14.v; L.17.1.15.i; L.17.1.15.v; L.17.1.18.i; L.17.1.18.v;
L.17.1.25.i;
L.17.1.25.v; L.l7.m.4.i; L.l7.m.4.v; L.l7.m.6.i; L.l7.m.6.v; L.l7.m.ll.i;
L.l7.m.11.v; L.l7.m.14.i; L.l7.m.14.v; L.l7.m.15.i; L.l7.m.15.v; L.l7.m.18.i;
L.l7.m.18.v; L.l7.m.25.i; L.l7.m.25.v; L.l7.o.4.i; L.l7.o.4.v; L.l7.o.6.i;
L.l7.o.6.v;
L.I7.o.ll.i; L.l7.o.ll.v; L.l7.o.14.i; L.l7.o.14.v; L.l7.o.15.i; L.l7.o.15.v;
L.l7.o.18.i; L.l7.o.18.v; L.l7.o.25.i; L.l7.o.25.v; L.33.a.4.i; L.33.a.4.v;
L.33.a.6.i;
L.33.a.6.v; L.33.a.ll.i; L.33.a.11.v; L.33.a.14.i; L.33.a.14.v; L.33.a.15.i;
L.33.a.15.v;
L.33.a.18.i; L.33.a.18.v; L.33.a.25.i; L.33.a.25.v; L.33.e.4.i; L.33.e.4.v;
L.33.e.6.i;
L.33.e.6.v; L.33.e.11.i; L.33.e.11.v; L.33.e.14.i; L.33.e.14.v; L.33.e.15.i;
L.33.e.15.v;
L.33.e.18.i; L.33.e.18.v; L.33.e.25.i; L.33.e.25.v; L.33.g.4.i; L.33.g.4.v;
L.33.g.6.i;
L.33.g.6.v; L.33.g.ll.i; L.33.g.ll.v; L.33.g.14.i; L.33.g.14.v; L.33.g.15.i;
L.33.g.15.v;
L.33.g.18.i; L.33.g.18.v; L.33.g.25.i; L.33.g.25.v; L.33.1.4.i; L.33.1.4.v;
L.33.1.6.i;
L.33.1.6.v; L.33.l.ll.i; L.33.l.ll.v; L.33.1.14.i; L.33.1.14.v; L.33.1.15.i;
L.33.1.15.v;
L.33.1.18.i; L.33.1.18.v; L.33.1.25.i; L.33.1.25.v; L.33.m.4.i; L.33.m.4.v;
L.33.m.6.i;
L.33.m.6.v; L.33.m.ll.i; L.33.m.ll.v; L.33.m.14.i; L.33.m.14.v; L.33.m.15.i;
L.33.m.15.v; L.33.m.18.i; L.33.m.18.v; L.33.m.25.i; L.33.m.25.v; L.33.o.4.i;
L.33.o.4.v; L.33.o.6.i; L.33.o.6.v; L.33.o.ll.i; L.33.o.ll.v; L.33.o.14.i;
L.33.o.14.v;
L.33.o.15.i; L.33.o.15.v; L.33.o.18.i; L.33.o.18.v; L.33.o.25.i; L.33.o.25.v;
L.49.a.4.i;
L.49.a.4.v; L.49.a.6.i; L.49.a.6.v; L.49.a.ll.i; L.49.a.11.v; L.49.a.14.i;
L.49.a.14.v;
L.49.a.15.i; L.49.a.15.v; L.49.a.18.i; L.49.a.18.v; L.49.a.25.i; L.49,a.25.v;
L.49.e.4.i;
L.49.e.4.v; L.49.e.6.i; L.49.e.6.v; L.49.e.11.i; L.49.e.ll.v; L.49.e.14.i;
L.49.e.14.v;
L.49.e.15.i; L.49.e.15.v; L.49.e.18.i; L.49.e.18.v; L.49.e.25.i; L.49.e.25.v;
L.49.g.4.i;
L.49.g.4.v; L.49.g.b.i; L.49.g.6.v; L.49.g.11.i; L.49.g.ll.v; L.49.g.14.i;
L.49.g.14.v;
L.49.g.15.i; L.49.g.15.v; L.49.g.18.i; L.49.g.18.v; L.49.g.25.i; L.49.g.25.v;
L.49.1.4.i;
L.49.1.4.v; L.49.1.6.i; L.49.1.6.v; L.49.1.11.i; L.49.1.11.v; L.49.1.14.i;
L.49.1.14.v;
L.49.1.15.i; L.49.1.15.v; L.49.1.18.i; L.49.1.18.v; L.49.1.25.i; L.49.1.25.v;
L.49.m.4.i;
L.49.m.4.v; L.49.m.6.i; L.49.m.6.v; L.49.m.ll.i; L.49.m.11.v; L.49.m.14.i;
L.49.m.14.v; L.49.m.15.i; L.49.m.15.v; L.49.m.18.i; L.49.m.18.v; L.49.m.25.i;
L.49.m.25.v; L.49.o.4.i; L.49.o.4.v; L.49.o.6.i; L.49.o.6.v; L.49.o.ll.i;
L.49.o.11.v;
L.49.o.14.i; L.49.o.14.v; L.49.o.15.i; L.49.o.15.v; L.49.o.18.i; L.49.o.18.v;
L.49.o.25.i; L.49.o.25.v; B.93.a.4.i; B.93.a.4.v; B.93.a.6.i; B.93.a.6.v;
B.93.a.11.i;
B.93.a.11.v; B.93.a.14.i; B.93.a.14.v; B.93.a.15.i; B.93.a.15.v; B.93.a.18.i;

B.93.a.18.v; 8.93.a.25.i; B.93.a.25.v; B.93.e.4.i; B.93.e.4.v; B.93.e.6.i;
B.93.e.6.v;
B.93.e.ll.i; B.93.e.11.v; B.93.e.14.i; B.93.e.14.v; B.93.e.15.i; B.93.e.15.v;
B.93.e.18.i; B.93.e.18.v; B.93.e.25.i; B.93.e.25.v; B.93.g.4.i; B.93.g.4.v;
B.93.g.6.i;
B.93.g.6.v; B.93.g.ll.i; B.93.g.ll.v; B.93.g.14.i; B.93.g.14.v; B.93.g.15.i;
B:93.g.15.v; B.93.g.18.i; B.93.g.18.v; B.93.g.25.i; B.93.g.25.v; B.93.1.4.i;
B.93.1.4.v;
B.93.1.6.i; B.93.1.6.v; B.93.1.11.i; B.93.l.ll.v; B.93.1.14.i; B.93.1.14.v;
B.93.1.15.i;
B.93.1.15.v; B.93.1.18.i; B.93.1.18.v; B.93.1.25.i; B.93.1.25.v; B.93.m.4.i;
B.93.m.4.v;
B.93.m.6.i; B.93.m.6.v; B.93.m.ll.i; B.93.m.ll.v; B.93.m.14.i; B.93.m.14.v;
B.93.m.15.i; B.93.m.15.v; B.93.m.18.i; B.93.m.18.v; B.93.m.25.i; B.93.m.25.v;
B.93.o.4.i; B.93.o.4.v; B.93.o.6.i; B.93.o.6.v; B.93.o.ll.i; B.93.o.11.v;
B.93.o.14.i;
B.93.o.14.v; B.93.o.15.i; B.93.o.15.v; B.93.o.18.i; B.93.o.18.v; B.93.o.25.i;
B.93.o.25.v; B.94.a.4.i; B.94.a.4.v; B.94.a.6.i; B.94.a.6.v; B.94.a.ll.i;
B.94.a.ll.v;
B.94.a.14.i; 8.94.a.14.v; B.94.a.15.i; B.94.a.15.v; B.94.a.18.i; B.94.a.18.v;
B.94.a.25.i; B.94.a.25.v; B.94.e.4.i; B.94.e.4.v; B.94.e.6.i; B.94.e.6.v;
B.94.e.ll.i;
B.94.e.11.v; B.94.e.14.i; B.94.e.14.v; B.94.e.15.i; B.94.e.15.v; B.94.e.18.i;
B.94.e.18.v; B.94.e.25.i; B.94.e.25.v; B.94.g.4.i; B.94.g.4.v; B.94.g.6.i;
B.94.g.6.v;
B.94.g.ll.i; B.94.g.11.v; B.94.g.14.i; B.94.g.14.v; B.94.g.15.i; B.94.g.15.v;
B.94.g.18.i; B.94.g.18.v; B.94.g.25.i; B.94.g.25.v; B.94.1.4.i; B.94.1.4.v;
B.94.1.6.i;
B.94.1.6.v; B.94.l.ll.i; B.94.l.ll.v; B.94.1.14.i; B.94.1.14.v; B.94.1.15.i;
B.94.1.15.v;
B.94.1.18.i; B.94.1.18.v; B.94.1.25.i; B.94.1.25.v; B.94.m.4.i; B.94.m.4.v;
B.94.m.6.i;
B.94.m.6.v; B.94.m.ll.i; B.94.m.ll.v; B.94.m.14.i; B.94.m.14.v; B.94.m.15.i;
B.94.m.15.v; B.94.m.18.i; B.94.m.18.v; B.94.m.25.i; B.94.m.25.v; B.94.o.4.i;
B.94.o.4.v; 8.94.o.6.i; B.94.o.6.v; B.94.o.ll.i; B.94.o.ll.v; B.94.o.14.i;
B.94.o.14.v;
B.94.o.15.i; B.94.o.15.v; B.94.o.18.i; B.94.o.18.v; B.94.o.25.i; B.94.o.25.v;
E.93.a.4.i; E.93.a.4.v; E.93.a.6.i; E.93.a.6.v; E.93.a.11.i; E.93.a.ll.v;
E.93.a.14.i;
E.93.a.14.v; E.93.a.15.i; E.93.a.15.v; E.93.a.18.i; E.93.a.18.v; E.93.a.25.i;
E.93.a.25.v; E.93.e.4.i; E.93.e.4.v; E.93.e.6.i; E.93.e.6.v; E.93.e.ll.i;
E.93.e.ll.v;
E.93.e.14.i; E.93.e.14.v; E.93.e.15.i; E.93.e.15.v; E.93.e.18.i; E.93.e.18.v;
E.93.e.25.i;
E.93.e.25.v; E.93.g.4.i; E.93.g.4.v; E.93.g.6.i; E.93.g.6.v; E.93.g.11.i;
E.93.g.ll.v;
E.93.g.14.i; E.93.g.14.v; E.93.g.15.i; E.93.g.15.v; E.93.g.18.i; E.93.g.18.v;
E.93.g.25.i;
E.93.g.25.v; E.93.1.4.i; E.93.1.4.v; E.93.L6.i; E.93.1.6.v; E.93.1.11.i;
E.93.l.ll.v;
E.93.1.14.i; E.93.1.14.v; E.93.1.15.i; E.93.1.15.v; E.93.1.18.i; E.93.1.18.v;
E.93.1.25.i;
E.93.1.25.v; E.93.m.4.i; E.93.m.4.v; E.93.m.6.i; E.93.m.6.v; E.93.m.ll.i;
E.93.m.11.v; E.93.m.14.i; E.93.m.14.v; E.93.m.15.i; E.93.m.15.v; E.93.m.18.i;
E.93.m.18.v; E.93.m.25.i; E.93.m.25.v; E.93.o.4.i; E.93.o.4.v; E.93.o.6.i;
E.93.o.6.v;
E.93.o.ll.i; E.93.o.11.v; E.93.o.14.i; E.93.o.14.v; E.93.o.15.i; E.93.o.15.v;
E.93.o.18.i; E.93.o.18.v; E.93.o.25.i; E.93.o.25.v; E.94.a.4.i; E.94.a.4.v;
E.94.a.6.i;
E.94.a.6.v; E.94.a.ll.i; E.94.a.11.v; E.94.a.14.i; E.94.a.14.v; E.94.a.15.i;
E.94.a.15.v;
E.94.a.18.i; E.94.a.18.v; E.94.a.25.i; E.94.a.25.v; E.94.e.4.i; E.94.e.4.v;
E.94.e.6.i;
E.94.e.6.v; E.94.e.ll.i; E.94.e.11.v; E.94.e.14.i; E.94.e.14.v; E.94.e.15.i;
E.94.e.15.v;
E.94.e.18.i; E.94.e.18.v; E.94.e.25.i; E.94.e.25.v; E.94.g.4.i; E.94.g.4.v;
E.94.g.6.i;
E.94.g.6.v; E.94.g.ll.i; E.94.g.ll.v; E.94.g.14.i; E.94.g.14.v; E.94.g.15.i;
E.94.g.15.v;
E.94.g.18.i; E.94.g.18.v; E.94.g.25.i; E.94.g.25.v; E.94.1.4.i; E.94.1.4.v;
E.94.1.6.i;
E.94.1.6.v; E.94.l.ll.i; E.94.1.11.v; E.94.1.14.i; E.94.1.14.v; E.94.1.15.i;
E.94.1.15.v;
E.94.1.18.i; E.94.1.18.v; E.94.1.25.i; E.94.L25.v; E.94.m.4.i; E.94.m.4.v;
E.94.m.6.i;
E.94.m.6.v; E.94.m.11.i; E.94.m.11.v; E.94.m.14.i; E.94.m.14.v; E.94.m.15.i;
E.94.m.15.v; E.94.m.18.i; E.94.m.18.v; E.94.m.25.i; E.94.m.25.v; E.94.o.4.i;

E.94.o.4.v; E.94.o.6.i; E.94.o.6.v; E.94.o.11.i; E.94.o.ll.v; E.94.o.14.i;
E.94.o.14.v;
E.94.o.15.i; E.94.o.15.v; E.94.o.18.i; E.94.o.18.v; E.94.o.25.i; E.94.o.25.v;
L93.a.4.i;
L93.a.4.v; L93.a.6.i; L93.a.6.v; L93.a.ll.i; i.93.a.ll.v; L93.a.14.i;
L93.a.14.v;
L93.a.15.i; L93.a.15.v; L93.a.18.i; L93.a.18.v; L93.a.25.i; L93.a.25.v;
L93.e.4.i;
L93.e.4.v; L93.e.6.i; L93.e.6.v; L93.e.ll.i; L93.e.ll.v; L93.e.I4.i;
L93.e.14.v;
L93.e.15.i; L93.e.15.v; L93.e.18.i; L93.e.18.v; L93.e.25.i; L93.e.25.v;
L93.g.4.i;
L93.g.4.v; L93.g.6.i; L93.g.6.v; L93.g.ll.i; L93.g.ll.v; L93.g.14.i;
L93.g.14.v;
L93.g.15.i; L93.g.15.v; L93.g.18.i; L93.g.18.v; L93.g.25.i; L93.g.25.v;
L93.1.4.i;
L93.1.4.v; L93.1.6.i; L93.1.6.v; L93.l.ll.i; i.93.1.11.v; L93.1.14.i;
L93.1.14.v;
L93.1.15.i; L93.1.15.v; L93.1.18.i; L93.1.18.v; L93.1.25.i; L93.1.25.v;
L93.m.4.i;
L93.m.4.v; L93.m.6.i; L93.m.6.v; L93.m.ll.i; L93.m.ll.v; L93.m.14.i;
L93.m.14.v; L93.m.15.i; L93.m.15.v; L93.m.18.i; L93.m.18.v; L93.m.25.i;
L93.m.25.v; L93.o.4.i; L93.o.4.v; L93.o.6.i; L93.o.6.v; L93.o.11.i;
L93.o.11.v;
L93.o.14.i; L93.o.14.v; L93.o.15.i; L93.o.15.v; L93.o.18.i; L93.o.18.v;
L93.o.25.i;
L93.o.25.v; L94.a.4.i; L94.a.4.v; L94.a.6.i; L94.a.6.v; L94.a.ll.i;
L94.a.ll.v;
L94.a.14.i; L94.a.14.v; L94.a.15.i; L94.a.15.v; i.94.a.18.i; L94.a.18.v;
L94.a.25.i;
L94.a.25.v; L94.e.4.i; L94.e.4.v; L94.e.6.i; L94.e.6.v; L94.e.ll.i;
L94.e.11.v;
L94.e.14.i; L94.e.14.v; L94.e.15.i; L94.e.15.v; L94.e.18.i; L94.e.18.v;
L94.e.25.i;
L94.e.25.v; L94.g.4.i; L94.g.4.v; L94.g.6.i; L94.g.6.v; L94.g.Il.i;
L94.g.ll.v;
L94.g.14.i; L94.g.14.v; L94.g.15.i; L94.g.15.v; L94.g.18.i; L94.g.18.v;
L94.g.25.i;
L94.g.25.v; L94.1.4.i; L94.1.4.v; L94.1.6.i; L94.1.6.v; L94.1.11.i;
L94.l.ll.v; L94.1.14.i;
L94.1.14.v; L94.1.15.i; L94.1.15.v; L94.1.18.i; L94.1.18.v; L94.1.25.i;
L94.1.25.v;
L94.m.4.i; L94.m.4.v; L94.m.6.i; L94.m.6.v; L94.m.11.i; L94.m.ll.v;
L94.m.14.i;
L94.m.14.v; L94.m.15.i; L94.m.15.v; L94.m.18.i; L94.m.18.v; L94.m.25.i;
L94.m.25.v; L94.o.4.i; L94.o.4.v; L94.o.6.i; L94.o.6.v; L94.o.ll.i;
L94.o.11.v;
L94.o.14.i; L94.o.14.v; L94.o.15.i; L94.o.15.v; L94.o.18.i; L94.o.18.v;
L94.o.25.i;
L94.o.25.v; L.93.a.4.i; L.93.a.4.v; L.93.a.6.i; L.93.a.6.v; L.93.a.ll.i;
L.93.a.ll.v;
L.93.a.14.i; L.93.a.14.v; L.93.a.15.i; L.93.a.15.v; L.93.a.18.i; L.93.a.18.v;
L.93.a.25.i;
L.93.a.25.v; L.93.e.4.i; L.93.e.4.v; L.93.e.6.i; L.93.e.6.v; L.93.e.11.i;
L.93.e.ll.v;
L.93.e.14.i; L.93.e.14.v; L.93.e.15.i; L.93.e.15.v; L.93.e.18.i; L.93.e.18.v;
L.93.e.25.i;
L.93.e.25.v; L.93.g.4.i; L.93.g.4.v; L.93.g.6.i; L.93.g.6.v; L.93.g.ll.i;
L.93.g.ll.v;
L.93.g.14.i; L.93.g.14.v; L.93.g.15.i; L.93.g.15.v; L.93.g.18.i; L.93.g.18.v;
L.93.g.25.i;
L.93.g.25.v; L.93.1.4.i; L.93.1.4.v; L.93.1.6.i; L.93.1.6.v; L.93.l.ll.i;
L.93.l.ll.v;
L.93.1.14.i; L.93.1.14.v; L.93.1.15.i; L.93.1.15.v; L.93.1.18.i; L.93.1.18.v;
L.93.1.25.i;
L.93.1.25.v; L.93.m.4.i; L.93.m.4.v; L.93.m.6.i; L.93.m.6.v; L.93.m.11.i;
L.93.m.11.v; L.93.m.14.i; L.93.m.14.v; L.93.m.15.i; L.93.m.15.v; L.93.m.18.i;
L.93.m.18.v; L.93.m.25.i; L.93.m.25.v; L.93.o.4.i; L.93.o.4.v; L.93.o.6.i;
L.93.o.6.v;
L.93.o.ll.i; L.93.o.ll.v; L.93.o.14.i; L.93.o.14.v; L.93.o.15.i; L.93.o.15.v;
L.93.o.18.i; L.93.o.18.v; L.93.o.25.i; L.93.o.25.v; L.94.a.4.i; L.94.a.4.v;
L.94.a.6.i;
L.94.a.6.v; L.94.a.11.i; L.94.a.11.v; L.94.a.14.i; L.94.a.14.v; L.94.a.15.i;
L.94.a.15.v;
L.94.a.18.i; L.94.a.18.v; L.94.a.25.i; L.94.a.25.v; L.94.e.4.i; L.94.e.4.v;
L.94.e.6.i;
L.94.e.6.v; L.94.e.ll.i; L.94.e.11.v; L.94.e.14.i; L.94.e.14.v; L.94.e.15.i;
L.94.e.15.v;
L.94.e.18.i; L.94.e.18.v; L.94.e.25.i; L.94.e.25.v; L.94.g.4.i; L.94.g.4.v;
L.94.g.6.i;
L.94.g.6.v; L.94.g.ll.i; L.94.g.ll.v; L.94.g.14.i; L.94.g.14.v; L.94.g.15.i;
L.94.g.15.v;
L.94.g.18.i; L.94.g.18.v; L.94.g.25.i; L.94.g.25.v; L.94.1.4.i; L.94.1.4.v;
L.94.1.6.i;
L.94.1.6.v; L.94.l.ll.i; L.94.l.ll.v; L.94.1.14.i; L.94.1.14.v; L.94.1.15.i;
L.94.1.15.v;
L.94.1.18.i; L.94.1.18.v; L.94.1.25.i; L.94.1.25.v; L.94.m.4.i; L.94.m.4.v;
L.94.m.6.i;

L.94.m.6.v; L.94.m.11.i; L.94.m.11.v; L.94.m.14.i; L.94.m.14.v; L.94.m.15.i;
L.94.m.15.v; L.94.m.18.i; L.94.m.18.v; L.94.m.25.i; L.94.m.25.v; L.94.o.4.i;
L.94.o.4.v; L.94.o.6.i; L.94.o.6.v; L.94.o.11.i; L.94.o.ll.v; L.94.o.14.i;
L.94.o.14.v;
L.94.o.15.i; L.94.o.15.v; L.94.o.18.i; L.94.o.18.v; L.94.o.25.i; L.94.o.25.v;
0.93.a.4.i;
0.93.a.4.v; 0.93.a.6.i; 0.93.a.6.v; 0.93.a.11.i; 0.93.a.11.v; 0.93.a.14.i;
0.93.a.14.v;
0.93.a.15.i; 0.93.a.15.v; 0.93.a.18.i; 0.93.a.18.v; 0.93.a.25.i; 0.93.a.25.v;
0.93.e.4.i; 0.93.e.4.v; 0.93.e.6.i; 0.93.e.6.v; 0.93.e.11.i; 0.93.e.ll.v;
0.93.e.14.i;
0.93.e.14.v; 0.93.e.15.i; 0.93.e.15.v; 0.93.e.18.i; 0.93.e.I8.v; 0.93.e.25.i;
0.93.e.25.v; 0.93.g.4.i; 0.93.g.4.v; 0.93.g.6.i; 0.93.g.6.v; 0.93.g.11.i;
0.93.g.ll.v;
0.93.g.14.i; 0.93.g.14.v; 0.93.g.15.i; 0.93.g.15.v; 0.93.g.18.i; 0.93.g.18.v;
0.93.g.25.i; 0.93.g.25.v; 0.93.1.4.1; 0.93.1.4.v; 0.93.1.6.1; 0.93.1.6.v;
0.93.1.11.1;
0.93.1.11.v; 0.93.1.14.1; 0.93.1.14.v; 0.93.1.15.1; 0.93.1.15.v; 0.93.1.18.1;
0.93.1.18.v; 0.93.1.25.1; 0.93.1.25.v; 0.93.m.4.i; 0.93.m.4.v; 0.93.m.6.i;
0.93.m.6.v; 0.93.m.ll.i; 0.93.m.ll.v; 0.93.m.14.i; 0.93.m.14.v; 0.93.m.15.i;
0.93.m.15.v; 0.93.m.18.i; 0.93.m.18.v; 0.93.m.25.i; 0.93.m.25.v; 0.93.o.4.i;
0.93.o.4.v; 0.93.o.6.i; 0.93.o.6.v; 0.93.o.11.i; 0.93.o.ll.v; 0.93.o.14.i;
0.93.o.14.v; 0.93.o.15.i; 0.93.o.15.v; 0.93.o.18.i; 0.93.o.18.v; 0.93.o.25.i;
0.93.o.2S.v; 0.94.a.4.i; 0.94.a.4.v; 0.94.a.6.i; 0.94.a.6.v; 0.94.a.ll.i;
0.94.a.11.v;
0.94.a.14.i; 0.94.a.14.v; 0.94.a.15.i; 0.94.a.15.v; 0.94.a.18.i; 0.94.a.18.v;
0.94.a.25.i; 0.94.a.25.v; 0.94.e.4.i; 0.94.e.4.v; 0.94.e.6.i; 0.94.e.6.v;
0.94.e.11.i;
0.94.e.ll.v; 0.94.e.14.i; 0.94.e.14.v; 0.94.e.15.i; 0.94.e.15.v; 0.94.e.18.i;
0.94.e.18.v; 0.94.e.25.i; 0.94.e.25.v; 0.94.g.4.i; 0.94.g.4.v; 0.94.g.6.i;
0.94.g.6.v;
0.94.g.ll.i; 0.94.g.ll.v; 0.94.g.14.i; 0.94.g.14.v; 0.94.g.15.i; 0.94.g.15.v;
0.94.g.18.i; 0.94.g.18.v; 0.94.g.25.i; 0.94.g.25.v; 0.94.1.4.1; 0.94.1.4.v;
0.94.1.6.1;
0.94.1.6.v; 0.94.1.11.1; 0.94.1.11.v; 0.94.1.14.1; 0.94.1.14.v; 0.94.1.15.1;
0.94.1.15.v;
0.94.1.18.1; 0.94.1.18.v; 0.94.1.25.1; 0.94.1.25.v; 0.94.m.4.i; 0.94.m.4.v;
0.94.m.6.i; 0.94.m.6.v; 0.94.m.ll.i; 0.94.m.ll.v; 0.94.m.14.i; 0.94.m.14.v;
0.94.m.15.i; 0.94.m.15.v; 0.94.m.18.i; 0.94.m.18.v; 0.94.m.25.i; 0.94.m.25.v;
0.94.o.4.i; 0.94.o.4.v; 0.94.o.6.i; 0.94.o.6.v; 0.94.o.ll.i; 0.94.o.ll.v;
0.94.o.14.i;
0.94.o.14.v; 0.94.o.15.i; 0.94.o.15.v; 0.94.o.18.i; 0.94.o.18.v; 0.94.o.25.i;
0.94.o.25.v; P.93.a.4.i; P.93.a.4.v; P.93.a.6.i; P.93.a.6.v; P.93.a.ll.i;
P.93.a.ll.v;
P.93.a.14.i; P.93.a.14.v; P.93.a.15.i; P.93.a.15.v; P.93.a.18.i; P.93.a.18.v;
P.93.a.25.i;
P.93.a.25.v; P.93.e.4.i; P.93.e.4.v; P.93.e.6.i; P.93.e.6.v; P.93.e.ll.i;
P.93.e.11.v;
P.93.e.14.i; P.93.e.14.v; P.93.e.15.i; P.93.e.15.v; P.93.e.18.i; P.93.e.18.v;
P.93.e.25.i;
P.93.e.25.v; P.93.g.4.i; P.93.g.4.v; P.93.g.6.i; P.93.g.6.v; P.93.g.11.i;
P.93.g.ll.v;
P.93.g.14.i; P.93.g.14.v; P.93.g.15.i; P.93.g.15.v; P.93.g.18.i; P.93.g.18.v;
P.93.g.25.i;
P.93.g.25.v; P.93.1.4.i; P.93.1.4.v; P.93.1.6.i; P.93.1.6.v; P.93.l.ll.i;
P.93.l.ll.v;
P.93.1.14.i; P.93.1.14.v; P.93.1.15.i; P.93.1.15.v; P.93.1.18.i; P.93.1.18.v;
P.93.1.25.i;
P.93.1.25.v; P.93.m.4.i; P.93.m.4.v; P.93.m.6.i; P.93.m.6.v; P.93.m.ll.i;
P.93.m.ll.v; P.93.m.14.i; P.93.m.14.v; P.93.m.15.i; P.93.m.15.v; P.93.m.18.i;
P.93.m.18.v; P.93.m.25.i; P.93.m.25.v; P.93.o.4.i; P.93.o.4.v; P.93.o.6.i;
P.93.o.6.v;
P.93.o.ll.i; P.93.o.11.v; P.93.o.14.i; P.93.o.14.v; P.93.o.15.i; P.93.o.15.v;
P.93.o.18.i; P.93.o.18.v; P.93.o.25.i; P.93.o.25.v; P.94.a.4.i; P.94.a.4.v;
P.94.a.6.i;
P.94.a.6.v; P.94.a.ll.i; P.94.a.11.v; P.94.a.14.i; P.94.a.14.v; P.94.a.15.i;
P.94.a.15.v;
P.94.a.18.i; P.94.a.18.v; P.94.a.25.i; P.94.a.25.v; P.94.e.4.i; P.94.e.4.v;
P.94.e.6.i;
P.94.e.6.v; P.94.e.11.i; P.94.e.ll.v; P.94.e.14.i; P.94.e.14.v; P.94.e.15.i;
P.94.e.15.v;
P.94.e.18.i; P.94.e.18.v; P.94.e.25.i; P.94.e.25.v; P.94.g.4.i; P.94.g.4.v;
P.94.g.6.i;

P.94.g.6.v; P.94.g.ll.i; P.94.g.ll.v; P.94.g.14.i; P.94.g.14.v; P.94.g.15.i;
P.94.g.15.v;
P.94.g.18.i; P.94.g.18.v; P.94.g.25.i; P.94.g.25.v; P.94.1.4.i; P.94.1.4.v;
P.94.1.6.i;
P.94.1.6.v; P.94.l.ll.i; P.94.l.ll.v; P.94.1.14.i; P.94.1.14.v; P.94.1.15.i;
P.94.1.15.v;
P.94.1.18.i; P.94.1.18.v; P.94.1.25.i; P.94.1.25.v; P.94.m.4.i; P.94.m.4.v;
P.94.m.6.i;
P.94.m.6.v; P.94.m.ll.i; P.94.m.11.v; P.94.m.14.i; P.94.m.14.v; P.94.m.15.i;
P.94.m.15.v; P.94.m.18.i; P.94.m.18.v; P.94.m.25.i; P.94.m.25.v; P.94.o.4.i;
P.94.o.4.v; P.94.o.6.i; P.94.o.6.v; P.94.o.ll.i; P.94.o.ll.v; P.94.o.14.i;
P.94.o.14.v;
P.94.o.15.i; P.94.o.15.v; P.94.o.18.i; P.94.o.18.v; P.94.o.25.i; P.94.o.25.v;
A.2.a.4.o;
A.2.a.4.bh; A.2.a.4.bi; A.2.a.4.bj; A.2.a.4.bk; A.2.a.11.o; A.2.a.ll.bh;
A.2.a.11.bi;
A.2.a.11.bj; A.2.a.11.bk; A.2.a.15.i; A.2.a.15.o; A.2.a.15.bh; A.2.a.15.bi;
A.2.a.15.bj; A.2.a.15.bk; A.2.a.37.i; A.2.a.37.o; A.2.a.37.bh; A.2.a.37.bi;
A.2.a.37.bj; A.2.a.37.bk; A.2.a.38.i; A.2.a.38.o; A.2.a.38.bh; A.2.a.38.bi;
A.2.a.38.bj; A.2.a.38.bk; A.2.a.39.i; A.2.a.39.o; A.2.a.39.bh; A.2.a.39.bi;
A.2.a.39.bj; A.2.a.39.bk; A.2.a.40.i; A.2.a.40.o; A.2.a.40.bh; A.2.a.40.bi;
A.2.a.40.bj; A.2.a.40.bk; A.2.a.41.i; A.2.a.41.o; A.2.a.41.bh; A.2.a.41.bi;
A.2.a.41.bj; A.2.a.41.bk; A.2.a.42.i; A.2.a.42.o; A.2.a.42.bh; A.2.a.42.bi;
A.2.a.42.bj; A.2.a.42.bk; A.2.a.43.i; A.2.a.43.o; A.2.a.43.bh; A.2.a.43.bi;
A.2.a.43.bj; A.2.a.43.bk;
A.3.a.4.o; A.3.a.4.bh; A.3.a.4.bi; A.3.a.4.bj; A.3.a.4.bk; A.3.a.ll.o;
A.3.a.11.bh;
A.3.a.ll.bi; A.3.a.11.bj; A.3.a.11.bk; A.3.a.15.i; A.3.a.15.o; A.3.a.15.bh;
A.3.a.15.bi; A.3.a.15.bj; A.3.a.15.bk; A.3.a.37.i; A.3.a.37.o; A.3.a.37.bh;
A.3.a.37.bi; A.3.a.37.bj; A.3.a.37.bk; A.3.a.38.i; A.3.a.38.o; A.3.a.38.bh;
A.3.a.38.bi; A.3.a.38.bj; A.3.a.38.bk; A.3.a.39.i; A.3.a.39.o; A.3.a.39.bh;
A.3.a.39.bi; A.3.a.39.bj; A.3.a.39.bk; A.3.a.40.i; A.3.a.40.o; A.3.a.40.bh;
A.3.a.40.bi; A.3.a.40.bj; A.3.a.40.bk; A.3.a.41.i; A.3.a.41.o; A.3.a.41.bh;
A.3.a.41.bi; A.3.a.41.bj; A.3.a.41.bk; A.3.a.42.i; A.3.a.42.o; A.3.a.42.bh;
A.3.a.42.bi; A.3.a.42.bj; A.3.a.42.bk; A.3.a.43.i; A.3.a.43.o; A.3.a.43.bh;
A.3.a.43.bi; A.3.a.43.bj; A.3.a.43.bk; A.4.a.4.o; A.4.a.4.bh; A.4.a.4.bi;
A.4.a.4.bj;
A.4.a.4.bk; A.4.a.ll.o; A.4.a.ll.bh; A.4.a.ll.bi; A.4.a.ll.bj; A.4.a.ll.bk;
A.4.a.15.i; A.4.a.15.o; A.4.a.15.bh; A.4.a.15.bi; A.4.a.15.bj; A.4.a.15.bk;
A.4.a.37.i;
A.4.a.37.o; A.4.a.37.bh; A.4.a.37.bi; A.4.a.37.bj; A.4.a.37.bk; A.4.a.38.i;
A.4.a.38.o; A.4.a.38.bh; A.4.a.38.bi; A.4.a.38.bj; A.4.a.38.bk; A.4.a.39.i;
A.4.a.39.o; A.4.a.39.bh; A.4.a.39.bi; A.4.a.39.bj; A.4.a.39.bk; A.4.a.40.i;
A.4.a.40.o; A.4.a.40.bh; A.4.a.40.bi; A.4.a.40.bj; A.4.a.40.bk; A.4.a.41.i;
A.4.a.41.o; A.4.a.41.bh; A.4.a.41.bi; A.4.a.41.bj; A.4.a.41.bk; A.4.a.42.i;
A.4.a.42.o; A.4.a.42.bh; A.4.a.42.bi; A.4.a.42.bj; A.4.a.42.bk; A.4.a.43.i;
A.4.a.43.o; A.4.a.43.bh; A.4.a.43.bi; A.4.a.43.bj; A.4.a.43.bk; A.7.a.4.o;
A.7.a.4.bh;
A.7.a.4.bi; A.7.a.4.bj; A.7.a.4.bk; A.7.a.ll.o; A.7.a.11.bh; A.7.a.11.bi;
A.7.a.ll.bj;
A.7.a.ll.bk; A.7.a.15.i; A.7.a.15.o; A.7.a.15.bh; A.7.a.15.bi; A.7.a.15.bj;
A.7.a.15.bk; A.7.a.37.i; A.7.a.37.o; A.7.a.37.bh; A.7.a.37.bi; A.7.a.37.bj;
A.7.a.37.bk; A.7.a.38.i; A.7.a.38.o; A.7.a.38.bh; A.7.a.38.bi; A.7.a.38.bj;
A.7.a.38.bk; A.7.a.39.i; A.7.a.39.o; A.7.a.39.bh; A.7.a.39.bi; A.7.a.39.bj;
A.7.a.39.bk; A.7.a.40.i; A.7.a.40.o; A.7.a.40.bh; A.7.a.40.bi; A.7.a.40.bj;
A.7.a.40.bk; A.7.a.41.i; A.7.a.41.o; A.7.a.4Lbh; A.7.a.41.bi; A.7.a.41.bj;
A.7.a.41.bk; A.7.a.42.i; A.7.a.42.o; A.7.a.42.bh; A.7.a.42.bi; A.7.a.42.bj;
A.7.a.42.bk; A.7.a.43.i; A.7.a.43.o; A.7.a.43.bh; A.7.a.43.bi; A.7.a.43.bj;
A.7.a.43.bk; A.l7.a.4.i; A.l7.a.4.o; A.l7.a.4.bh; A.l7.a.4.bi; A.l7.a.4.bj;

A.l7.a.4.bk; A.l7.a.11.i; A.l7.a.ll.o; A.l7.a.ll.bh; A.l7.a.11.bi;
A.l7.a.ll.bj;
A.l7.a.ll.bk; A.l7.a.15.i; A.l7.a.15.o; A.l7.a.15.bh; A.l7.a.15.bi;
A.l7.a.15.bj;
A.l7.a.15.bk; A.l7.a.37.i; A.l7.a.37.o; A.l7.a.37.bh; A.l7.a.37.bi;
A.l7.a.37.bj;
A.l7.a.37.bk; A.l7.a.38.i; A.l7.a.38.o; A.l7.a.38.bh; A.l7.a.38.bi;
A.l7.a.38.bj;
A.l7.a.38.bk; A.l7.a.39.i; A.l7.a.39.o; A.l7.a.39.bh; A.l7.a.39.bi;
A.l7.a.39.bj;
A.l7.a.39.bk; A.l7.a.40.i; A.l7.a.40.o; A.l7.a.40.bh; A.l7.a.40.bi;
A.l7.a.40.bj;
A.l7.a.40.bk; A.l7.a.41.i; A.l7.a.41.o; A.l7.a.41.bh; A.I7.a.41.bi;
A.l7.a.41.bj;
A.l7.a.41.bk; A.l7.a.42.i; A.l7.a.42.o; A.l7.a.42.bh; A.l7.a.42.bi;
A.l7.a.42.bj;
A.l7.a.42.bk; A.l7.a.43.i; A.l7.a.43.o; A.l7.a.43.bh; A.l7.a.43.bi;
A.l7.a.43.bj;
A.l7.a.43.bk; A.l8.a.4.i; A.l8.a.4.o; A.l8.a.4.bh; A.l8.a.4.bi; A.l8.a.4.bj;
A.l8.a.4.bk; A.l8.a.ll.i; A.l8.a.11.o; A.l8.a.11.bh; A.l8.a.ll.bi;
A.l8.a.11.bj;
A.IB.a.ll.bk; A.l8.a.15.i; A.l8.a.15.o; A.l8.a.15.bh; A.l8.a.15.bi;
A.l8.a.15.bj;
A.l8.a.15.bk; A.l8.a.37.i; A.l8.a.37.o; A.l8.a.37.bh; A.l8.a.37.bi;
A.l8.a.37.bj;
A.l8.a.37.bk; A.l8.a.38.i; A.l8.a.38.o; A.l8.a.38.bh; A.l8.a.38.bi;
A.l8.a.38.bj;
A.l8.a.38.bk; A.l8.a.39.i; A.l8.a.39.o; A.l8.a.39.bh; A.l8.a.39.bi;
A.l8.a.39.bj;
A.l8.a.39.bk; A.l8.a.40.i; A.l8.a.40.o; A.l8.a.40.bh; A.l8.a.40.bi;
A.l8.a.40.bj;
A.l8.a.40.bk; A.l8.a.41.i; A.l8.a.41.o; A.l8.a.41.bh; A.l8.a.41.bi;
A.l8.a.41.bj;
A.l8.a.41.bk; A.l8.a.42.i; A.l8.a.42.o; A.l8.a.42.bh; A.l8.a.42.bi;
A.l8.a.42.bj;
A.l8.a.42.bk; A.l8.a.43.i; A.l8.a.43.o; A.l8.a.43.bh; A.l8.a.43.bi;
A.l8.a.43.bj;
A.l8.a.43.bk; A.l9.a.4.i; A.l9.a.4.o; A.l9.a.4.bh; A.l9.a.4.bi; A.l9.a.4.bj;
A.l9.a.4.bk; A.l9.a.ll.i; A.l9.a.11.o; A.l9.a.11.bh; A.l9.a.11.bi;
A.l9.a.11.bj;
A.l9.a.ll.bk; A.l9.a.15.i; A.l9.a.15.o; A.19.~.15.bh; A.l9.a.15.bi;
A.l9.a.15.bj;
A.l9.a.15.bk; A.l9.a.37.i; A.l9.a.37.o; A.l9.a.37.bh; A.l9.a.37.bi;
A.l9.a.37.bj;
A.l9.a.37.bk; A.l9.a.38.i; A.l9.a.38.o; A.l9.a.38.bh; A.l9.a.38.bi;
A.l9.a.38.bj;
A.l9.a.38.bk; A.l9.a.39.i; A.l9.a.39.o; A.l9.a.39.bh; A.l9.a.39.bi;
A.l9.a.39.bj;
A.l9.a.39.bk; A.l9.a.40.i; A.l9.a.40.o; A.l9.a.40.bh; A.l9.a.40.bi;
A.l9.a.40.bj;
A.l9.a.40.bk; A.l9.a.41.i; A.l9.a.41.o; A.l9.a.41.bh; A.l9.a.41.bi;
A.l9.a.41.bj;
A.l9.a.41.bk; A.l9.a.42.i; A.l9.a.42.o; A.l9.a.42.bh; A.l9.a.42.bi;
A.l9.a.42.bj;
A.l9.a.42.bk; A.l9.a.43.i; A.l9.a.43.o; A.l9.a.43.bh; A.l9.a.43.bi;
A.l9.a.43.bj;
A.l9.a.43.bk; A.97.a.4.i; A.97.a.4.o; A.97.a.4.bh; A.97.a.4.bi; A.97.a.4.bj;
A.97.a.4.bk; A.97.a.ll.i; A.97.a.11.o; A.97.a.11.bh; A.97.a.ll.bi;
A.97.a.ll.bj;
A.97.a.ll.bk; A.97.a.15.i; A.97.a.15.o; A.97.a.15.bh; A.97.a.15.bi;
A.97.a.15.bj;
A.97.a.15.bk; A.97.a.37.i; A.97.a.37.o; A.97.a.37.bh; A.97.a.37.bi;
A.97.a.37.bj;
A.97.a.37.bk; A.97.a.38.i; A.97.a.38.o; A.97.a.38.bh; A.97.a.38.bi;
A.97.a.38.bj;
A.97.a.38.bk; A.97.a.39.i; A.97.a.39.o; A.97.a.39.bh; A.97.a.39.bi;
A.97.a.39.bj;
A.97.a.39.bk; A.97.a.40.i; A.97.a.40.o; A.97.a.40.bh; A.97.a.40.bi;
A.97.a.40.bj;
A.97.a.40.bk; A.97.a.41.i; A.97.a.41.o; A.97.a.41.bh; A.97.a.41.bi;
A.97.a.41.bj;
A.97.a.41.bk; A.97.a.42.i; A.97.a.42.o; A.97.a.42.bh; A.97.a.42.bi;
A.97.a.42.bj;
A.97.a.42.bk; A.97.a.43.i; A.97.a.43.o; A.97.a.43.bh; A.97.a.43.bi;
A.97.a.43.bj;
A.97.a.43.bk; A.98.a.4.i; A.98.a.4.o; A.98.a.4.bh; A.98.a.4.bi; A.98.a.4.bj;
A.98.a.4.bk; A.98.a.11.i; A.98.a.ll.o; A.98.a.11.bh; A.98.a.ll.bi;
A.98.a.11.bj;
A.98.a.ll.bk; A.98.a.15.i; A.98.a.15.o; A.98.a.15.bh; A.98.a.15.bi;
A.98.a.15.bj;
A.98.a.15.bk; A.98.a.37.i; A.98.a.37.o; A.98.a.37.bh; A.98.a.37.bi;
A.98.a.37.bj;
A.98.a.37.bk; A.98.a.38.i; A.98.a.38.o; A.98.a.38.bh; A.98.a.38.bi;
A.98.a.38.bj;
A.98.a.38.bk; A.98.a.39.i; A.98.a.39.o; A.98.a.39.bh; A.98.a.39.bi;
A.98.a.39.bj;
A.98.a.39.bk; A.98.a.40.i; A.98.a.40.o; A.98.a.40.bh; A.98.a.40.bi;
A.98.a.40.bj;
A.98.a.40.bk; A.98.a.41.i; A.98.a.41.o; A.98.a.41.bh; A.98.a.41.bi;
A.98.a.41.bj;

A.98.a.41.bk; A.98.a.42.i; A.98.a.42.o; A.98.a.42.bh; A.98.a.42.bi;
A.98.a.42.bj;
A.98.a.42.bk; A.98.a.43.i; A.98.a.43.o; A.98.a.43.bh; A.98.a.43.bi;
A.98.a.43.bj;
A.98.a.43.bk; A.2.a.4.i; A.3.a.4.i; A.4.a.4.i; A.5.a.4.i; A.6.a.4.i;
A.7.a.4.i; A.9.a.4.i;
A.l0.a.4.i; A.l5.a.4.i; A.100.a.4.i; A.101.a.4.i; A.102.a.4.i; A.103.a.4.i;
A.104.a.4.i;
A.105.a.4.i; A.106.a.4.i; A.107.a.4.i; A.108.a.4.i; A.109.a.4.i; A.110.a.4.i;
A.111.a.4.i; A.112.a.4.i; A.113.a.4.i; A.114.a.4.i; A.115.a.4.i; A.116.a.4.i;
A.117.a.4.i; A.118.a.4.i; A.119.a.4.i; A.120.a.4.i; A.121.a.4.i; A.122.a.4.i;
A.123.a.4.i; A.124.a.4.i; A.125.a.4.i; A.126.a.4.i; A.127.a.4.i; A.128.a.4.i;
A.129.a.4.i; A.130.a.4.i; A.131.a.4.i; A.132.a.4.i; A.133.a.4.i; A.134.a.4.i;
A.135.a.4.i; A.136.a.4.i; A.137.a.4.i; A.138.a.4.i; A.139.a.4.i; A.140.a.4.i;
A.141.a.4.i; A.142.a.4.i; A.143.a.4.i; A.144.a.4.i; A.145.a.4.i; A.146.a.4.i;
A.I47.a.4.i; A.148.a.4.i; A.149.a.4.i; A.150.a.4.i; A.151.a.4.i; A.152.a.4.i;
A.153.a.4.i; A.154.a.4.i; A.155.a.4.i; A.156.a.4.i; A.157.a.4.i; A.158.a.4.i;
A.159.a.4.i; A.160.a.4.i; A.lbl.a.4.i; A.162.a.4.i; A.163.a.4.i; A.164.a.4.i;
A.165.a.4.i; A.166.a.4.i; A.167.a.4.i; A.168.a.4.i; A.169.a.4.i; A.170.a.4.i;
A.171.a.4.i; A.172.a.4.i; A.173.a.4.i; A.174.a.4.i; A.175.a.4.i; A.176.a.4.i;
A.177.a.4.i; A.178.a.4.i; A.179.a.4.i; A.180.a.4.i; A.181.a.4.i; A.182.a.4.i;
A.183.a.4.i; A.184.a.4.i; A.185.a.4.i; A.186.a.4.i; A.187.a.4.i; A.188.a.4.i;
A.189.a.4.i; A.190.a.4.i; A.191.a.4.i; A.192.a.4.i; A.193.a.4.i; A.194.a.4.i;
A.195.a.4.i; A.196.a.4.i; A.197.a.4.i; A.198.a.4.i; A.199.a.4.i; A.200.a.4.i;
A.201.a.4.i; A.202.a.4.i; A.203.a.4.i; A.204.a.4.i; A.205.a.4.i; A.206.a.4.i;
A.207.a.4.i; A.208.a.4.i; A.209.a.4.i; A.210.a.4.i; A.211.a.4.i; A.212.a.4.i;
A.213.a.4.i; A.214.a.4.i; A.215.a.4.i; A.216.a.4.i; A.217.a.4.i; A.218.a.4.i;
A.219.a.4.i; A.220.a.4.i; A.221.a.4.i; A.222.a.4.i; A.223.a.4.i; A.224.a.4.i;
A.225.a.4.i; A.226.a.4.i; A.227.a.4.i; A.228.a.4.i; A.229.a.4.i; A.230.a.4.i;
A.231.a.4.i; A.232.a.4.i; A.233.a.4.i; A.234.a.4.i; A.235.a.4.i; A.236.a.4.i;
A.237.a.4.i; A.238.a.4.i; A.239.a.4.i; A.240.a.4.i; A.241.a.4.i; A.242.a.4.i;
A.243.a.4.i; A.244.a.4.i; A.245.a.4.i; A.246.a.4.i; A.247.a.4.i; A.248.a.4.i;
A.249.a.4.i; A.250.a.4.i; A.251.a.4.i; A.252.a.4.i; A.253.a.4.i; A.254.a.4.i;
A.255.a.4.i; A.256.a.4.i; A.257.a.4.i; A.258.a.4.i; A.259.a.4.i; A.260.a.4.i;
A.261.a.4.i; A.262.a.4.i; A.263.a.4.i; A.264.a.4.i; A.265.a.4.i; A.266.a.4.i;
A.267.a.4.i; A.268.a.4.i; A.269.a.4.i; A.270.a.4.i; A.271.a.4.i; A.272.a.4.i;
A.273.a.4.i; A.274.a.4.i; A.275.a.4.i; A.276.a.4.i; A.277.a.4.i; A.278.a.4.i;
A.279.a.4.i; A.280.a.4.i; A.281.a.4.i; A.282.a.4.i; A.283.a.4.i; A.284.a.4.i;
A.285.a.4.i; A.286.a.4.i; A.287.a.4.i; A.288.a.4.i; A.289.a.4.i; A.290.a.4.i;
A.291.a.4.i; A.292.a.4.i; A.293.a.4.i; A.294.a.4.i; A.295.a.4.i; A.296.a.4.i;
A.297.a.4.i; A.298.a.4.i; A.299.a.4.i; A.300.a.4.i; A.301.a.4.i; A.302.a.4.i;
A.303.a.4.i; A.304.a.4.i; A.305.a.4.i; A.306.a.4.i; A.307.a.4.i; A.308.a.4.i;
A.309.a.4.i; A.310.a.4.i; A.311.a.4.i; A.312.a.4.i; A.313.a.4.i; A.314.a.4.i;
A.315.a.4.i; A.316.a.4.i; A.317.a.4.i; A.318.a.4.i; A.319.a.4.i; A.320.a.4.i;
A.321.a.4.i; A.323.a.4.i; A.324.a.4.i; A.325.a.4.i; A.326.a.4.i; A.327.a.4.i;
A.328.a.4.i; A.329.a.4.i; A.330.a.4.i; A.331.a.4.i; A.332.a.4.i; A.333.a.4.i;
A.334.a.4.i; A.335.a.4.i; A.336.a.4.i; A.337.a.4.i; A.338.a.4.i; A.339.a.4.i;
A.340.a.4.i; A.341.a.4.i; A.342.a.4.i; A.343.a.4.i; A.344.a.4.i; A.345.a.4.i;
A.346.a.4.i; A.347.a.4.i; A.348.a.4.i; A.349.a.4.i; A.350.a.4.i; A.351.a.4.i;
A.352.a.4.i; A.353.a.4.i; A.354.a.4.i; A.355.a.4.i; A.356.a.4.i; A.357.a.4.i;
A.358.a.4.i; A.359.a.4.i; A.360.a.4.i; A.361.a.4.i; A.362.a.4.i; A.363.a.4.i;

A.364.a.4.i; A.365.a.4.i; A.366.a.4.i; A.367.a.4.i; A.368.a.4.i; A.369.a.4.i;
A.370.a.4.i; A.371.a.4.i; A.372.a.4.i; A.373.a.4.i; A.374.a.4.i; A.375.a.4.i;
A.376.a.4.i; A.377.a.4.i; A.378.a.4.i; A.379.a.4.i; A.380.a.4.i; A.381.a.4.i;
A.382.a.4.i; A.383.a.4.i; A.384.a.4.i; A.385.a.4.i; A.386.a.4.i; A.387.a.4.i;
A.388.a.4.i; A.389.a.4.i; A.390.a.4.i; A.391.a.4.i; A.392.a.4.i; A.393.a.4.i;
A.394.a.4.i; A.395.a.4.i; A.396.a.4.i; A.397.a.4.i; A.398.a.4.i; A.399.a.4.i;
A.400.a.4.i; A.401.a.4.i; A.402.a.4.i; A.403.a.4.i; A.404.a.4.i; A.405.a.4.i;
A.406.a.4.i; A.407.a.4.i; A.408.a.4.i; A.409.a.4.i; A.410.a.4.i; A.411.a.4.i;
A.412.a.4.i; A.413.a.4.i; A.414.a.4.i; A.415.a.4.i; A.416.a.4.i; A.417.a.4.i;
A.418.a.4.i; A.419.a.4.i; A.420.a.4.i; A.421.a.4.i; A.422.a.4.i; A.423.a.4.i;
A.424.a.4.i; A.425.a.4.i; A.426.a.4.i; A.427.a.4.i; A.428.a.4.i; A.429.a.4.i;
A.430.a.4.i; A.431.a.4.i; A.432.a.4.i; A.433.a.4.i; A.434.a.4.i; A.435.a.4.i;
A.436.a.4.i; A.437.a.4.i; A.438.a.4.i; A.439.a.4.i; A.440.a.4.i; A.441.a.4.i;
A.442.a.4.i; A.443.a.4.i; A.444.a.4.i; A.445.a.4.i; A.446.a.4.i; A.447.a.4.i;
A.448.a.4.i; A.449.a.4.i; A.450.a.4.i; A.451.a.4.i; A.452.a.4.i; A.453.a.4.i;
A.454.a.4.i; A.455.a.4.i; A.456.a.4.i; A.457.a.4.i; A.458.a.4.i; A.459.a.4.i;
A.460.a.4.i; A.461.a.4.i; A.462.a.4.i; A.463.a.4.i; A.464.a.4.i; A.465.a.4.i;
A.466.a.4.i; A.467.a.4.i; A.468.a.4.i; A.469.a.4.i; A.470.a.4.i; A.471.a.4.i;
A.472.a.4.i; A.473.a.4.i; A.474.a.4.i; A.475.a.4.i; A.476.a.4.i; A.477.a.4.i;
A.478.a.4.i; A.479.a.4.i; A.480.a.4.i; A.481.a.4.i; A.482.a.4.i; A.483.a.4.i;
A.4$4.a.4.i; A.485.a.4.i; A.486.a.4.i; A.487.a.4.i; A.488.a.4.i; A.489.a.4.i;
A.490.a.4.i; A.491.a.4.i; A.492.a.4.i; A.493.a.4.i; A.494.a.4.i; A.495.a.4.i;
A.496.a.4.i; A.497.a.4.i; A.498.a.4.i; A.499.a.4.i; A.500.a.4.i; A.501.a.4.i;
A.502.a.4.i; A.503.a.4.i; A.504.a.4.i; A.505.a.4.i; A.506.a.4.i; A.507.a.4.i;
A.508.a.4.i; A.509.a.4.i; A.510.a.4.i; A.511.a.4.i; A.512.a.4.i; A.512.a.4.i;
A.513.a.4.i; A.514.a.4.i; A.515.a.4.i; A.516.a.4.i; A.517.a.4.i; A.518.a.4.i;
A.519.a.4.i; A.520.a.4.i; A.521.a.4.i; A.522.a.4.i; A.523.a.4.i; A.524.a.4.i;
A.525.a.4.i; A.526.a.4.i; A.527.a.4.i; A.528.a.4.i; A.529.a.4.i; A.530.a.4.i;
A.531.a.4.i; A.532.a.4.i; A.533.a.4.i; A.534.a.4.i; A.535.a.4.i; A.536.a.4.i;
A.537.a.4.i; A.538.a.4.i; A.539.a.4.i; A.540.a.4.i; A.541.a.4.i; A.542.a.4.i;
A.543.a.4.i; A.544.a.4.i; A.545.a.4.i; A.546.a.4.i; A.547.a.4.i; A.548.a.4.i;
A.549.a.4.i; A.550.a.4.i; A.551.a.4.i; A.552.a.4.i; A.553.a.4.i; A.554.a.4.i;
A.555.a.4.i; A.556.a.4.i; A.557.a.4.i; A.558.a.4.i; A.559.a.4.i; A.560.a.4.i;
A.561.a.4.i; A.562.a.4.i; A.563.a.4.i; A.564.a.4.i; A.565.a.4.i; A.566.a.4.i;
A.567.a.4.i; A.568.a.4.i; A.569.a.4.i; A.570.a.4.i; A.571.a.4.i; A.572.a.4.i;
A.573.a.4.i; A.574.a.4.i; A.575.a.4.i; A.576.a.4.i; A.577.a.4.i; A.578.a.4.i;
A.579.a.4.i; A.580.a.4.i; A.581.a.4.i; A.582.a.4.i; A.583.a.4.i; A.584.a.4.i;
A.585.a.4.i; A.586.a.4.i; A.587.a.4.i; A.588.a.4.i; A.589.a.4.i; A.590.a.4.i;
A.591.a.4.i; A.592.a.4.i; A.593.a.4.i; A.594.a.4.i; A.595.a.4.i; A.596.a.4.i;
A.597.a.4.i; A.598.a.4.i; A.599.a.4.i; A.600.a.4.i; A.601.a.4.i; A.602.a.4.i;
A.603.a.4.i; A.604.a.4.i; A.605.a.4.i; A.606.a.4.i; A.607.a.4.i; A.608.a.4.i;
A.609.a.4.i; A.610.a.4.i; A.611.a.4.i; A.612.a.4.i; A.613.a.4.i; A.614.a.4.i;
A.615.a.4.i; A.616.a.4.i; A.617.a.4.i; A.618.a.4.i; A.619.a.4.i; A.620.a.4.i;
A.621.a.4.i; A.622.a.4.i; A.623.a.4.i; A.624.a.4.i; A.625.a.4.i; A.626.a.4.i;
A.627.a.4.i; A.628.a.4.i; A.629.a.4.i; A.630.a.4.i; A.631.a.4.i; A.632.a.4.i;
A.633.a.4.i; A.634.a.4.i; A.635.a.4.i; A.636.a.4.i; A.637.a.4.i; A.638.a.4.i;
A.639.a.4.i; A.640.a.4.i; A.641.a.4.i; A.642.a.4.i; A.643.a.4.i; A.644.a.4.i;

A.645.a.4.i; A.646.a.4.i; A.647.a.4.i; A.648.a.4.i; A.649.a.4.i; A.650.a.4.i;
A.651.a.4.i; A.652.a.4.i; A.653.a.4.i; A.654.a.4.i; A.655.a.4.i; A.656.a.4.i;
A.657.a.4.i; A.658.a.4.i; A.659.a.4.i; A.660.a.4.i; A.2.a.ll.i; A.3.a.11.i;
A.4.a.11.i;
A.S.a.ll.i; A.b.a.ll.i; A.7.a.ll.i; A.9.a.ll.i; A.l0.a.11.i; A.lS.a.ll.i;
A.100.a.11.i;
A.lOl.a.ll.i; A.102.a.11.i; A.103.a.ll.i; A.104.a.11.i; A.105.a.11.i;
A.106.a.ll.i;
A.107.a.ll.i; A.108.a.11.i; A.109.a.11.i; A.110.a.ll.i; A.111.a.ll.i;
A.lI2.a.ll.i;
A.113.a.ll.i; A.114.a.ll.i; A.115.a.11.i; A.116.a.ll.i; A.117.a.ll.i;
A.118.a.11.i;
A.119.a.ll.i; A.120.a.ll.i; A.121.a.ll.i; A.122.a.ll.i; A.123.a.ll.i;
A.124.a.11.i;
A.125.a.ll.i; A.126.a.ll.i; A.127.a.ll.i; A.128.a.ll.i; A.129.a.11.i;
A.130.a.11.i;
A.131.a.ll.i; A.132.a.ll.i; A.133.a.ll.i; A.134.a.ll.i; A.135.a.ll.i;
A.136.a.ll.i;
A.137.a.11.i; A.138.a.11.i; A.139.a.ll.i; A.140.a.11.i; A.141.a.ll.i;
A.142.a.ll.i;
A.143.a.ll.i; A.144.a.11.i; A.145.a.ll.i; A.146.a.ll.i; A.147.a.ll.i;
A.148.a.ll.i;
A.149.a.11.i; A.150.a.ll.i; A.151.a.ll.i; A.152.a.12.i; A.153.a.ll.i;
A.154.a.11.i;
A.155.a.11.i; A.156.a.ll.i; A.157.a.ll.i; A.158.a.ll.i; A.159.a.ll.i;
A.160.a.11.i;
A.161.a.11.i; A.162.a.ll.i; A.163.a.11.i; A.164.a.11.i; A.165.a.11.i;
A.166.a.11.i;
A.167.a.ll.i; A.168.a.ll.i; A.169.a.ll.i; A.170.a.ll.i; A.171.a.11.i;
A.172.a.ll.i;
A.173.a.ll.i; A.174.a.ll.i; A.175.a.ll.i; A.176.a.ll.i; A.177.a.Il.i;
A.17$.a.ll.i;
A.179.a.ll.i; A.180.a.ll.i; A.181.a.ll.i; A.182.a.ll.i; A.183.a.11.i;
A.184.a.ll.i;
A.185.a.11.i; A.186.a.11.i; A.187.a.11.i; A.188.a.ll.i; A.189.a.ll.i;
A.190.a.ll.i;
A.191.a.ll.i; A.192.a.11.i; A.193.a.11.i; A.194.a.ll.i; A.195.a.ll.i;
A.196.a.11.i;
A.197.a.ll.i; A.198.a.11.i; A.I99.a.ll.i; A.200.a.11.i; A.201.a.ll.i;
A.202.a.11.i;
A.203.a.ll.i; A.204.a.11.i; A.205.a.ll.i; A.206.a.ll.i; A.207.a.ll.i;
A.208.a.ll.i;
A.209.a.11.i; A.210.a.ll.i; A.211.a.ll.i; A.212.a.li.i; A.213.a.11.i;
A.214.a.ll.i;
A.215.a.11.i; A.216.a.ll.i; A.217.a.ll.i; A.218.a.ll.i; A.219.a.ll.i;
A.220.a.11.i;
A.ZZl.a.ll.i; A.222.a.11.i; A.223.a.ll.i; A.224.a.ll.i; A.225.a.ll.i;
A.226.a.ll.i;
A.227.a.ll.i; A.228.a.ll.i; A.229.a.ll.i; A.230.a.ll.i; A.231.a.ll.i;
A.232.a.ll.i;
A.233.a.11.i; A.234.a.ll.i; A.235.a.ll.i; A.236.a.ll.i; A.237.a.ll.i;
A.238.a.ll.i;
A.239.a.ll.i; A.240.a.11.i; A.241.a.11.i; A.242.a.ll.i; A.243.a.ll.i;
A.244.a.11.i;
A.245.a.11.i; A.246.a.ll.i; A.247.a.11.i; A.248.a.11.i; A.249.a.ll.i;
A.250.a.ll.i;
A.251.a.ll.i; A.252.a.11.i; A.253.a.ll.i; A.254.a.ll.i; A.255.a.ll.i;
A.256.a.ll.i;
A.257.a.ll.i; A.258.a.ll.i; A.259.a.ll.i; A.260.a.11.i; A.261.a.ll.i;
A.262.a.ll.i;
A.263.a.ll.i; A.264.a.ll.i; A.265.a.ll.i; A.266.a.11.i; A.267.a.11.i;
A.268.a.11.i;
A.269.a.ll.i; A.270.a.lLi; A.271.a.11.i; A.272.a.ll.i; A.273.a.ll.i;
A.274.a.ll.i;
A.275.a.ll.i; A.276.a.1Li; A.277.a.ll.i; A.278.a.ll.i; A.279.a.ll.i;
A.280.a.ll.i;
A.281.a.ll.i; A.282.a.11.i; A.283.a.ll.i; A.284.a.11.i; A.285.a.ll.i;
A.286.a.ll.i;
A.287.a.11.i; A.288.a.ll.i; A.289.a.11.i; A.290.a.ll.i; A.291.a.ll.i;
A.292.a.ll.i;
A.293.a.11.i; A.294.a.11.i; A.295.a.ll.i; A.296.a.12.i; A.297.a.ll.i;
A.298.a.ll.i;
A.299.a.ll.i; A.300.a.11.i; A.301.a.ll.i; A.302.a.ll.i; A.303.a.ll.i;
A.304.a.11.i;
A.305.a.ll.i; A.306.a.11.i; A.307.a.ll.i; A.308.a.ll.i; A.309.a.ll.i;
A.310.a.ll.i;
A.311.a.11.i; A.312.a.11.i; A.313.a.ll.i; A.314.a.ll.i; A.315.a.ll.i;
A.316.a.11.i;
A.317.a.ll.i; A.318.a.11.i; A.319.a.11.i; A.320.a.ll.i; A.321.a.ll.i;
A.323.a.11.i;
A.324.a.11.i; A.325.a.11.i; A.326.a.ll.i; A.327.a.ll.i; A.328.a.11.i;
A.329.a.ll.i;
A.330.a.11.i; A.331.a.11.i; A.332.a.11.i; A.333.a.11.i; A.334.a.ll.i;
A.335.a.ll.i;
A.336.a.ll.i; A.337.a.ll.i; A.338.a.ll.i; A.339.a.11.i; A.340.a.ll.i;
A.341.a.ll.i;
A.342.a.11.i; A.343.a.11.i; A.344.a.ll.i; A.345.a.ll.i; A.34b.a.1l.i;
A.347.a.11.i;
A.348.a.ll.i; A.349.a.ll.i; A.350.a.11.i; A.351.a.11.i; A.352.a.11.i;
A.353.a.ll.i;
A.354.a.ll.i; A.355.a.11.i; A.356.a.11.i; A.357.a.11.i; A.358.a.11.i;
A.359.a.11.i;

A.360.a.ll.i; A.361.a.11.i; A.362.a.ll.i; A.363.a.11.i; A.364.a.11.i;
A.365.a.ll.i;
A.366.a.11.i; A.367.a.ll.i; A.368.a.ll.i; A.369.a.ll.i; A.370.a.ll.i;
A.371.a.ll.i;
A.372.a.ll.i; A.373.a.11.i; A.374.a.ll.i; A.375.a.ll.i; A.376.a.ll.i;
A.377.a.ll.i;
A.378.a.ll.i; A.379.a.ll.i; A.380.a.ll.i; A.381.a.11.i; A.382.a.ll.i;
A.383.a.11.i;
A.384.a.ll.i; A.3$5.a.ll.i; A.386.a.ll.i; A.387.a.ll.i; A.388.a.11.i;
A.389.a.ll.i;
A.390.a.ll.i; A.391.a.ll.i; A.392.a.ll.i; A.393.a.ll.i; A.394.a.11.i;
A.395.a.ll.i;
A.396.a.ll.i; A.397.a.11.i; A.398.a.ll.i; A.399.a.ll.i; A.400.a.ll.i;
A.401.a.il.i;
A.402.a.11.i; A.403.a.11.i; A.404.a.ll.i; A.405.a.ll.i; A.406.a.ll.i;
A.407.a.ll.i;
A.408.a.11.i; A.409.a.ll.i; A.410.a.ll.i; A.411.a.11.i; A.412.a.11.i;
A.413.a.11.i;
A.414.a.ll.i; A.415.a.ll.i; A.416.a.ll.i; A.417.a.ll.i; A.418.a.ll.i;
A.419.a.ll.i;
A.420.a.1i.i; A.421.a.11.i; A.422.a.ll.i; A.423.a.ll.i; A.424.a.ll.i;
A.425.a.ll.i;
A.426.a.ll.i; A.427.a.ll.i; A.428.a.ll.i; A.429.a.ll.i; A.430.a.ll.i;
A.431.a.11.i;
A.432.a.11.i; A.433.a.ll.i; A.434.a.ll.i; A.435.a.ll.i; A.436.a.11.i;
A.437.a.11.i;
A.438.a.ll.i; A.439.a.ll.i; A.440.a.ll.i; A.441.a.ll.i; A.442.a.ll.i;
A.443.a.ll.i;
A.444.a.ll.i; A.445.a.11.i; A.446.a.ll:i; A.447.a.ll.i; A.448.a.ll.i;
A.449.a.ll.i;
A.450.a.ll.i; A.451.a.ll.i; A.452.a.11.i; A.453.a.ll.i; A.454.a.ll.i;
A.455.a.ll.i;
A.456.a.11.i; A.457.a.ll.i; A.458.a.ll.i; A.459.a.ll.i; A.460.a.li.i;
A.461.a.11.i;
A.462.a.il.i; A.463.a.11.i; A.464.a.ll.i; A.465.a.11.i; A.466.a.ll.i;
A.467.a.11.i;
A.468.a.11.i; A.469.a.ll.i; A.470.a.11.i; A.471.a.11.i; A.472.a.11.i;
A.473.a.ll.i;
A.474.a.ll.i; A.475.a.ll.i; A.476.a.ll.i; A.477.a.ll.i; A.478.a.ll.i;
A.479.a.ll.i;
A.480.a.ll.i; A.481.a.11.i; A.482.a.ll.i; A.483.a.ll.i; A.484.a.ll.i;
A.485.a.11.i;
A.486.a.11.i; A.487.a.11.i; A.488.a.ll.i; A.489.a.11.i; A.490.a.ll.i;
A.491.a.ll.i;
A.492.a.11.i; A.493.a.11.i; A.494.a.ll.i; A.495.a.ll.i; A.496.a.ll.i;
A.497.a.ll.i;
A.498.a.ll.i; A.499.a.ll.i; A.500.a.11.i; A.501.a.11.i; A.502.a.ll.i;
A.503.a.ll.i;
A.504.a.ll.i; A.505.a.11.i; A.506.a.ll.i; A.507.a.ll.i; A.508.a.ll.i;
A.509.a.ll.i;
A.510.a.ll.i; A.511.a.11.i; A.512.a.ll.i; A.512.a.ll.i; A.513.a.11.i;
A.514.a.11.i;
A.515.a.ll.i; A.516.a.ll.i; A.517.a.ll.i; A.518.a.11.i; A.519.a.ll.i;
A.520.a.ll.i;
A.521.a.ll.i; A.522.a.ll.i; A.523.a.ll.i; A.524.a.Il.i; A.525.a.ll.i;
A.526.a.ll.i;
A.527.a.11.i; A.528.a.11.i; A.529.a.11.i; A.530.a.11.i; A.531.a.ll.i;
A.532.a.11.i;
A.533.a.ll.i; A.534.a.ll.i; A.535.a.ll.i; A.536.a.11.i; A.537.a.11.i;
A.538.a.ll.i;
A.539.a.11.i; A.540.a.ll.i; A.541.a.ll.i; A.542.a.11.i; A.543.a.11.i;
A.544.a.ll.i;
A.545.a.ll.i; A.546.a.ll.i; A.547.a.ll.i; A.548.a.11.i; A.549.a.11.i;
A.550.a.11.i;
A.551.a.ll.i; A.552.a.ll.i; A.553.a.ll.i; A.554.a.11.i; A.555.a.11.i;
A.556.a.ll.i;
A.557.a.ll.i; A.558.a.ll.i; A.559.a.11.i; A.560.a.ll.i; A.561.a.ll.i;
A.562.a.ll.i;
A.563.a.11.i; A.564.a.ll.i; A.565.a.ll.i; A.566.a.11.i; A.567.a.11.i;
A.568.a.ll.i;
A.569.a.11.i; A.570.a.ll.i; A.571.a.ll.i; A.572.a.ll.i; A.573.a.11.i;
A.574.a.ll.i;
A.575.a.ll.i; A.576.a.11.i; A.577.a.11.i; A.578.a.ll.i; A.579.a.11.i;
A.580.a.11.i;
A.581.a.ll.i; A.582.a.ll.i; A.583.a.ll.i; A.584.a.11.i; A.585.a.ll.i;
A.586.a.ll.i;
A.587.a.ll.i; A.588.a.11.i; A.589.a.11.i; A.590.a.ll.i; A.591.a.11.i;
A.592.a.11.i;
A.593.a.11.i; A.594.a.11.i; A.595.a.11.i; A.596.a.ll.i; A.597.a.ll.i;
A.598.a.ll.i;
A.599.a.ll.i; A.600.a.ll.i; A.601.a.ll.i; A.602.a.ll.i; A.603.a.ll.i;
A.604.a.ll.i;
A.605.a.ll.i; A.606.a.11.i; A.607.a.ll.i; A.608.a.11.i; A.609.a.ll.i;
A.610.a.11.i;
A.611.a.ll.i; A.612.a.ll.i; A.613.a.ll.i; A.614.a.ll.i; A.615.a.ll.i;
A.616.a.ll.i;
A.617.a.ll.i; A.618.a.11.i; A.619.a.ll.i; A.620.a.11.i; A.621.a.ll.i;
A.622.a.ll.i;
A.623.a.ll.i; A.624.a.11.i; A.625.a.ll.i; A.626.a.ll.i; A.627.a.ll.i;
A.628.a.11.i;
A.629.a.ll.i; A.630.a.11.i; A.631.a.ll.i; A.632.a.11.i; A.633.a.11.i;
A.634.a.ll.i;
A.635.a.ll.i; A.636.a.11.i; A.d37.a.ll.i; A.638.a.11.i; A.639.a.11.i;
A.640.a.11.i;

A.641.a.ll.i; A.642.a.ll.i; A.643.a.11.i; A.644.a.ll.i; A.645.a.ll.i;
A.646.a.ll.i;
A.647.a.ll.i; A.648.a.ll.i; A.649.a.ll.i; A.650.a.ll.i; A.651.a.11.i;
A.652.a.ll.i;
A.653.a.ll.i; A.654.a.ll.i; A.655.a.11.i; A.656.a.ll.i; A.657.a.11.i;
A.658.a.ll.i;
A.659.a.ll.i; A.660.a.ll.i; A.2.b.4.i; A.3.b.4.i; A.4.b.4.i; A.5.b.4.i;
A.6.b.4.i;
A.7.b.4.i; A.9.b.4.i; A.l0.b.4.i; A.l5.b.4.i; A.100.b.4.i; A.lOl.b.4.i;
A.102.b.4.i;
A.103.b.4.i; A.104.b.4.i; A.105.b.4.i; A.106.b.4.i; A.107.b.4.i; A.lO8.b.4.i;
A.109.b.4.i; A.110.b.4.i; A.lll.b.4.i; A.112.b.4.i; A.lI3.b.4.i; A.114.b.4.i;
A.115.b.4.i; A.116.b.4.i; A.117.b.4.i; A.118.b.4.i; A.119.b.4.i; A.120.b.4.i;
A.121.b.4.i; A.122.b.4.i; A.123.b.4.i; A.124.b.4.i; A.125.b.4.i; A.126.b.4.i;
A.127.b.4.i; A.128.b.4.i; A.129.b.4.i; A.130.b.4.i; A.131.b.4.i; A.132.b.4.i;
A.133.b.4.i; A.134.b.4.i; A.135.b.4.i; A.136.b.4.i; A.137.b.4.i; A.138.b.4.i;
A.139.b.4.i; A.140.b.4.i; A.141.b.4.i; A.142.b.4.i; A.143.b.4.i; A.144.b.4.i;
A.145.b.4.i; A.146.b.4.i; A.147.b.4.i; A.148.b.4.i; A.149.b.4.i; A.150.b.4.i;
A.151.b.4.i; A.152.b.4.i; A.153.b.4.i; A.154.b.4.i; A.155.b.4.i; A.156.b.4.i;
A.157.b.4.i; A.158.b.4.i; A.159.b.4.i; A.160.b.4.i; A.161.b.4.i; A.162.b.4.i;
A.163.b.4.i; A.164.b.4.i; A.165.b.4.i; A.166.b.4.i; A.167.b.4.i; A.168.b.4.i;
A.169.b.4.i; A.170.b.4.i; A.171.b.4.i; A.172.b.4.i; A.173.b.4.i; A.174.b.4.i;
A.175.b.4.i; A.176.b.4.i; A.177.b.4.i; A.178.b.4.i; A.179.b.4.i; A.180.b.4.i;
A.181.b.4.i; A.182.b.4.i; A.183.b.4.i; A.184.b.4.i; A.185.b.4.i; A.186.b.4.i;
A.187.b.4.i; A.188.b.4.i; A.189.b.4.i; A.190.b.4.i; A.191.b.4.i; A.192.b.4.i;
A.193.b.4.i; A.194.b.4.i; A.195.b.4.i; A.196.b.4.i; A.197.b.4.i; A.198.b.4.i;
A.199.b.4.i; A.200.b.4.i; A.201.b.4.i; A.202.b.4.i; A.203.b.4.i; A.204.b.4.i;
A.205.b.4.i; A.206.b.4.i; A.207.b.4.i; A.208.b.4.i; A.209.b.4.i; A.210.b.4.i;
A.211.b.4.i; A.212.b.4.i; A.213.b.4:i; A.214.b.4.i; A.215.b.4.i; A.216.b.4.i;
A.217.b.4.i; A.218.b.4.i; A.219.b.4.i; A.220.b.4.i; A.221.b.4.i; A.222.b.4.i;
A.223.b.4.i; A.224.b.4.i; A.225.b.4.i; A.226.b.4.i; A.227.b.4.i; A.228.b.4.i;
A.229.b.4.i; A.230.b.4.i; A.231.b.4.i; A.232.b.4.i; A.233.b.4.i; A.234.b.4.i;
A.235.b.4.i; A.236.b.4.i; A.237.b.4.i; A.238.b.4.i; A.239.b.4.i; A.240.b.4.i;
A.241.b.4.i; A.242.b.4.i; A.243.b.4.i; A.244.b.4.i; A.245.b.4.i; A.246.b.4.i;
A.247.b.4.i; A.248.b.4.i; A.249.b.4.i; A.250.b.4.i; A.251.b.4.i; A.252.b.4.i;
A.253.b.4.i; A.254.b.4.i; A.255.b.4.i; A.256.b.4.i; A.257.b.4.i; A.258.b.4.i;
A.259.b.4.i; A.260.b.4.i; A.261.b.4.i; A.262.b.4.i; A.263.b.4.i; A.264.b.4.i;
A.265.b.4.i; A.266.b.4.i; A.267.b.4.i; A.268.b.4.i; A.269.b.4.i; A.270.b.4.i;
A.271.b.4.i; A.272.b.4.i; A.273.b.4.i; A.274.b.4.i; A.275.b.4.i; A.276.b.4.i;
A.277.b.4.i; A.278.b.4.i; A.279.b.4.i; A.280.b.4.i; A.281.b.4.i; A.282.b.4.i;
A.283.b.4.i; A.284.b.4.i; A.285.b.4.i; A.286.b.4.i; A.287.b.4.i; A.288.b.4.i;
A.289.b.4.i; A.290.b.4.i; A.291.b.4.i; A.292.b.4.i; A.293.b.4.i; A.294.b.4.i;
A.295.b.4.i; A.296.b.4.i; A.297.b.4.i; A.298.b.4.i; A.299.b.4.i; A.300.b.4.i;
A.301.b.4.i; A.302.b.4.i; A.303.b.4.i; A.304.b.4.i; A.305.b.4.i; A.306.b.4.i;
A.307.b.4:i; A.308.b.4.i; A.309.b.4.i; A.310.b.4.i; A.311.b.4.i; A.312.b.4.i;
A.313.b.4.i; A.314.b.4.i; A.315.b.4.i; A.316.b.4.i; A.317.b.4.i; A.318.b.4.i;
A.319.b.4.i; A.320.b.4.i; A.321.b.4.i; A.323.b.4.i; A.324.b.4.i; A.325.b.4.i;
A.326.b.4.i; A.327.b.4.i; A.328.b.4.i; A.329.b.4.i; A.330.b.4.i; A.331.b.4.i;
A.332.b.4.i; A.333.b.4.i; A.334.b.4.i; A.335.b.4.i; A.336.b.4.i; A.337.b.4.i;
A.338.b.4.i; A.339.b.4.i; A.340.b.4.i; A.341.b.4.i; A.342.b.4.i; A.343.b.4.i;
A.344.b.4.i; A.345.b.4.i; A.346.b.4.i; A.347.b.4.i; A.348.b.4.i; A.349.b.4.i;
A.350.b.4.i; A.351.b.4.i; A.352.b.4.i; A.353.b.4.i; A.354.b.4.i; A.355.b.4.i;

A.356.b.4.i; A.357.b.4.i; A.358.b.4.i; A.359.b.4.i; A.360.b.4.i; A.361.b.4.i;
A.362.b.4.i; A.363.b.4.i; A.364.b.4.i; A.365.b.4.i; A.366.b.4.i; A.367.b.4.i;
A.368.b.4.i; A.369.b.4.i; A.370.b.4.i; A.371.b.4.i; A.372.b.4.i; A.373.b.4.i;
A.374.b.4.i; A.375.b.4.i; A.376.b.4.i; A.377.b.4.i; A.378.b.4.i; A.379.b.4.i;
A.380.b.4.i; A.381.b.4.i; A.382.b.4.i; A.383.b.4.i; A.384.b.4.i; A.385.b.4.i;
A.386.b.4.i; A.387.b.4.i; A.388.b.4.i; A.389.b.4.i; A.390.b.4.i; A.391.b.4.i;
A.392.b.4.i; A.393.b.4.i; A.394.b.4.i; A.395.b.4.i; A.396.b.4.i; A.397.b.4.i;
A.398.b.4.i; A.399.b.4.i; A.400.b.4.i; A.401.b.4.i; A.402.b.4.i; A.403.b.4.i;
A.404.b.4.i; A.405.b.4.i; A.406.b.4.i; A.407.b.4.i; A.408.b.4.i; A.409.b.4.i;
A.410.b.4.i; A.411.b.4.i; A.412.b.4.i; A.413.b.4.i; A.414.b.4.i; A.415.b.4.i;
A.416.b.4.i; A.417.b.4.i; A.418.b.4.i; A.419.b.4.i; A.420.b.4.i; A.421.b.4.i;
A.422.b.4.i; A.423.b.4.i; A.424.b.4.i; A.425.b.4.i; A.426.b.4.i; A.427.b.4.i;
A.428.b.4.i; A.429.b.4.i; A.430.b.4.i; A.431.b.4.i; A.432.b.4.i; A.433.b.4.i;
A.434.b.4.i; A.435.b.4.i; A.436.b.4.i; A.437.b.4.i; A.438.b.4.i; A.439.b.4.i;
A.440.b.4.i; A.441.b.4.i; A.442.b.4.i; A.443.b.4.i; A.444.b.4.i; A.445.b.4.i;
A.446.b.4.i; A.447.b.4.i; A.448.b.4.i; A.449.b.4.i; A.450.b.4.i; A.451.b.4.i;
A.452.b.4.i; A.453.b.4.i; A.454.b.4.i; A.455.b.4.i; A.456.b.4.i; A.457.b.4.i;
A.458.b.4.i; A.459.b.4.i; A.460.b.4.i; A.461.b.4.i; A.462.b.4.i; A.463.b.4.i;
A.464.b.4.i; A.465.b.4.i; A.466.b.4.i; A.467.b.4.i; A.468.b.4.i; A.469.b.4.i;
A.470.b.4.i; A.471.b.4.i; A.472.b.4.i; A.473.b.4.i; A.474.b.4.i; A.475.b.4.i;
A.476.b.4.i; A.477.b.4.i; A.478.b.4.i; A.479.b.4.i; A.480.b.4.i; A.481.b.4.i;
A.482.b.4.i; A.483.b.4.i; A.484.b.4.i; A.485.b.4.i; A.486.b.4.i; A.487.b.4.i;
A.488.b.4.i; A.489.b.4.i; A.490.b.4.i; A.491.b.4.i; A.492.b.4.i; A.493.b.4.i;
A.494.b.4.i; A.495.b.4.i; A.496.b.4.i; A.497.b.4.i; A.498.b.4.i; A.499.b.4.i;
A.500.b.4.i; A.501.b.4.i; A.502.b.4.i; A.503.b.4.i; A.504.b.4.i; A.505.b.4.i;
A.506.b.4.i; A.507.b.4.i; A.508.b.4.i; A.509.b.4.i; A.510.b.4.i; A.511.b.4.i;
A.512.b.4.i; A.512.b.4.i; A.513.b.4.i; A.514.b.4.i; A.515.b.4.i; A.516.b.4.i;
A.517.b.4.i; A.518.b.4.i; A.519.b.4.i; A.520.b.4.i; A.521.b.4.i; A.522.b.4.i;
A.523.b.4.i; A.524.b.4.i; A.525.b.4.i; A.526.b.4.i; A.527.b.4.i; A.528.b.4.i;
A.529.b.4.i; A.530.b.4.i; A.531.b.4.i; A.532.b.4.i; A.533.b.4.i; A.534.b.4.i;
A.535.b.4.i; A.536.b.4.i; A.537.b.4.i; A.538.b.4.i; A.539.b.4.i; A.540.b.4.i;
A.541.b.4.i; A.542.b.4.i; A.543.b.4.i; A.544.b.4.i; A.545.b.4.i; A.546.b.4.i;
A.547.b.4.i; A.548.b.4.i; A.549.b.4.i; A.550.b.4.i; A.551.b.4.i; A.552.b.4.i;
A.553.b.4.i; A.554.b.4.i; A.555.b.4.i; A.556.b.4.i; A.557.b.4.i; A.558.b.4.i;
A.559.b.4.i; A.560.b.4.i; A.561.b.4.i; A.562.b.4.i; A.563.b.4.i; A.564.b.4.i;
A.565.b.4.i; A.566.b.4.i; A.567.b.4.i; A.568.b.4.i; A.569.b.4.i; A.570.b.4.i;
A.571.b.4.i; A.572.b.4.i; A.573.b.4.i; A.574.b.4.i; A.575.b.4.i; A.576.b.4.i;
A.577.b.4.i; A.578.b.4.i; A.579.b.4.i; A.580.b.4.i; A.581.b.4.i; A.582.b.4.i;
A.583.b.4.i; A.584.b.4.i; A.585.b.4.i; A.586.b.4.i; A.587.b.4.i; A.588.b.4.i;
A.589.b.4.i; A.590.b.4.i; A.591.b.4.i; A.592.b.4.i; A.593.b.4.i; A.594.b.4.i;
A.595.b.4.i; A.596.b.4.i; A.597.b.4.i; A.598.b.4.i; A.599.b.4.i; A.600.b.4.i;
A.601.b.4.i; A.602.b.4.i; A.603.b.4.i; A.604.b.4.i; A.605.b.4.i; A.606.b.4.i;
A.607.b.4.i; A.608.b.4.i; A.609.b.4.i; A.610.b.4.i; A.611.b.4.i; A.612.b.4.i;
A.613.b.4.i; A.614.b.4.i; A.615.b.4.i; A.616.b.4.i; A.617.b.4.i; A.618.b.4.i;
A.619.b.4.i; A.620.b.4.i; A.621.b.4.i; A.622.b.4.i; A.623.b.4.i; A.624.b.4.i;
A.625.b.4.i; A.626.b.4.i; A.627.b.4.i; A.628.b.4.i; A.629.b.4.i; A.630.b.4.i;
A.631.b.4.i; A.632.b.4.i; A.633.b.4.i; A.634.b.4.i; A.635.b.4.i; A.636.b.4.i;

A.637.b.4.i; A.638.b.4.i; A.639.b.4.i; A.640.b.4.i; A.641.b.4.i; A.642.b.4.i;
A.643.b.4.i; A.644.b.4.i; A.645.b.4.i; A.646.b.4.i; A.647.b.4.i; A.648.b.4.i;
A.649.b.4.i; A.650.b.4.i; A.651.b.4.i; A.652.b.4.i; A.653.b.4.i; A.654.b.4.i;
A.655.b.4.i; A.656.b.4.i; A.657.b.4.i; A.658.b.4.i; A.659.b.4.i; A.660.b.4.i;
A.2.b.11.i;
A.3.b.ll.i; A.4.b.11.i; A.5.b.11.i; A.6.b.ll.i; A.7.b.ll.i; A.9.b.ll.i;
A.lO.b.ll.i;
A.l5.b.11.i; A.100.b.ll.i; A.lOl.b.ll.i; A.102.b.ll.i; A.103.b.ll.i;
A.104.b.ll.i;
A.105.b.ll.i; A.106.b.ll.i; A.107.b.ll.i; A.lO8.b.11.i; A.109.b.ll.i;
A.110.b.ll.i;
A.lll.b.ll.i; A.112.b.ll.i; A.113.b.ll.i; A.114.b.ll.i; A.lIS.b.ll.i;
A.116.b.11.i;
A.117.b.ll.i; A.118.b.ll.i; A.119.b.ll.i; A.120.b.ll.i; A.121.b.ll.i;
A.122.b.ll.i;
A.123.b.11.i; A.124.b.ll.i; A.125.b.ll.i; A.126.b.ll.i; A.127.b.ll.i;
A.128.b.ll.i;
A.129.b.ll.i; A.130.b.ll.i; A.131.b.11.i; A.132.b.ll.i; A.I33.b.ll.i;
A.134.b.11.i;
A.135.b.ll.i; A.136.b.ll.i; A.137.b.11.i; A.138.b.ll.i; A.139.b.ll.i;
A.140.b.11.i;
A.141.b.ll.i; A.142.b.ll.i; A.143.b.ll.i; A.144.b.11.i; A.145.b.11.i;
A.146.b.ll.i;
A.147.b.11.i; A.148.b.ll.i; A.149.b.ll.i; A.150.b.11.i; A.151.b.ll.i;
A.152.b.ll.i;
A.153.b.ll.i; A.154.b.11.i; A.155.b.ll.i; A.156.b.ll.i; A.157.b.ll.i;
A.158.b.ll.i;
A.159.b.11.i; A.160.b.ll.i; A.161.b.11.i; A.162.b.ll.i; A.163.b.ll.i;
A.164.b.ll.i;
A.165.b.11.i; A.166.b.ll.i; A.167.b.11.i; A.168.b.11.i; A.169.b.ll.i;
A.170.b.ll.i;
A.171.b.11.i; A.172.b.11.i; A.173.b.ll.i; A.174.b.ll.i; A.175.b.ll.i;
A.176.b.ll.i;
A.177.b.11.i; A.178.b.11.i; A.179.b.ll.i; A.180.b.ll.i; A.181.b.ll.i;
A.182.b.ll.i;
A.183.b.ll.i; A.184.b.11.i; A.185.b.ll.i; A.186.b.11.i; A.187.b.ll.i;
A.188.b.ll.i;
A.189.b.11.i; A.190.b.ll.i; A.191.b.11.i; A.192.b.11.i; A.193.b.ll.i;
A.194.b.ll.i;
A.195.b.ll.i; A.196.b.ll.i; A.197.b.ll.i; A.198.b.ll.i; A.199.b.ll.i;
A.200.b.ll.i;
A.201.b.ll.i; A.202.b.ll.i; A.203.b.ll.i; A.204.b.ll.i; A.205.b.11.i;
A.206.b.ll.i;
A.207.b.11.i; A.208.b.11.i; A.209.b.11.i; A,210.b.11.i; A.211.b.ll.i;
A.212.b.ll.i;
A.213.b.ll.i; A.214.b.ll.i; A.215.b.11.i; A.216.b.ll.i; A.217.b.ll.i;
A.218.b.ll.i;
A.219.b.ll.i; A.220.b.ll.i; A.221.b.11.i; A.222.b.11.i; A.223.b.11.i;
A.224.b.ll.i;
A.225.b.ll.i; A.226.b.11.i; A.227.b.ll.i; A.228.b.ll.i; A.229.b.ll.i;
A.230.b.ll.i;
A.231.b.11.i; A.232.b.ll.i; A.233.b.ll.i; A.234.b.11.i; A.235.b.ll.i;
A.236.b.ll.i;
A.237.b.ll.i; A.238.b.11.i; A.239.b.ll.i; A.240.b.ll.i; A.241.b.ll.i;
A.242.b.ll.i;
A.243.b.ll.i; A.244.b.11.i; A.245.b.ll.i; A.246.b.ll.i; A.247.b.ll.i;
A.248.b.ll.i;
A.249.b.ll.i; A.250.b.ll.i; A.251.b.ll.i; A.252.b.11.i; A.253.b.ll.i;
A.254.b.ll.i;
A.255.b.11.i; A.256.b.ll.i; A.257.b.11.i; A.258.b.11.i; A.259.b.11.i;
A.260.b.11.i;
A.261.b.11.i; A.262.b.ll.i; A.263.b.ll.i; A.264.b.11.i; A.265.b.ll.i;
A.266.b.11.i;
A.267.b.ll.i; A.268.b.ll.i; A.269.b.ll.i; A.270.b.11.i; A.271.b.11.i;
A.272.b.ll.i;
A.273.b.ll.i; A.274.b.11.i; A.275.b.ll.i; A.276.b.ll.i; A.277.b.ll.i;
A.278.b.ll.i;
A.279.b.11.i; A.280.b.11.i; A.281.b.11.i; A.282.b.11.i; A.283.b.11.i;
A.284.b.ll.i;
A.285.b.11.i; A.286.b.11.i; A.287.b.ll.i; A.288.b.11.i; A.289.b.11.i;
A.290.b.ll.i;
A.291.b.ll.i; A.292.b.ll.i; A.293.b.ll.i; A.294.b.11.i; A.295.b.ll.i;
A.296.b.ll.i;
A.297.b.11.i; A.298.b.11.i; A.299.b.11.i; A.300.b.11.i; A.301.b.ll.i;
A.302.b.11.i;
A.303.b.ll.i; A.304.b.ll.i; A.305.b.ll.i; A.306.b.11.i; A.307.b.ll.i;
A.308.b.11.i;
A.309.b.ll.i; A.310.b.ll.i; A.311.b.11.i; A.312.b.ll.i; A.313.b.ll.i;
A.314.b.11.i;
A.315.b.11.i; A.316.b.11.i; A.317.b.ll.i; A.318.b.11.i; A.319.b.11.i;
A.320.b.ll.i;
A.321.b.11.i; A.323.b.11.i; A.324.b.11.i; A.325.b.ll.i; A.326.b.ll.i;
A.327.b.11.i;
A.328.b.11.i; A.329.b.ll.i; A.330.b.11.i; A.331.b.ll.i; A.332.b.ll.i;
A.333.b.ll.i;
A.334.b.11.i; A.335.b.11.i; A.336.b.ll.i; A.337.b.11.i; A.338.b.ll.i;
A.339.b.ll.i;
A.340.b.ll.i; A.341.b.11.i; A.342.b.11.i; A.343.b.ll.i; A.344.b.ll.i;
A.345.b.ll.i;
A.346.b.ll.i; A.347.b.ll.i; A.348.b.11.i; A.349.b.11.i; A.350.b.11.i;
A.351.b.ll.i;

A.352.b.11.i; A.353.b.11.i; A.354.b.ll.i; A.355.b.ll. i; A.356.b.ll.i;
A.357.b.11.i;
A.358.b.11.i; A.359.b.11.i; A.360.b.ll.i; A.361.b.ll.i; A.362.b.ll.i;
A.363.b.11.i;
A.364.b.ll.i; A.365.b.ll.i; A.366.b.ll.i; A.367.b.ll.i; A.368.b.11.i;
A.369.b.ll.i;
A.370.b.ll.i; A.371.b.ll.i; A.372.b.ll.i; A.373.b.11.i; A.374.b.11.i;
A.375.b.11.i;
A.376.b.ll.i; A.377.b.11.i; A.378.b.ll.i; A.379.b.11.i; A.380.b.ll.i;
A.381.b.11.i;
A.382.b.11.i; A.383.b.11.i; A.384.b.11.i; A.385.b.11.i; A.386.b.ll.i;
A.387.b.11.i;
A.388.b.11.i; A.389.b.ll.i; A.390.b.11.i; A.391.b.ll.i; A.392.b.ll.i;
A.393.b.ll.i;
A.394.b.ll.i; A.395.b.ll.i; A.396.b.ll.i; A.397.b.ll.i; A.398.b.ll.i;
A.399.b.11.i;
A.400.b.ll.i; A.401.b.ll.i; A.402.b.11.i; A.403.b.ll.i; A.404.b.ll.i;
A.405.b.ll.i;
A.406.b.ll.i; A.407.b.ll.i; A.408.b.ll.i; A.409.b.ll.i; A.410.b.ll.i;
A.411.b.ll.i;
A.412.b.ll.i; A.413.b.11.i; A.414.b.11.i; A.415.b.11.i; A.416.b.ll.i;
A.417.b.ll.i;
A.418.b.ll.i; A.419.b.ll.i; A.420.b.ll.i; A.421.b.ll.i; A.422.b.ll.i;
A.423.b.ll.i;
A.424.b.11.i; A.425.b.ll.i; A.426.b.11.i; A.427.b.11.i; A.428.b.ll.i;
A.429.b.ll.i;
A.430.b.ll.i; A.431.b.ll.i; A.432.b.ll.i; A.433.b.11.i; A.434.b.ll.i;
A.435.b.ll.i;
A.436.b.ll.i; A.437.b.11.i; A.438.b.ll.i; A.439.b.ll.i; A.440.b.ll.i;
A.441.b.11.i;
A.442.b.ll.i; A.443.b.ll.i; A.444.b.ll.i; A.445.b.11.i; A.446.b.11.i;
A.447.b.11.i;
A.448.b.11.i; A.449.b.ll.i; A.450.b.11.i; A.451.b.ll.i; A.452.b.ll.i;
A.453.b.11.i;
A.454.b.ll.i; A.455.b.11.i; A.456.b.ll.i; A.457.b.ll.i; A.458.b.11.i;
A.459.b.ll.i;
A.460.b.11.i; A.461.b.11.i; A.462.b.11.i; A.463.b.11.i; A.464.b.ll.i;
A.465.b.ll.i;
A.466.b.11.i; A.467.b.ll.i; A.468.b.ll.i; A.469.b.11.i; A.470.b.11.i;
A.471.b.11.i;
A.472.b.ll.i; A.473.b.ll.i; A.474.b.ll.i; A.475.b.11.i; A.476.b.ll.i;
A.477.b.11.i;
A.478.b.ll.i; A.479.b.11.i; A.480.b.ll.i; A.481.b.ll.i; A.482.b.ll.i;
A.483.b.ll.i;
A.484.b.11.i; A.485.b.lLi; A.486.b.ll.i; A.487.b.ll.i; A.488.b.11.i;
A.489.b.ll.i;
A.490.b.11.i; A.491.b.ll.i; A.492.b.11.i; A.493.b.ll.i; A.494.b.11.i;
A.495.b.11.i;
A.496.b.ll.i; A.497.b.ll.i; A.498.b.11.i; A.499.b.ll.i; A.500.b.ll.i;
A.501.b.ll.i;
A.502.b.11.i; A.503.b.11.i; A.504.b.11.i; A.505.b.11.i; A.506.b.ll.i;
A.507.b.11.i;
A.508.b.ll.i; A.509.b.11.i; A.510.b.ll.i; A.511.b.11.i; A.512.b.11.i;
A.512.b.ll.i;
A.513.b.ll.i; A.514.b.ll.i; A.515.b.ll.i; A.516.b.ll.i; A.517.b.11.i;
A.518.b.ll.i;
A.519.b.ll.i; A.520.b.ll.i; A.521.b.11.i; A.522.b.ll.i; A.523.b.ll.i;
A.524.b.11.i;
A.525.b.ll.i; A.526.b.11.i; A.527.b.ll.i; A.528.b.11.i; A.529.b.11.i;
A.530.b.11.i;
A.531.b.11.i; A.532.b.11.i; A.533.b.ll.i; A.534.b.11.i; A.535.b.11.i;
A.536.b.11.i;
A.537.b.11.i; A.538.b.ll.i; A.539.b.11.i; A.540.b.11.i; A.541.b.11.i;
A.542.b.ll.i;
A.543.b.ll.i; A.544.b.11.i; A.545.b.ll.i; A.546.b.11.i; A.547.b.11.i;
A.548.b.11.i;
A.549.b.11.i; A.550.b.ll.i; A.551.b.11.i; A.552.b.11.i; A.553.b.ll.i;
A.554.b.ll.i;
A.555.b.ll.i; A.556.b.11.i; A.557.b.ll.i; A.558.b.11.i; A.559.b.11.i;
A.560.b.11.i;
A.561.b.11.i; A.562.b.ll.i; A.563.b.ll.i; A.564.b.11.i; A.565.b.ll.i;
A.566.b.ll.i;
A.567.b.ll.i; A.568.b.11.i; A.569.b.ll.i; A.570.b.11.i; A.571.b.11.i;
A.572.b.11.i;
A.573.b.11.i; A.574.b.11.i; A.575.b.11.i; A.576.b.ll.i; A.577.b.11.i;
A.578.b.ll.i;
A.579.b.11.i; A.580.b.11.i; A.581.b.ll.i; A.582.b.11.i; A.583.b.11.i;
A.584.b.ll.i;
A.585.b.ll.i; A.586.b.ll.i; A.587.b.ll.i; A.588.b.11.i; A.589.b.11.i;
A.590.b.ll.i;
A.591.b.ll.i; A.592.b.ll.i; A.593.b.11.i; A.594.b.11.i; A.595.b.ll.i;
A.596.b.ll.i;
A.597.b.11.i; A.598.b.ll.i; A.599.b.ll.i; A.600.b.11.i; A.601.b.11.i;
A.602.b.ll.i;
A.603.b.11.i; A.604.b.11.i; A.605.b.11.i; A.606.b.11.i; A.607.b.ll.i;
A.608.b.ll.i;
A.609.b.ll.i; A.610.b.ll.i; A.611.b.11.i; A.612.b.ll.i; A.613.b.11.i;
A.614.b.11.i;
A.615.b.11.i; A.616.b.11.i; A.617.b.ll.i; A.618.b.ll.i; A.619.b.11.i;
A.620.b.ll.i;
A.621.b.ll.i; A.622.b.ll.i; A.623.b.ll.i; A.624.b.11.i; A.625.b.ll.i;
A.626.b.ll.i;
A.627.b.ll.i; A.628.b.11.i; A.629.b.11.i; A.630.b.11.i; A.631.b.ll.i;
A.632.b.11.i;

A.633.b.ll.i; A.634.b.11.i; A.635.b.11.i; A.63b.b.ll.i; A.637.b.11.i;
A.638.b.ll.i;
A.639.b.ll.i; A.640.b.11.i; A.641.b.11.i; A.642.b.11.i; A.643.b.11.i;
A.644.b.ll.i;
A.645.b.ll.i; A.646.b.ll.i; A.647.b.ll.i; A.648.b.11.i; A.649.b.ll.i;
A.650.b.ll.i;
A.651.b.11.i; A.652.b.ll.i; A.653.b.ll.i; A.654.b.ll.i; A.655.b.11.i;
A.656.b.ll.i;
A.657.b.11.i; A.658.b.11.i; A.659.b.ll.i; A.660.b.ll.i; A.2.x.4.i; A.3.x.4.i;
A.4.x.4.i;
A.5.x.4.i; A.6.x.4.i; A.7.x.4.i; A.9.x.4.i; A.l0.x.4.i; A.l5.x.4.i;
A.100.x.4.i;
A.lOl.x.4.i; A.102.x.4.i; A.103.x.4.i; A.104.x.4.i; A.105.x.4.i; A.106.x.4.i;
A.107.x.4.i; A.108.x.4.i; A.109.x.4.i; A.110.x.4.i; A.111.x.4.i; A.112.x.4.i;
A.113.x.4.i; A.114.x.4.i; A.115.x.4.i; A.116.x.4.i; A.117.x.4.i; A.118.x.4.i;
A.119.x.4.i; A.120.x.4.i; A.121.x.4.i; A.122.x.4.i; A.123.x.4.i; A.124.x.4.i;
A.125.x.4.i; A.126.x.4.i; A.127.x.4.i; A.128.x.4.i; A.129.x.4.i; A.130.x.4.i;
A.131.x.4.i; A.132.x.4.i; A.133.x.4.i; A.134.x.4.i; A.135.x.4.i; A.136.x.4.i;
A.137.x.4.i; A.138.x.4.i; A.139.x.4.i; A.140.x.4.i; A.141.x.4.i; A.142.x.4.i;
A.143.x.4.i; A.144.x.4.i; A.145.x.4.i; A.146.x.4.i; A.147.x.4.i; A.148.x.4.i;
A.149.x.4.i; A.150.x.4.i; A.151.x.4.i; A.152.x.4.i; A.153.x.4.i; A.154.x.4.i;
A.155.x.4.i; A.156.x.4.i; A.157.x.4.i; A.158.x.4.i; A.159.x.4.i; A.160.x.4.i;
A.161.x.4.i; A.162.x.4.i; A.163.x.4.i; A.164.x.4.i; A.165.x.4.i; A.166.x.4.i;
A.167.x.4.i; A.168.x.4.i; A.169.x.4.i; A.170.x.4.i; A.171.x.4.i; A.172.x.4.i;
A.173.x.4.i; A.174.x.4.i; A.175.x.4.i; A.176.x.4.i; A.177.x.4.i; A.178.x.4.i;
A.179.x.4.i; A.180.x.4.i; A.181.x.4.i; A.182.x.4.i; A.183.x.4.i; A.184.x.4.i;
A.185.x.4.i; A.186.x.4.i; A.187.x.4.i; A.188.x.4.i; A.189.x.4.i; A.190.x.4.i;
A.191.x.4.i; A.192.x.4.i; A.193.x.4.i; A.194.x.4.i; A.195.x.4.i; A.196.x.4.i;
A.197.x.4.i; A.198.x.4.i; A.199.x.4.i; A.200.x.4.i; A.201.x.4.i; A.202.x.4.i;
A.203.x.4.i; A.204.x.4.i; A.205.x.4.i; A.206.x.4.i; A.207.x.4.i; A.208.x.4.i;
A.209.x.4.i; A.210.x.4.i; A.211.x.4.i; A.212.x.4.i; A.213.x.4.i; A.214.x.4.i;
A.215.x.4.i; A.216.x.4.i; A.217.x.4.i; A.218.x.4.i; A.219.x.4.i; A.220.x.4.i;
A.221.x.4.i; A.222.x.4.i; A.223.x.4.i; A.224.x.4.i; A.225.x.4.i; A.226.x.4.i;
A.227.x.4.i; A.228.x.4.i; A.229.x.4.i; A.230.x.4.i; A.231.x.4.i; A.232.x.4.i;
A.233.x.4.i; A.234.x.4.i; A.235.x.4.i; A.236.x.4.i; A.237.x.4.i; A.238.x.4.i;
A.239.x.4.i; A.240.x.4.i; A.241.x.4.i; A.242.x.4.i; A.243.x.4.i; A.244.x.4.i;
A.245.x.4.i; A.246.x.4.i; A.247.x.4.i; A.248.x.4.i; A.249.x.4.i; A.250.x.4.i;
A.251.x.4.i; A.252.x.4.i; A.253.x.4.i; A.254.x.4.i; A.255.x.4.i; A.256.x.4.i;
A.257.x.4.i; A.258.x.4.i; A.259.x.4.i; A.260.x.4.i; A.261.x.4.i; A.262.x.4.i;
A.263.x.4.i; A.264.x.4.i; A.265.x.4.i; A.266.x.4.i; A.267.x.4.i; A.268.x.4.i;
A.269.x.4.i; A.270.x.4.i; A.271.x.4.i; A.272.x.4.i; A.273.x.4.i; A.274.x.4.i;
A.275.x.4.i; A.276.x.4.i; A.277.x.4.i; A.278.x.4.i; A.279.x.4.i; A.280.x.4.i;
A.281.x.4.i; A.282.x.4.i; A.283.x.4.i; A.284.x.4.i; A.285.x.4.i; A.286.x.4.i;
A.287.x.4.i; A.288.x.4.i; A.289.x.4.i; A.290.x.4.i; A.291.x.4.i; A.292.x.4.i;
A.293.x.4.i; A.294.x.4.i; A.295.x.4.i; A.296.x.4.i; A.297.x.4.i; A.298.x.4.i;
A.299.x.4:i; A.300.x.4.i; A.301.x.4.i; A.302.x.4.i; A.303.x.4.i; A.304.x.4.i;
A.305.x.4.i; A.306.x.4.i; A.307.x.4.i; A.308.x.4.i; A.309.x.4.i; A.310.x.4.i;
A.311.x.4.i; A.312.x.4.i; A.313.x.4.i; A.314.x.4.i; A.315.x.4.i; A.316.x.4.i;
A.317.x.4.i; A.318.x.4.i; A.319.x.4.i; A.320.x.4.i; A.321.x.4.i; A.323.x.4.i;
A.324.x.4.i; A.325.x.4.i; A.326.x.4.i; A.327.x.4.i; A.328.x.4.i; A.329.x.4.i;
A.330.x.4.i; A.331.x.4.i; A.332.x.4.i; A.333.x.4.i; A.334.x.4.i; A.335.x.4.i;
A.336.x.4.i; A.337.x.4.i; A.338.x.4.i; A.339.x.4.i; A.340.x.4.i; A.341.x.4.i;
A.342.x.4.i; A.343.x.4.i; A.344.x.4.i; A.345.x.4.i; A.346.x.4.i; A.347.x.4.i;

A.348.x.4.i; A.349.x.4.i; A.350.x.4.i; A.351.x.4.i; A.352.x.4.i; A.353.x.4.i;
A.354.x.4.i; A.355.x.4.i; A.356.x.4.i; A.357.x.4.i; A.358.x.4.i; A.359.x.4.i;
A.360.x.4.i; A.361.x.4.i; A.362.x.4.i; A.363.x.4.i; A.364.x.4.i; A.365.x.4.i;
A.366.x.4.i; A.367.x.4.i; A.368.x.4.i; A.369.x.4.i; A.370.x.4.i; A.371.x.4.i;
A.372.x.4.i; A.373.x.4.i; A.374.x.4.i; A.375.x.4.i; A.376.x.4.i; A.377.x.4.i;
A.378.x.4.i; A.379.x.4.i; A.380.x.4.i; A.381.x.4.i; A.382.x.4.i; A.383.x.4.i;
A.384.x.4.i; A.385.x.4.i; A.386.x.4.i; A.387.x.4.i; A.388.x.4.i; A.389.x.4.i;
A.390.x.4.i; A.391.x.4.i; A.392.x.4.i; A.393.x.4.i; A.394.x.4.i; A.395.x.4.i;
A.396.x.4.i; A.397.x.4.i; A.398.x.4.i; A.399.x.4.i; A.400.x.4.i; A.401.x.4.i;
A.402.x.4.i; A.403.x.4.i; A.404.x.4.i; A.405.x.4.i; A.406.x.4.i; A.407.x.4.i;
A.408.x.4.i; A.409.x.4.i; A.410.x.4.i; A.411.x.4.i; A.412.x.4.i; A.413.x.4.i;
A.414.x.4.i; A.415.x.4.i; A.416.x.4.i; A.417.x.4.i; A.418.x.4.i; A.419.x.4.i;
A.420.x.4.i; A.421.x.4.i; A.422.x.4.i; A.423.x.4.i; A.424.x.4.i; A.425.x.4.i;
A.426.x.4.i; A.427.x.4.i; A.428.x.4.i; A.429.x.4.i; A.430.x.4.i; A.431.x.4.i;
A.432.x.4.i; A.433.x.4.i; A.434.x.4.i; A.435.x.4.i; A.436.x.4.i; A.437.x.4.i;
A.438.x.4.i; A.439.x.4.i; A.440.x.4.i; A.441.x.4.i; A.442.x.4.i; A.443.x.4.i;
A.444.x.4.i; A.445.x.4.i; A.446.x.4.i; A.447.x.4.i; A.448.x.4.i; A.449.x.4.i;
A.450.x.4.i; A.45i.x.4.i; A.452.x.4.i; A.453.x.4.i; A.454.x.4.i; A.455.x.4.i;
A.456.x.4.i; A.457.x.4.i; A.458.x.4.i; A.459.x.4.i; A.460.x.4.i; A.461.x.4.i;
A.462.x.4.i; A.463.x.4.i; A.464.x.4.i; A.465.x.4.i; A.466.x.4.i; A.467.x.4.i;
A.468.x.4.i; A.469.x.4.i; A.470.x.4.i; A.471.x.4.i; A.472.x.4.i; A.473.x.4.i;
A.474.x.4.i; A.475.x.4.i; A.476.x.4.i; A.477.x.4.i; A.478.x.4.i; A.479.x.4.i;
A.480.x.4.i; A.481.x.4.i; A.482.x.4.i; A.483.x.4.i; A.484.x.4.i; A.485.x.4.i;
A.486.x.4.i; A.487.x.4.i; A.488.x.4.i; A.489.x.4.i; A.490.x.4.i; A.491.x.4.i;
A.492.x.4.i; A.493.x.4.i; A.494.x.4.i; A.495.x.4.i; A.496.x.4.i; A.497.x.4.i;
A.498.x.4.i; A.499.x.4.i; A.500.x.4.i; A.501.x.4.i; A.502.x.4.i; A.503.x.4.i;
A.504.x.4.i; A.505.x.4.i; A.506.x.4.i; A.507.x.4.i; A.508.x.4.i; A.509.x.4.i;
A.510.x.4.i; A.511.x.4.i; A.512.x.4.i; A.512.x.4.i; A.513.x.4.i; A.514.x.4.i;
A.515.x.4.i; A.516.x.4.i; A.517.x.4.i; A.518.x.4.i; A.519.x.4.i; A.520.x.4.i;
A.521.x.4.i; A.522.x.4.i; A.523.x.4.i; A.524.x.4.i; A.525.x.4.i; A.526.x.4.i;
A.527.x.4.i; A.528.x.4.i; A.529.x.4.i; A.530.x.4.i; A.531.x.4.i; A.532.x.4.i;
A.533.x.4.i; A.534.x.4.i; A.535.x.4.i; A.536.x.4.i; A.537.x.4.i; A.538.x.4.i;
A.539.x.4.i; A.540.x.4.i; A.541.x.4.i; A.542.x.4.i; A.543.x.4.i; A.544.x.4.i;
A.545.x.4.i; A.546.x.4.i; A.547.x.4.i; A.548.x.4.i; A.549.x.4.i; A.550.x.4.i;
A.551.x.4.i; A.552.x.4.i; A.553.x.4.i; A.554.x.4.i; A.555.x.4.i; A.556.x.4.i;
A.557.x.4.i; A.558.x.4.i; A.559.x.4.i; A.560.x.4.i; A.561.x.4.i; A.562.x.4.i;
A.563.x.4.i; A.564.x.4.i; A.565.x.4.i; A.566.x.4.i; A.567.x.4.i; A.568.x.4.i;
A.569.x.4.i; A.570.x.4.i; A.571.x.4.i; A.572.x.4.i; A.573.x.4.i; A.574.x.4.i;
A.575.x.4.i; A.576.x.4.i; A.577.x.4.i; A.578.x.4.i; A.579.x.4.i; A.580.x.4.i;
A.581.x.4.i; A.582.x.4.i; A.583.x.4.i; A.584.x.4.i; A.585.x.4.i; A.586.x.4.i;
A.5$7.x.4.i; A.588.x.4.i; A.589.x.4.i; A.590.x.4.i; A.591.x.4.i; A.592.x.4.i;
A.593.x.4.i; A.594.x.4.i; A.595.x.4.i; A.596.x.4.i; A.597.x.4.i; A.598.x.4.i;
A.599.x.4.i; A.600.x.4.i; A.601.x.4.i; A.602.x.4.i; A.603.x.4.i; A.604.x.4.i;
A.605.x.4.i; A.606.x.4.i; A.607.x.4.i; A.608.x.4.i; A.609.x.4.i; A.610.x.4.i;
A.611.x.4.i; A.612.x.4.i; A.613.x.4.i; A.614.x.4.i; A.615.x.4.i; A.616.x.4.i;
A.617.x.4.i; A.618.x.4.i; A.619.x.4.i; A.620.x.4.i; A.621.x.4.i; A.622.x.4.i;
A.623.x.4.i; A.624.x.4.i; A.625.x.4.i; A.626.x.4.i; A.627.x.4.i; A.628.x.4.i;

A.629.x.4.i; A.630.x.4.i; A.631.x.4.i; A.632.x.4.i; A.633.x.4.i; A.634.x.4.i;
A.635.x.4.i; A.636.x.4.i; A.637.x.4.i; A.638.x.4.i; A.639.x.4.i; A.640.x.4.i;
A.b41.x.4.i; A.b42.x.4.i; A.643.x.4.i; A.644.x.4.i; A.645.x.4.i; A.646.x.4.i;
A.647.x.4.i; A.b48.x.4.i; A.649.x.4.i; A.650.x.4.i; A.651.x.4.i; A.652.x.4.i;
A.653.x.4.i; A.654.x.4.i; A.655.x.4.i; A.656.x.4.i; A.657.x.4.i; A.658.x.4.i;
A.659.x.4.i; A.660.x.4.i; A.2.x.ll.i; A.3.x.ll.i; A.4.x.11.i; A.S.x.ll.i;
A.6.x.11.i;
A.7.x.ll.i; A.9.x.ll.i; A.l0.x.11.i; A.l5.x.11.i; A.100.x.ll.i; A.lOl.x.ll.i;
A.102.x.11.i; A.103.x.ll.i; A.104.x.11.i; A.105.x.ll.i; A.lOd.x.ll.i;
A.107.x.ll.i;
A.108.x.ll.i; A.109.x.11.i; A.110.x.ll.i; A.111.x.ll.i; A.112.x.11.i;
A.113.x.ll.i;
A.114.x.ll.i; A.115.x,11.i; A.116.x.ll.i; A.117.x.ll.i; A.118.x.ll.i;
A.119.x.ll.i;
A.120.x.ll.i; A.121.x.11.i; A.122.x.ll.i; A.123.x.ll.i; A.124.x.11.i;
A.125.x.11.i;
A.126.x.ll.i; A.127.x.ll.i; A.128.x.ll.i; A.129.x.ll.i; A.130.x.ll.i;
A.131.x.ll.i;
A.132.x.ll.i; A.133.x.ll.i; A.134.x.ll.i; A.135.x.ll.i; A.136.x.ll.i;
A.137.x.ll.i;
A.138.x.ll.i; A.139.x.ll.i; A.140.x.ll.i; A.141.x.ll.i; A.142.x.ll.i;
A.143.x.ll.i;
A.144.x.ll.i; A.145.x.ll.i; A.146.x.11.i; A.147.x.ll.i; A.148.x.ll.i;
A.149.x.ll.i;
A.150.x.11.i; A.151.x.11.i; A.152.x.ll.i; A.153.x.11.i; A.154.x.ll.i;
A.155.x.ll.i;
A.156.x.ll.i; A.157.x.ll.i; A.158.x.11.i; A.159.x.ll.i; A.160.x.ll.i;
A.161.x.ll.i;
A.162.x.11.i; A.163.x.11.i; A.164.x.ll.i; A.165.x.11.i; A.166.x.11.i;
A.167.x.ll.i;
A.168.x.11.i; A.169.x.ll.i; A.170.x.11.i; A.171.x.ll.i; A.172.x.ll.i;
A.173.x.11.i;
A.174.x.ll.i; A.175.x.11.i; A.176.x.11.i; A.177.x.ll.i; A.178.x.ll.i;
A.179.x.ll.i;
A.180.x.11.i; A.181.x.ll.i; A.182.x.ll.i; A.183.x.ll.i; A.184.x.ll.i;
A.185.x.ll.i;
A.186.x.ll.i; A.187.x.ll.i; A.188.x.ll.i; A.189.x.ll.i; A.190.x.ll.i;
A.191.x.ll.i;
A.192.x.11.i; A.193.x.ll.i; A.194.x.11.i; A.195.x.ll.i; A.196.x.11.i;
A.197.x.11.i;
A.198.x.ll.i; A.199.x.ll.i; A.200.x.ll.i; A.201.x.ll.i; A.202.x.ll.i;
A.203.x.ll.i;
A.204.x.ll.i; A.205.x.ll.i; A.206.x.ll.i; A.207.x.ll.i; A.208.x.ll.i;
A.209.x.ll.i;
A.210.x.11.i; A.211.x.ll.i; A.212.x.ll.i; A.213.x.ll.i; A.214.x.ll.i;
A.215.x.ll.i;
A.216.x.ll.i; A.217.x.ll.i; A.218.x.ll.i; A.219.x.ll.i; A.220.x.ll.i;
A.221.x.ll.i;
A.222.x.ll.i; A.223.x.ll.i; A.224.x.ll.i; A.225.x.ll.i; A.226.x.ll:i;
A.227.x.ll.i;
A.228.x.11.i; A.229.x.ll.i; A.230.x.11.i; A.231.x.11.i; A.232.x.ll.i;
A.233.x.ll.i;
A.234.x.11.i; A.235.x.ll.i; A.236.x.11.i; A.237.x.11.i; A.238.x.ll.i;
A.239.x.ll.i;
A.240.x.ll.i; A.241.x.11.i; A.242.x.11.i; A.243.x.ll.i; A.244.x.11.i;
A.245.x.11.i;
A.246.x.ll.i; A.247.x.ll.i; A.248.x.ll.i; A.249.x.ll.i; A.250.x.ll.i;
A.251.x.ll.i;
A.252.x.ll.i; A.253.x.ll.i; A.254.x.11.i; A.255.x.ll.i; A.256.x.ll.i;
A.257.x.11.i;
A.258.x.ll.i; A.259.x.11.i; A.260.x.ll.i; A.261.x.11.i; A.262.x.ll.i;
A.263.x.ll.i;
A.264.x.ll.i; A.265.x.ll.i; A.266.x.ll.i; A.267.x.11.i; A.268.x.ll.i;
A.269.x.ll.i;
A.270.x.ll.i; A.271.x.11.i; A.272.x.ll.i; A.273.x.11.i; A.274.x.ll.i;
A.275.x.11.i;
A.276.x.ll.i; A.277.x.ll.i; A,278.x.11.i; A.279.x.11.i; A.280.x.ll.i;
A.281.x.ll.i;
A.282.x.ll.i; A.283.x.11.i; A.284.x.11.i; A.285.x.11.i; A.286.x.ll.i;
A.287.x.11.i;
A.288.x.11.i; A.289.x.ll.i; A.290.x.ll.i; A.291.x.ll.i; A.292.x.11.i;
A.293.x.11.i;
A.294.x.ll.i; A.295.x.ll.i; A.296.x.11.i; A.297.x.ll.i; A.298.x.ll.i;
A.299.x.ll.i;
A.300.x.ll.i; A.301.x.11.i; A.302.x.11.i; A.303.x.ll.i; A.304.x.ll.i;
A.305.x.ll.i;
A.306.x.ll.i; A.307.x.ll.i; A.308.x.ll.i; A.309.x.ll.i; A.310.x.ll.i;
A.311.x.11.i;
A.312.x.11.i; A.313.x.11.i; A.314.x.ll.i; A.315.x.11.i; A.316.x.ll.i;
A.317.x.ll.i;
A.318.x.11.i; A.319.x.ll.i; A.320.x.ll.i; A.321.x.11.i; A.323.x.ll.i;
A.324.x.ll.i;
A.325.x.11.i; A.326.x.11.i; A.327.x.ll.i; A.328.x.ll.i; A.329.x.ll.i;
A.330.x.11.i;
A.331.x.11.i; A.332.x.11.i; A.333.x.11.i; A.334.x.11.i; A.335.x.11.i;
A.336.x.ll.i;
A.337.x.11.i; A.338.x.11.i; A.339.x.11.i; A.340.x.ll.i; A.341.x.11.i;
A.342.x.ll.i;

A.343.x.ll.i; A.344.x.ll.i; A.345.x.ll.i; A.346.x.ll.i; A.347.x.11.i;
A.348.x.11.i;
A.349.x.11.i; A.350.x.ll.i; A.35Lx.11.i; A.352.x.ll.i; A.353.x.ll.i;
A.354.x.ll.i;
A.355.x.ll.i; A.356.x.11.i; A.357.x.11.i; A.358.x.ll.i; A.359.x.ll.i;
A.360.x.ll.i;
A.361.x.ll.i; A.362.x.ll.i; A.363.x.ll.i; A.364.x.ll.i; A.365.x.ll.i;
A.366.x.11.i;
A.367.x.11.i; A.368.x.11.i; A.369.x.11.i; A.370.x.11.i; A.371.x.11.i;
A.372.x.ll.i;
A.373.x.11.i; A.374.x.11.i; A.375.x.ll.i; A.376.x.11.i; A.377.x.ll.i;
A.378.x.ll.i;
A.379.x.11.i; A.380.x.ll.i; A.381.x.ll.i; A.382.x.ll.i; A.383.x.ll.i;
A.384.x.ll.i;
A.385.x.ll.i; A.386.x.ll.i; A.387.x.11.i; A.388.x.ll.i; A.389.x.11.i;
A.390.x.ll.i;
A.391.x.ll.i; A.392.x.11.i; A.393.x.11.i; A.394.x.11.i; A.395.x.ll.i;
A.396.x.ll.i;
A.397.x.ll.i; A.398.x.ll.i; A.399.x.11.i; A.400.x.ll.i; A.401.x.11.i;
A.402.x.ll.i;
A.403.x.ll.i; A.404.x.ll.i; A.405.x.ll.i; A.406.x.ll.i; A.407.x.ll.i;
A.408.x.ll.i;
A.409.x.11.i; A.410.x.ll.i; A.411.x.ll.i; A.412.x.11.i; A.413.x.ll.i;
A.414.x.11.i;
A.415.x.ll.i; A.416.x.11.i; A.417.x.11.i; A.418.x.ll.i; A.419.x.ll.i;
A.420.x.ll.i;
A.421.x.ll.i; A.422.x.ll.i; A.423.x.ll.i; A.424.x.11.i; A.425.x.ll.i;
A.426.x.ll.i;
A.427.x.ll.i; A.428.x.11.i; A.429.x.11.i; A.430.x.11.i; A.431.x.il.i;
A.432.x.ll.i;
A.433.x.11.i; A.434.x.ll.i; A.435.x.11.i; A.436.x.ll.i; A.437.x.11.i;
A.438.x.11.i;
A.439.x.11.i; A.440.x.ll.i; A.441.x.ll.i; A.442.x.ll.i; A.443.x.11.i;
A.444.x.ll.i;
A.445.x.11.i; A.446.x.ll.i; A.447.x.ll.i; A.448.x.11.i; A.449.x.ll.i;
A.450.x.ll.i;
A.451.x.11.i; A.452.x.11.i; A.453.x.ll.i; A.454.x.11.i; A.455.x.11.i;
A.456.x.ll.i;
A.457.x.ll.i; A.458.x.11.i; A.459.x.11.i; A.460.x.ll.i; A.461.x.11.i;
A.462.x.ll.i;
A.463.x.ll.i; A.464.x.ll.i; A.465.x.11.i; A.466.x.ll.i; A.467.x.ll.i;
A.468.x.ll.i;
A.469.x.ll.i; A.470.x.ll.i; A.471.x.ll.i; A.472.x.ll.i; A.473.x.ll.i;
A.474.x.ll.i;
A.475.x.11.i; A.476.x.11.i; A.477.x.ll.i; A.478.x.ll.i; A.479.x.ll.i;
A.480.x.ll.i;
A.481.x.11.i; A.482.x.11.i; A.483.x.ll.i; A.484.x.11.i; A.485.x.ll.i;
A.486.x.ll.i;
A.487.x.ll.i; A.488.x.ll.i; A.489.x.ll.i; A.490.x.11.i; A.491.x.ll.i;
A.492.x.ll.i;
A.493.x.ll.i; A.494.x.ll.i; A.495.x.ll.i; A.496.x.11.i; A.497.x.ll.i;
A.498.x.ll.i;
A.499.x.ll.i; A.500.x.11.i; A.501.x.ll.i; A.502.x.11.i; A.503.x.11.i;
A.504.x.ll.i;
A.505.x.ll.i; A.506.x.11.i; A.507.x.11.i; A.508.x.11.i; A.509.x.11.i;
A.510.x.il.i;
A.511.x.ll.i; A.512.x.11.i; A.512.x.ll.i; A.513.x.ll.i; A.514.x.11.i;
A.515.x.Il.i;
A.516.x.ll.i; A.517.x.ll.i; A.518.x.11.i; A.519.x.11.i; A.520.x.ll.i;
A.521.x.ll.i;
A.522.x.11.i; A.523.x.11.i; A.524.x.11.i; A.525.x.ll.i; A.526.x.11.i;
A.527.x.ll.i;
A.528.x.11.i; A.529.x.11.i; A.530.x.ll.i; A.531.x.11.i; A.532.x.ll.i;
A.533.x.ll.i;
A.534.x.ll.i; A.535.x.ll.i; A.536.x.ll.i; A.537.x.11.i; A.538.x.11.i;
A.539.x.11.i;
A.540.x.ll.i; A.541.x.11.i; A.542.x.ll.i; A.543.x.11.i; A.544.x.11.i;
A.545.x.ll.i;
A.546.x.11.i; A.547.x.ll.i; A.548.x.ll.i; A.549.x.ll.i; A.550.x.11.i;
A.551.x.ll.i;
A.552.x.ll.i; A.553.x.11.i; A.554.x.11.i; A.555.x.ll.i; A.556.x.11.i;
A.557.x.ll.i;
A.558.x.11.i; A.559.x.ll.i; A.560.x.ll.i; A.561.x.11.i; A.562.x.ll.i;
A.563.x.ll.i;
A.564.x.11.i; A.565.x.11.i; A.566.x.11.i; A.567.x.ll.i; A.568.x.11.i;
A.569.x.11.i;
A.570.x.ll.i; A.571.x.11.i; A.572.x.11.i; A.573.x.ll.i; A.574.x.11.i;
A.575.x.ll.i;
A.576.x.11.i; A.577.x.11.i; A.578.x.11.i; A.579.x.11.i; A.580.x.ll.i;
A.581.x.11.i;
A.582.x.11.i; A.583.x.11.i; A.584.x.11.i; A.585.x.11.i; A.586.x.11.i;
A.587.x.ll.i;
A.588.x.11.i; A.589.x.ll.i; A.590.x.ll.i; A.591.x.ll.i; A.592.x.11.i;
A.593.x.ll.i;
A.594.x.ll.i; A.595.x.ll.i; A.596.x.11.i; A.597.x.11.i; A.598.x.11.i;
A.599.x.ll.i;
A.600.x.ll.i; A.601.x.11.i; A.602.x.ll.i; A.603.x.ll.i; A.604.x.11.i;
A.605.x.ll.i;
A.606.x.ll.i; A.607.x.11.i; A.608.x.11.i; A.609.x.11.i; A.610.x.11.i;
A.611.x.ll.i;
A.612.x.11.i; A.613.x.ll.i; A.614.x.ll.i; A.615.x.ll.i; A.616.x.11.i;
A.617.x.11.i;
A.618.x.ll.i; A.619.x.11.i; A.620.x.ll.i; A.621.x.11.i; A.622.x.11.i;
A.623.x.11.i;

A.624.x.11.i; A.625.x.ll.i; A.626.x.11.i; A.627.x.ll.i; A.628.x.ll.i;
A.629.x.11.i;
A.630.x.Il.i; A.631.x.11.i; A.632.x.ll.i; A.633.x.ll.i; A.634.x.lLi;
A.635.x.ll.i;
A.636.x.ll.i; A.637.x.11.i; A.638.x.ll.i; A.639.x.ll.i; A.640.x.11.i;
A.641.x.ll.i;
A.642.x.ll.i; A.643.x.ll.i; A.644.x.11.i; A.645.x.11.i; A.b46.x.ll.i;
A.647.x.11.i;
A.648.x.ll.i; A.649.x.ll.i; A.650.x.ll.i; A.651.x.ll.i; A.652.x.ll.i;
A.653.x.ll.i;
A.654.x.11.i; A.655.x.ll.i; A.656.x.ll.i; A.657.x.11.i; A.658.x.ll.i;
A.659.x.ll.i;
A.660.x.ll.i; A.2.y.4.i; A.3.y.4.i; A.4.y.4.i; A.5.y.4.i; A.6.y.4.i;
A.7.y.4.i; A.9.y.4.i;
A.l0.y.4.i; A.l5.y.4.i; A.100.y.4.i; A.101.y.4.i; A.102.y.4.i; A.103.y.4.i;
A.104.y.4.i;
A.105.y.4.i; A.106.y.4.i; A.107.y.4.i; A.108.y.4.i; A.109.y.4.i; A.120.y.4.i;
A.lll.y.4.i; A.112.y.4.i; A.113.y.4.i; A.114.y.4.i; A.115.y.4.i; A.116.y.4.i;
A.117.y.4.i; A.118.y.4.i; A.119.y.4.i; A.120.y.4.i; A.121.y.4.i; A.122.y.4.i;
A.123.y.4.i; A.124.y.4.i; A.125.y.4.i; A.126.y.4.i; A.127.y.4.i; A.128.y.4.i;
A.129.y.4.i; A.130.y.4.i; A.131.y.4.i; A.132.y.4.i; A.133.y.4.i; A.134.y.4.i;
A.135.y.4.i; A.136.y.4.i; A.137.y.4.i; A.138.y.4.i; A.139.y.4.i; A.140.y.4.i;
A.141.y.4.i; A.142.y.4.i; A.143.y.4.i; A.144.y.4.i; A.145.y.4.i; A.146.y.4.i;
A.147.y.4.i; A.148.y.4.i; A.149.y.4.i; A.150.y.4.i; A.151.y.4.i; A.152.y.4.i;
A.153.y.4.i; A.154.y.4.i; A.155.y.4.i; A.156.y.4.i; A.157.y.4.i; A.158.y.4.i;
A.159.y.4.i; A.160.y.4.i; A.161.y.4.i; A.162.y.4.i; A.163.y.4.i; A.164.y.4.i;
A.165.y.4.i; A.166.y.4.i; A.167.y.4.i; A.168.y.4.i; A.169.y.4.i; A.170.y.4.i;
A.171.y.4.i; A.172.y.4.i; A.173.y.4.i; A.174.y.4.i; A.175.y.4.i; A.176.y.4.i;
A.177.y.4.i; A.178.y.4.i; A.179.y.4.i; A.180.y.4.i; A.181.y.4.i; A.182.y.4.i;
A.183.y.4.i; A.184.y.4.i; A.185.y.4.i; A.186.y.4.i; A.187.y.4.i; A.188.y.4.i;
A.189.y.4.i; A.190.y.4.i; A.191.y.4.i; A.192.y.4.i; A.193.y.4.i; A.194.y.4.i;
A.195.y.4.i; A.196.y.4.i; A.197.y.4.i; A.198.y.4.i; A.199.y.4.i; A.200.y.4.i;
A.201.y.4.i; A.202.y.4.i; A.203.y.4.i; A.204.y.4.i; A.205.y.4.i; A.206.y.4.i;
A.207.y.4.i; A.208.y.4.i; A.209.y.4.i; A.210.y.4.i; A.211.y.4.i; A.212.y.4.i;
A.213.y.4.i; A.214.y.4.i; A.215.y.4.i; A.216.y.4.i; A.217.y.4.i; A.218.y.4.i;
A.219.y.4.i; A.220.y.4.i; A.221.y.4.i; A.222.y.4.i; A.223.y.4.i; A.224.y.4.i;
A.225.y.4.i; A.226.y.4.i; A.227.y.4.i; A.228.y.4.i; A.229.y.4.i; A.230.y.4.i;
A.231.y.4.i; A.232.y.4.i; A.233.y.4.i; A.234.y.4.i; A.235.y.4.i; A.236.y.4.i;
A.237.y.4.i; A.238.y.4.i; A.239.y.4.i; A.240.y.4.i; A.241.y.4.i; A.242.y.4.i;
A.243.y.4.i; A.244.y.4.i; A.245.y.4.i; A.246.y.4.i; A.247.y.4.i; A.248.y.4.i;
A.249.y.4.i; A.250.y.4.i; A.251.y.4.i; A.252.y.4.i; A.253.y.4.i; A.254.y.4.i;
A.255.y.4.i; A.256.y.4.i; A.257.y.4.i; A.258.y.4.i; A.259.y.4.i; A.260.y.4.i;
A.261.y.4.i; A.262.y.4.i; A.263.y.4.i; A.264.y.4.i; A.265.y.4.i; A.266.y.4.i;
A.267.y.4.i; A.268.y.4.i; A.269.y.4.i; A.270.y.4.i; A.271.y.4.i; A.272.y.4.i;
A.273.y.4.i; A.274.y.4.i; A.275.y.4.i; A.276.y.4.i; A.277.y.4.i; A.278.y.4.i;
A.279.y.4.i; A.280.y.4.i; A.281.y.4.i; A.282.y.4.i; A.283.y.4.i; A.284.y.4.i;
A.285.y.4.i; A.286.y.4.i; A.287.y.4.i; A.288.y.4.i; A.289.y.4.i; A.290.y.4.i;
A.291.y.4.i; A.292.y.4.i; A.293.y.4.i; A.294.y.4.i; A.295.y.4.i; A.296.y.4.i;
A.297.y.4.i; A.298.y.4.i; A.299.y.4.i; A.300.y.4.i; A.301.y.4.i; A.302.y.4.i;
A.303.y.4.i; A.304.y.4.i; A.305.y.4.i; A.306.y.4.i; A.307.y.4.i; A.308.y.4.i;
A.309.y.4.i; A.310.y.4.i; A.311.y.4.i; A.312.y.4.i; A.313.y.4.i; A.314.y.4.i;
A.315.y.4.i; A.316.y.4.i; A.317.y.4.i; A.318.y.4.i; A.319.y.4.i; A.320.y.4.i;
A.321.y.4.i; A.323.y.4.i; A.324.y.4.i; A.325.y.4.i; A.326.y.4.i; A.327.y.4.i;
A.328.y.4.i; A.329.y.4.i; A.330.y.4.i; A.331.y.4.i; A.332.y.4.i; A.333.y.4.i;
A.334.y.4.i; A.335.y.4.i; A.336.y.4.i; A.337.y.4.i; A.338.y.4.i; A.339.y.4.i;

A.340.y.4.i; A.341.y.4.i; A.342.y.4.i; A.343.y.4.i; A.344.y.4.i; A.345.y.4.i;
A.346.y.4.i; A.347.y.4.i; A.348.y.4.i; A.349.y.4.i; A.350.y.4.i; A.351.y.4.i;
A.352.y.4.i; A.353.y.4.i; A.354.y.4.i; A.355.y.4.i; A.356.y.4.i; A.357.y.4.i;
A.358.y.4.i; A.359.y.4.i; A.360.y.4.i; A.361.y.4.i; A.362.y.4.i; A.363.y.4.i;
A.364.y.4.i; A.365.y.4.i; A.36b.y.4.i; A.367.y.4.i; A.368.y.4.i; A.369.y.4.i;
A.370.y.4.i; A.371.y.4.i; A.372.y.4.i; A.373.y.4.i; A.374.y.4.i; A.375.y.4.i;
A.376.y.4.i; A.377.y.4.i; A.378.y.4.i; A.379.y.4.i; A.380.y.4.i; A.381.y.4.i;
A.382.y.4.i; A.383.y.4.i; A.384.y.4.i; A.385.y.4.i; A.386.y.4.i; A.387.y.4.i;
A.388.y.4.i; A.389.y.4.i; A.390.y.4.i; A.391.y.4.i; A.392.y.4.i; A.393.y.4.i;
A.394.y.4.i; A.395.y.4.i; A.396.y.4.i; A.397.y.4.i; A.398.y.4.i; A.399.y.4.i;
A.400.y.4.i; A.401.y.4.i; A.402.y.4.i; A.403.y.4.i; A.404.y.4.i; A.405.y.4.i;
A.406.y.4.i; A.407.y.4.i; A.408.y.4.i; A.409.y.4.i; A.410.y.4.i; A.411.y.4.i;
A.412.y.4.i; A.413.y.4.i; A.414.y.4.i; A.415.y.4.i; A.416.y.4.i; A.417.y.4.i;
A.418.y.4.i; A.419.y.4.i; A.420.y.4.i; A.421.y.4.i; A.422.y.4.i; A.423.y.4.i;
A.424.y.4.i; A.425.y.4.i; A.426.y.4.i; A.427.y.4.i; A.428.y.4.i; A.429.y.4.i;
A.430.y.4.i; A.431.y.4.i; A.432.y.4,i; A.433.y.4.i; A.434.y.4.i; A.435.y.4.i;
A.436.y.4.i; A.437.y.4.i; A.438.y.4.i; A.439.y.4.i; A.440.y.4.i; A.441.y.4.i;
A.442.y.4.i; A.443.y.4.i; A.444.y.4.i; A.445.y.4.i; A.446.y.4.i; A.447.y.4.i;
A.448.y.4.i; A.449.y.4.i; A.450.y.4.i; A.451.y.4.i; A.452.y.4.i; A.453.y.4.i;
A.454.y.4.i; A.455.y.4.i; A.456.y.4.i; A.457.y.4.i; A.458.y.4.i; A.459.y.4.i;
A.460.y.4.i; A.461.y.4.i; A.462.y.4.i; A.463.y.4.i; A.464.y.4.i; A.465.y.4.i;
A.466.y.4.i; A.467.y.4.i; A.468.y.4.i; A.469.y.4.i; A.470.y.4.i; A.471.y.4.i;
A.472.y.4.i; A.473.y.4.i; A.474.y.4.i; A.475.y.4.i; A.476.y.4.i; A.477.y.4.i;
A.478.y.4.i; A.479.y.4.i; A.480.y.4.i; A.481.y.4.i; A.482.y.4.i; A.483.y.4.i;
A.484.y.4.i; A.485.y.4.i; A.486.y.4.i; A.487.y.4.i; A.488.y.4.i; A.489.y.4.i;
A.490.y.4.i; A.491.y.4.i; A.492.y.4.i; A.493.y.4.i; A.494.y.4.i; A.495.y.4.i;
A.496.y.4.i; A.497.y.4.i; A.498.y.4.i; A.499.y.4.i; A.500.y.4.i; A.501.y.4.i;
A.502.y.4.i; A.503.y.4.i; A.504.y.4.i; A.505.y.4.i; A.506.y.4.i; A.507.y.4.i;
A.508.y.4.i; A.509.y.4.i; A.510.y.4.i; A.511.y.4.i; A.512.y.4.i; A.512.y.4.i;
A.513.y.4.i; A.514.y.4.i; A.515.y.4.i; A.516.y.4.i; A.517.y.4.i; A.518.y.4.i;
A.519.y.4.i; A.520.y.4.i; A.521.y.4.i; A.522.y.4.i; A.523.y.4.i; A.524.y.4.i;
A.525.y.4.i; A.526.y.4.i; A.527.y.4.i; A.528.y.4.i; A.529.y.4.i; A.530.y.4.i;
A.531.y.4.i; A.532.y.4.i; A.533.y.4.i; A.534.y.4.i; A.535.y.4.i; A.536.y.4.i;
A.537.y.4.i; A.538.y.4.i; A.539.y.4.i; A.540.y.4.i; A.541.y.4.i; A.542.y.4.i;
A.543.y.4.i; A.544.y.4.i; A.545.y.4.i; A.546.y.4.i; A.547.y.4.i; A.548.y.4.i;
A.549.y.4.i; A.550.y.4.i; A.551.y.4.i; A.552.y.4.i; A.553.y.4.i; A.554.y.4.i;
A.555.y.4.i; A.556.y.4.i; A.557.y.4.i; A.558.y.4.i; A.559.y.4.i; A.560.y.4.i;
A.561.y.4.i; A.562.y.4.i; A.563.y.4.i; A.564.y.4.i; A.565.y.4.i; A.566.y.4.i;
A.567.y.4.i; A.568.y.4.i; A.569.y.4.i; A.570.y.4.i; A.571.y.4.i; A.572.y.4.i;
A.573.y.4.i; A.574.y.4.i; A.575.y.4.i; A.576.y.4.i; A.577.y.4.i; A.578.y.4.i;
A.579.y.4.i; A.580.y.4.i; A.581.y.4.i; A.582.y.4.i; A.583.y.4.i; A.584.y.4.i;
A.585.y.4.i; A.586.y.4.i; A.587.y.4.i; A.588.y.4.i; A.589.y.4.i; A.590.y.4.i;
A.591.y.4.i; A.592.y.4.i; A.593.y.4.i; A.594.y.4.i; A.595.y.4.i; A.596.y.4.i;
A.597.y.4.i; A.598.y.4.i; A.599.y.4.i; A.600.y.4.i; A.601.y.4.i; A.602.y.4.i;
A.603.y.4.i; A.604.y.4.i; A.605.y.4.i; A.606.y.4.i; A.607.y.4.i; A.608.y.4.i;
A.609.y.4.i; A.610.y.4.i; A.611.y.4.i; A.612.y.4.i; A.613.y.4.i; A.614.y.4.i;
A.615.y.4.i; A.616.y.4.i; A.617.y.4.i; A.618.y.4.i; A.619.y.4.i; A.620.y.4.i;

A.621.y.4.i; A.622.y.4.i; A.623.y.4.i; A.624.y.4.i; A.625.y.4.i; A.626.y.4.i;
A.627.y.4.i; A.628.y.4.i; A.629.y.4.i; A.630.y.4.i; A.631.y.4.i; A.632.y.4.i;
A.633.y.4.i; A.634.y.4.i; A.635.y.4.i; A.636.y.4.i; A.637.y.4.i; A.638.y.4.i;
A.639.y.4.i; A.640.y.4.i; A.641.y.4.i; A.642.y.4.i; A.643.y.4.i; A.644.y.4.i;
A.645.y.4.i; A.646.y.4.i; A.647.y.4.i; A.648.y.4.i; A.649.y.4.i; A.650.y.4.i;
A.651.y.4.i; A.652.y.4.i; A.653.y.4.i; A.654.y.4.i; A.655.y.4.i; A.656.y.4.i;
A.657.y.4.i; A.658.y.4.i; A.659.y.4.i; A.660.y.4.i; A.2.y.11.i; A.3.y.11.i;
A.4.y.11.i;
A.S.y.ll.i; A.6.y.11.i; A.7.y.ll.i; A.9.y.11.i; A.lO.y.ll.i; A.l5.y.ll.i;
A.100.y.ll.i;
A.lOl.y.ll.i; A.102.y.ll.i; A.103.y.ll.i; A.104.y.11.i; A.105.y.11.i;
A.106.y.ll.i;
A.107.y.11.i; A.108.y.11.i; A.109.y.ll.i; A.110.y.ll.i; A.lll.y.ll.i;
A.112.y.ll.i;
A.113.y.ll.i; A.114.y.ll.i; A.115.y.ll.i; A.116.y.11.i; A.117.y.11.i;
A.118.y.ll.i;
A.119.y.11.i; A.120.y.11.i; A.121.y.11.i; A.122.y.ll.i; A.123.y.ll.i;
A.124.y.ll.i;
A.125.y.ll.i; A.126.y.ll.i; A.127.y.ll.i; A.128.y.ll.i; A.129.y.ll.i;
A.130.y.ll.i;
A.131.y.ll.i; A.132.y.11.i; A.133.y.ll.i; A.134.y.ll.i; A.135.y.ll.i;
A.136.y.ll.i;
A.137.y.ll.i; A.138.y.ll.i; A.139.y.ll.i; A.140.y.ll.i; A.141.y.ll.i;
A.142.y.ll.i;
A.143.y.11.i; A.144.y.ll.i; A.145.y.ll.i; A.146.y.ll.i; A.147.y.11.i;
A.148.y.ll.i;
A.149.y.ll.i; A.150.y.11.i; A.151.y.ll.i; A.152.y.ll.i; A.153.y.11.i;
A.154.y.11.i;
A.155.y.ll.i; A.156.y.ll.i; A.157.y.ll.i; A.158.y.ll.i; A.159.y.ll.i;
A.160.y.11.i;
A.161.y.ll.i; A.162.y.ll.i; A.163.y.ll.i; A.164.y.ll.i; A.165.y.ll.i;
A.166.y.11.i;
A.167.y.11.i; A.168.y.ll.i; A.169.y.ll.i; A.170.y.11.i; A.171.y.ll.i;
A.172.y.11.i;
A.173.y.11.i; A.174.y.ll.i; A.175.y.ll.i; A.176.y.11:i; A.177.y.11.i;
A.178.y.ll.i;
A.179.y.ll.i; A.180.y.ll.i; A.181.y.ll.i; A.182.y.ll.i; A.183.y.ll.i;
A.184.y.ll.i;
A.185.y.ll.i; A.186.y.ll.i; A.187.y.ll.i; A.188.y.ll.i; A.189.y.11.i;
A.190.y.11.i;
A.191.y.ll.i; A.192.y.ll.i; A.193.y.ll.i; A.194.y.ll.i; A.195.y.ll.i;
A.196.y.ll.i;
A.197.y.11.i; A.198.y.ll.i; A.199.y.ll.i; A.200.y.ll.i; A.201.y.11.i;
A.202.y.ll.i;
A.203.y.11.i; A.204.y.ll.i; A.205.y.ll.i; A.206.y.ll.i; A.207.y.ll.i;
A.208.y.11.i;
A.209.y.11.i; A.210.y.ll.i; A.211.y.ll.i; A.212.y.ll.i; A.213.y.ll.i;
A.214.y.ll.i;
A.215.y.11.i; A.216.y.11.i; A.217.y.ll.i; A.218.y.ll.i; A.219.y.ll.i;
A.220.y.ll.i;
A.221.y.11.i; A.222.y.ll.i; A.223.y.11.i; A.224.y.ll.i; A.225.y.11.i;
A.226.y.ll.i;
A.227.y.ll.i; A.228.y.11.i; A.229.y.ll.i; A.230.y.11.i; A.231.y.11.i;
A.232.y.ll.i;
A.233.y.ll.i; A.234.y.11.i; A.235.y.ll.i; A.236.y.ll.i; A.237.y.ll.i;
A.238.y.ll.i;
A.239.y.ll.i; A.240.y.ll.i; A.241.y.ll.i; A.242.y.ll.i; A.243.y.11.i;
A.244.y.ll.i;
A.245.y.11.i; A.246.y.11.i; A.247.y.ll.i; A.248.y.ll.i; A.249.y.ll.i;
A.250.y.ll.i;
A.251.y.11.i; A.252.y.ll.i; A.253.y.11.i; A.254.y.11.i; A.255.y.11.i;
A.256.y.ll.i;
A.257.y.ll.i; A.258.y.ll.i; A.259.y.11.i; A.260.y.ll.i; A.261.y.ll.i;
A.262.y.ll.i;
A.263.y.ll.i; A.264.y.ll.i; A.265.y.ll.i; A.266.y.Il.i; A.267.y.ll.i;
A.268.y.ll.i;
A.269.y.11.i; A.270.y.ll.i; A.271.y.11.i; A.272.y.11.i; A.273.y.ll.i;
A.274.y.ll.i;
A.275.y.ll.i; A.276.y.ll.i; A.277.y.11.i; A.278.y.11.i; A.279.y.ll.i;
A.280.y.11.i;
A.281.y.ll.i; A.282.y.11.i; A.283.y.Il.i; A.2$4.y.11.i; A.285.y.11.i;
A.286.y.ll.i;
A.287.y.ll.i; A.288.y.11.i; A.289.y.11.i; A.290.y.11.i; A.291.y.ll.i;
A.292.y.ll.i;
A.293.y.ll.i; A.294.y.ll.i; A.295.y.11.i; A.296.y.11.i; A.297.y.ll.i;
A.298.y.ll.i;
A.299.y.ll.i; A.300.y.ll.i; A.301.y.11.i; A.302.y.ll.i; A.303.y.11.i;
A.304.y.ll.i;
A.305.y.ll.i; A.306.y.ll.i; A.307.y.ll.i; A.308.y.11.i; A.309.y.ll.i;
A.310.y.ll.i;
A.311.y.11.i; A.312.y.ll.i; A.313.y.ll.i; A.314.y.ll.i; A.315.y.11.i;
A.316.y.ll.i;
A.317.y.ll.i; A.318.y.11.i; A.319.y.11.i; A.320.y.ll.i; A.321.y.ll.i;
A.323.y.ll.i;
A.324.y.ll.i; A.325.y.ll.i; A.326.y.ll.i; A.327.y.11.i; A.328.y.11.i;
A.329.y.11.i;
A.330.y.11.i; A.331.y.ll.i; A.332.y.ll.i; A.333.y.ll.i; A.334.y.11.i;
A.335.y.ll.i;

A.336.y.11.i; A.337.y.11.i; A.338.y.11.i; A.339.y.Il.i; A.340.y.11.i;
A.341.y.11.i;
A.342.y.ll.i; A.343.y.ll.i; A.344.y.11.i; A.345.y.ll.i; A.346.y.ll.i;
A.347.y.11.i;
A.348.y.11.i; A.349.y.11.i; A.350.y.ll.i; A.351.y.11.i; A.352.y.11.i;
A.353.y.11.i;
A.354.y.11.i; A.355.y.ll.i; A.356.y.11.i; A.357.y.11.i; A.358.y.ll.i;
A.359.y.11.i;
A.360.y.11.i; A.361.y.ll.i; A.362.y.ll.i; A.363.y.ll.i; A.364.y.11.i;
A.365.y.11.i;
A.366.y.11.i; A.367.y.11.i; A.368.y.ll.i; A.369.y.ll.i; A.370.y.11.i;
A.371.y.ll.i;
A.372.y.ll.i; A.373.y.11.i; A.374.y.11.i; A.375.y.ll.i; A.376.y.ll.i;
A.377.y.11.i;
A.378.y.ll.i; A.379.y.ll.i; A.380.y.11.i; A.381.y.11.i; A.382.y.11.i;
A.383.y.11.i;
A.384.y.11.i; A.385.y.ll.i; A.386.y.ll.i; A.387.y.11.i; A.388.y.ll.i;
A.389.y.ll.i;
A.390.y.ll.i; A.391.y.ll.i; A.392.y.ll.i; A.393.y.ll.i; A.394.y.ll.i;
A.395.y.ll.i;
A.396.y.11.i; A.397.y.11.i; A.398.y.11.i; A.399.y.11.i; A.400.y.ll.i;
A.401.y.11.i;
A.402.y.ll.i; A.403.y.11.i; A.404.y.11.i; A.405.y.ll.i; A.406.y.11.i;
A.407.y.11.i;
A.408.y.ll.i; A.409.y.11.i; A.410.y.11.i; A.411.y.11.i; A.412.y.ll.i;
A.413.y.ll.i;
A.414.y.11.i; A.415.y.ll.i; A.416.y.11.i; A.417.y.11.i; A.418.y.ll.i;
A.419.y.ll.i;
A.420.y.ll.i; A.421.y.11.i; A.422.y.11.i; A.423.y.11.i; A.424.y.11.i;
A.425.y.11.i;
A.426.y.ll.i; A.427.y.ll.i; A.428.y.ll.i; A.429.y.ll.i; A.430.y.ll.i;
A.431.y.ll.i;
A.432.y.ll.i; A.433.y.ll.i; A.434.y.ll.i; A.435.y.11.i; A.436.y.11.i;
A.437.y.ll.i;
A.438.y.ll.i; A.439.y.11.i; A.440.y.ll.i; A.441.y.ll.i; A.442.y.ll.i;
A.443.y.ll.i;
A.444.y.ll.i; A.445.y.ll.i; A.446.y.11.i; A.447.y.11.i; A.448.y.11.i;
A.449.y.ll.i;
A.450.y.11.i; A.451.y.ll.i; A.452.y.ll.i; A.453.y.ll.i; A.454.y.11.i;
A.455.y.11.i;
A.456.y.11.i; A.457.y.ll.i; A.458.y.ll.i; A.459.y.11.i; A.460.y.11.i;
A.461.y.11.i;
A.462.y.11.i; A.463.y.11.i; A.464.y.ll.i; A.465.y.11.i; A.466.y.ll.i;
A.467.y.11.i;
A.468.y.11.i; A.469.y.11.i; A.470.y.11.i; A.471.y.ll.i; A.472.y.ll.i;
A.473.y.ll.i;
A.474.y.ll.i; A.475.y.ll.i; A.476.y.ll.i; A.477.y.ll.i; A.478.y.ll.i;
A.479.y.ll.i;
A.480.y.ll.i; A.481.y.11.i; A.482.y.11.i; A.483.y.11.i; A.484.y.11.i;
A.485.y.11.i;
A.486.y.11.i; A.487.y.ll.i; A.488.y.11.i; A.489.y.11.i; A.490.y.11.i;
A.491.y.ll.i;
A.492.y.11.i; A.493.y.11.i; A.494.y.ll.i; A.495.y.ll.i; A.496.y.11.i;
A.497.y.ll.i;
A.498.y.ll.i; A.499.y.11.i; A.500.y.ll.i; A.501.y.11.i; A.502.y.ll.i;
A.503.y.ll.i;
A.504.y.11.i; A.505.y.ll.i; A.506.y.11.i; A.507.y.ll.i; A.508.y.ll.i;
A.509.y.ll.i;
A.510.y.11.i; A.511.y.ll.i; A.512.y.11.i; A.5i2.y.ll.i; A.513.y.ll.i;
A.514.y.ll.i;
A.515.y.11.i; A.516.y.11.i; A.517.y.11.i; A.518.y.11.i; A.519.y.11.i;
A.520.y.ll.i;
A.521.y.ll.i; A.522.y.ll.i; A.523.y.11.i; A.524.y.ll.i; A.525.y.ll.i;
A.526.y.ll.i;
A.527.y.11.i; A.528.y.11.i; A.529.y.11.i; A.530.y.ll.i; A.531.y.ll.i;
A.532.y.ll.i;
A.533.y.11.i; A.534.y.11.i; A.535.y.ll.i; A.536.y.ll.i; A.537.y.11.i;
A.538.y.11.i;
A.539.y.11.i; A.540.y.11.i; A.541.y.ll.i; A.542.y.11.i; A.543.y.11.i;
A.544.y.11.i;
A.545.y.ll.i; A.546.y.ll.i; A.547.y.ll.i; A.548.y.ll.i; A.549.y.ll.i;
A.550.y.ll.i;
A.551.y.11.i; A.552.y.11.i; A.553.y.ll.i; A.554.y.11.i; A.555.y.ll.i;
A.556.y.ll.i;
A.557.y.ll.i; A.558.y.11.i; A.559.y.ll.i; A.560.y.11.i; A.561.y.11.i;
A.562.y.11.i;
A.563.y.11.i; A.564.y.11.i; A.565.y.11.i; A.566.y.11.i; A.567.y.11.i;
A.568.y.11.i;
A.569.y.ll.i; A.570.y.ll.i; A.571.y.11.i; A.572.y.11.i; A.573.y.ll.i;
A.574.y.11.i;
A.575.y.11.i; A.576.y.ll.i; A.577.y.11.i; A.578.y.ll.i; A.579.y.11.i;
A.580.y.ll.i;
A.581.y.ll.i; A.582.y.11.i; A.583.y.ll.i; A.5$4.y.11.i; A.585.y.ll.i;
A.586.y.ll.i;
A.587.y.11.i; A.588.y.11.i; A.589.y.11.i; A.590.y.11.i; A.591.y.11.i;
A.592.y.11.i;
A.593.y.11.i; A.594.y.11.i; A.595.y.ll.i; A.596.y.11.i; A.597.y.11.i;
A.598.y.11.i;
A.599.y.11.i; A.600.y.ll.i; A.601.y.ll.i; A.602.y.11.i; A.603.y.ll.i;
A.604.y.ll.i;
A.605.y.ll.i; A.606.y.11.i; A.607.y.11.i; A.608.y.11.i; A.609.y.ll.i;
A.610.y.11.i;
A.611.y.11.i; A.612.y.11.i; A.613.y.11.i; A.614.y.11.i; A.615.y.11.i;
A.616.y.11.i;

A.617.y.11.i; A.618.y.ll.i; A.619.y.ll.i; A.620.y.11.i; A.621.y.11.i;
A.622.y.11.i;
A.623.y.ll.i; A.624.y.11.i; A.625.y.11.i; A.626.y.ll.i; A.627.y.ll.i;
A.628.y.ll.i;
A.629.y.11.i; A.630.y.ll.i; A.631.y.11.i; A.632.y.ll.i; A.633.y.ll.i;
A.634.y.ll.i;
A.635.y.11.i; A.636.y.11.i; A.637.y.11.i; A.638.y.ll.i; A.639.y.11.i;
A.640.y.11.i;
A.641.y.ll.i; A.642.y.11.i; A.643.y.ll.i; A.644.y.11.i; A.645.y.11.i;
A.646.y.ll.i;
A.647.y.ll.i; A.648.y.lLi; A.649.y.11.i; A.650.y.ll.i; A.651.y.11.i;
A.652.y.ll.i;
A.653.y.11.i; A.654.y.11.i; A.655.y.ll.i; A.656.y.11.i; A.657.y.11.i;
A.658.y.ll.i;
A.659.y.ll.i; A.660.y.11.i; A.2.z.4.i; A.3.z.4.i; A.4.z.4.i; A.5.z.4.i;
A.6.z.4.i;
A.7.z.4.i; A.9.z.4.i; A.l0.z.4.i; A.l5.z.4.i; A.100.z.4.i; A.101.z.4.i;
A.102.z.4.i;
A.103.z.4.i; A.104.z.4.i; A.105.z.4.i; A.106.z.4.i; A.107.z.4.i; A.108.z.4.i;
A.109.z.4.i; A.110.z.4.i; A.lll.z.4.i; A.112.z.4.i; A.113.z.4.i; A.114.z.4.i;
A.115.z.4.i; A.116.z.4.i; A.117.z.4.i; A.118.z.4.i; A.119.z.4.i; A.120.z.4.i;
A.121.z.4.i; A.122.z.4.i; A.123.z.4.i; A.124.z.4.i; A.125.z.4.i; A.126.z.4.i;
A.127.z.4.i; A.128.z.4.i; A.129.z.4.i; A.130.z.4.i; A.131.z.4.i; A.132.z.4.i;
A.133.z.4.i; A.134.z.4.i; A.135.z.4.i; A.136.z.4.i; A.137.z.4.i; A.138.z.4.i;
A.139.z.4.i; A.140.z.4.i; A.141.z.4.i; A.142.z.4.i; A.143.z.4.i; A.144.z.4.i;
A.145.z.4.i; A.146.z.4.i; A.147.z.4.i; A.148.z.4.i; A.149.z.4.i; A.150.z.4.i;
A.151.z.4.i; A.152.z.4.i; A.153.z.4.i; A.154.z.4.i; A.I55.z.4.i; A.156.z.4.i;
A.157.z.4.i; A.158.z.4.i; A.159.z.4.i; A.160.z.4.i; A.161.z.4.i; A.162.z.4.i;
A.163.z.4.i; A.164.z.4.i; A.165.z.4.i; A.166.z.4.i; A.167.z.4.i; A.168.z.4.i;
A.169.z.4.i; A.170.z.4.i; A.171.z.4.i; A.172.z.4.i; A.173.z.4.i; A.174.z.4.i;
A.175.z.4.i; A.176.z.4.i; A.177.z.4.i; A.178.z.4.i; A.179.z.4.i; A.180.z.4.i;
A.181.z.4.i; A.182.z.4.i; A.183.z.4.i; A.184.z.4.i; A.185.z.4.i; A.186.z.4.i;
A.187.z.4.i; A.188.z.4.i; A.189.z.4.i; A.190.z.4.i; A.191.z.4.i; A.192.z.4.i;
A.193.z.4.i; A.194.z.4.i; A.195.z.4.i; A.196.z.4.i; A.197.z.4.i; A.198.z.4.i;
A.199.z.4.i; A.200.z.4.i; A.201.z.4.i; A.202.z.4.i; A.203.z.4.i; A.204.z.4.i;
A.205.z.4.i; A.206.z.4.i; A.207.z.4.i; A.208.z.4.i; A.209.z.4.i; A.210.z.4.i;
A.211.z.4.i; A.212.z.4.i; A.213.z.4.i; A.214.z.4.i; A.215.z.4.i; A.216.z.4.i;
A.217.z.4.i; A.218.z.4.i; A.219.z.4.i; A.220.z.4.i; A.221.z.4.i; A.222.z.4.i;
A.223.z.4.i; A.224.z.4.i; A.225.z.4.i; A.226.z.4.i; A.227.z.4.i; A.228.z.4.i;
A.229.z.4.i; A.230.z.4.i; A.231.z.4.i; A.232.z.4.i; A.233.z.4.i; A.234.z.4.i;
A.235.z.4.i; A.236.z.4.i; A.237.z.4.i; A.238.z.4.i; A.239.z.4.i; A.240.z.4.i;
A.241.z.4.i; A.242.z.4.i; A.243.z.4.i; A.244.z.4.i; A.245.z.4.i; A.246.z.4.i;
A.247.z.4.i; A.248.z.4.i; A.249.z.4.i; A.250.z.4.i; A.251.z.4.i; A.252.z.4.i;
A.253.z.4.i; A.254.z.4.i; A.255.z.4.i; A.256.z.4.i; A.257.z.4.i; A.258.z.4.i;
A.259.z.4.i; A.260.z.4.i; A.261.z.4.i; A.262.z.4.i; A.263.z.4.i; A.264.z.4.i;
A.265.z.4.i; A.266.z.4.i; A.267.z.4.i; A.268.z.4.i; A.269.z.4.i; A.270.z.4.i;
A.271.z.4.i; A.272.z.4.i; A.273.z.4.i; A.274.z.4.i; A.275.z.4.i; A.276.z.4.i;
A.277.z.4.i; A.278.z.4.i; A.279.z.4.i; A.280.z.4.i; A.281.z.4.i; A.282.z.4.i;
A.283.z.4.i; A.284.z.4.i; A.285.z.4.i; A.286.z.4.i; A.287.z.4.i; A.288.z.4.i;
A.289.z.4.i; A.290.z.4.i; A.291.z.4.i; A.292.z.4.i; A.293.z.4.i; A.294.z.4.i;
A.295.z.4.i; A.296.z.4.i; A.297.z.4.i; A.298.z.4.i; A.299.z.4.i; A.300.z.4.i;
A.301.z.4.i; A.302.z.4.i; A.303.z.4.i; A.304.z.4.i; A.305.z.4.i; A.306.z.4.i;
A.307.z.4.i; A.308.z.4.i; A.309.z.4.i; A.310.z.4.i; A.311.z.4.i; A.312.z.4.i;
A.313.z.4.i; A.314.z.4.i; A.315.z.4.i; A.316.z.4.i; A.317.z.4.i; A.318.z.4.i;
A.319.z.4.i; A.320.z.4.i; A.321.z.4.i; A.323.z.4.i; A.324.z.4.i; A.325.z.4.i;
A.326.z.4.i; A.327.z.4.i; A.328.z.4.i; A.329.z.4.i; A.330.z.4.i; A.331.z.4.i;

A.332.z.4.i; A.333.z.4.i; A.334.z.4.i; A.335.z.4.i; A.336.z.4.i; A.337.z.4.i;
A.338.z.4.i; A.339.z.4.i; A.340.z.4.i; A.341.z.4.i; A.342.z.4.i; A.343.z.4.i;
A.344.z.4.i; A.345.z.4.i; A.346.z.4.i; A.347.z.4.i; A.348.z.4.i; A.349.z.4.i;
A.350.z.4.i; A.351.z.4.i; A.352.z.4.i; A.353.z.4.i; A.354.z.4.i; A.355.z.4.i;
A.356.z.4.i; A.357.z.4.i; A.358.z.4.i; A.359.z.4.i; A.360.z.4.i; A.361.z.4.i;
A.362.z.4.i; A.363.z.4.i; A.364.z.4.i; A.365.z.4.i; A.366.z.4.i; A.367.z.4.i;
A.368.z.4.i; A.369.z.4.i; A.370.z.4.i; A.371.z.4.i; A.372.z.4.i; A.373.z.4.i;
A.374.z.4.i; A.375.z.4.i; A.376.z.4.i; A.377.z.4.i; A.378.z.4.i; A.379.z.4.i;
A.380.z.4.i; A.381.z.4.i; A.382.z.4.i; A.383.z.4.i; A.384.z.4.i; A.38S.z.4.i;
A.386.z.4.i; A.387.z.4.i; A.388.z.4.i; A.389.z.4.i; A.390.z.4.i; A.391.z.4.i;
A.392.z.4.i; A.393.z.4.i; A.394.z.4.i; A.395.z.4.i; A.396.z.4.i; A.397.z.4.i;
A.398.z.4.i; A.399.z.4.i; A.400.z.4.i; A.401.z.4.i; A.402.z.4.i; A.403.z.4.i;
A.404.z.4.i; A.405.z.4.i; A.406.z.4.i; A.407.z.4.i; A.408.z.4.i; A.409.z.4.i;
A.410.z.4.i; A.411.z.4.i; A.412.z.4.i; A.413.z.4.i; A.414.z.4.i; A.415.z.4.i;
A.416.z.4.i; A.417.z.4.i; A.418.z.4.i; A.419.z.4.i; A.420.z.4.i; A.421.z.4.i;
A.422.z.4.i; A.423.z.4.i; A.424.z.4.i; A.42S.z.4.i; A.426.z.4.i; A.427.z.4.i;
A.428.z.4.i; A.429.z.4.i; A.430.z.4.i; A.431.z.4.i; A.432.z.4.i; A.433.z.4.i;
A.434.z.4.i; A.435.z.4.i; A.436.z.4.i; A.437.z.4.i; A.438.z.4.i; A.439.z.4.i;
A.440.z.4.i; A.441.z.4.i; A.442.z.4.i; A.443.z.4.i; A.444.z.4.i; A.445.z.4.i;
A.446.z.4.i; A.447.z.4.i; A.448.z.4.i; A.449.z.4.i; A.450.z.4.i; A.451.z.4.i;
A.452.z.4.i; A.453.z.4.i; A.454.z.4.i; A.455.z.4.i; A.456.z.4.i; A.457.z.4.i;
A.458.z.4.i; A.459.z.4.i; A.460.z.4.i; A.461.z.4.i; A.462.z.4.i; A.463.z.4.i;
A.464.z.4.i; A.465.z.4.i; A.466.z.4.i; A.467.z.4.i; A.468.z.4.i; A.469.z.4.i;
A.470.z.4.i; A.471.z.4.i; A.472.z.4.i; A.473.z.4.i; A.474.z.4.i; A.475.z.4.i;
A.476.z.4.i; A.477.z.4.i; A.478.z.4.i; A.479.z.4.i; A.480.z.4.i; A.481.z.4.i;
A.482.z.4.i; A.483.z.4.i; A.4$4.z.4.i; A.485.z.4.i; A.486.z.4.i; A.487.z.4.i;
A.488.z.4.i; A.489.z.4.i; A.490.z.4.i; A.491.z.4.i; A.492.z.4.i; A.493.z.4.i;
A.494.z.4.i; A.495.z.4.i; A.496.z.4.i; A.497.z.4.i; A.498.z.4.i; A.499.z.4.i;
A.500.z.4.i; A.501.z.4.i; A.502.z.4.i; A.503.z.4.i; A.504.z.4.i; A.505.z.4.i;
A.506.z.4.i; A.507.z.4.i; A.508.z.4.i; A.509.z.4.i; A.510.z.4.i; A.511.z.4.i;
A.512.z.4.i; A.512.z.4.i; A.513.z.4.i; A.514.z.4.i; A.515.z.4.i; A.516.z.4.i;
A.517.z.4.i; A.518.z.4.i; A.519.z.4.i; A.520.z.4.i; A.521.z.4.i; A.522.z.4.i;
A.523.z.4.i; A.524.z.4.i; A.525.z.4.i; A.526.z.4.i; A.527.z.4.i; A.528.z.4.i;
A.529.z.4.i; A.530.z.4.i; A.531.z.4.i; A.532.z.4.i; A.533.z.4.i; A.534.z.4.i;
A.535.z.4.i; A.536.z.4.i; A.537.z.4.i; A.538.z.4.i; A.539.z.4.i; A.540.z.4.i;
A.541.z.4.i; A.542.z.4.i; A.543.z.4.i; A.544.z.4.i; A.545.z.4.i; A.546.z.4.i;
A.547.z.4.i; A.548.z.4.i; A.549.z.4.i; A.550.z.4.i; A.551.z.4.i; A.552.z.4.i;
A.553.z.4.i; A.554.z.4.i; A.555.z.4.i; A.556.z.4.i; A.557.z.4.i; A.558.z.4.i;
A.559.z.4.i; A.560.z.4.i; A.561.z.4.i; A.562.z.4.i; A.563.z.4.i; A.564.z.4.i;
A.565.z.4.i; A.566.z.4.i; A.567.z.4.i; A.568.z.4.i; A.569.z.4.i; A.570.z.4.i;
A.571.z.4.i; A.572.z.4.i; A.573.z.4.i; A.574.z.4.i; A.575.z.4.i; A.576.z.4.i;
A.577.z.4.i; A.578.z.4.i; A.579.z.4.i; A.580.z.4.i; A.581.z.4.i; A.582.z.4.i;
A.583.z.4.i; A.584.z.4.i; A.585.z.4.i; A.586.z.4.i; A.587.z.4.i; A.588.z.4.i;
A.589.z.4.i; A.590.z.4.i; A.591.z.4.i; A.592.z.4.i; A.593.z.4.i; A.594.z.4.i;
A.595.z.4.i; A.596.z.4.i; A.597.z.4.i; A.598.z.4.i; A.599.z.4.i; A.600.z.4.i;
A.601.z.4.i; A.602.z.4.i; A.603.z.4.i; A.604.z.4.i; A.605.z.4.i; A.606.z.4.i;
A.607.z.4.i; A.608.z.4.i; A.609.z.4.i; A.610.z.4.i; A.611.z.4.i; A.612.z.4.i;

A.613.z,4.i; A.614.z.4.i; A.615.z.4.i; A.616.z.4.i; A.617.z.4.i; A.618.z.4.i;
A.619.z.4.i; A.620.z.4.i; A.621.z.4.i; A.622.z.4.i; A.623.z.4.i; A.624.z.4.i;
A.625.z.4.i; A.626.z.4.i; A.627.z.4.i; A.628.z.4.i; A.629.z.4.i; A.630.z.4.i;
A.631.z.4.i; A.632.z.4.i; A.633.z.4.i; A.634.z.4.i; A.635.z.4.i; A.636.z.4.i;
A.637.z.4.i; A.638.z.4.i; A.639.z.4.i; A.640.z.4.i; A.641.z.4.i; A.642.z.4.i;
A.643.z.4.i; A.644.z.4.i; A.645.z.4.i; A.646.z.4.i; A.647.z.4.i; A.648.z.4.i;
A.649.z.4.i; A.650.z.4.i; A.651.z.4.i; A.652.z.4.i; A.653.z.4.i; A.654.z.4.i;
A.655.z.4.i; A.656.z.4.i; A.657.z.4.i; A.658.z.4.i; A.659.z.4.i; A.660.z.4.i;
A.2.z.ll.i;
A.3.z.ll.i; A.4.z.11.i; A.S.z.ll.i; A.6.z.ll.i; A.7.z.ll.i; A.9.z.11.i;
A.lO.z.ll.i;
A.l5.z.11.i; A.100.z.11.i; A.lOl.z.ll.i; A.102.z.ll.i; A.103.z.ll.i;
A.104.z.ll.i;
A.105.z.11.i; A.106.z.ll.i; A.107.z.ll.i; A.lOB.z.ll.i; A.109.z.11.i;
A.110.z.11.i;
A.lll.z.ll.i; A.112.z.11.i; A.113.z.11.i; A.114.z.ll.i; A.115.z.11.i;
A.116.z.11.i;
A.117.z.ll.i; A.118.z.ll.i; A.119.z.Il.i; A.120.z.Il.i; A.121.z.ll.i;
A.122.z.ll.i;
A.123.z.ll.i; A.124.z.ll.i; A.125.z.ll.i; A.126.z.ll.i; A.I27.z.ll.i;
A.128.z.11.i;
A.129.z.11.i; A.130.z.11.i; A.131.z.11.i; A.132.z.11.i; A.133.z.ll.i;
A.134.z.ll.i;
A.135.z.11.i; A.136.z.ll.i; A.137.z.ll.i; A.138.z.ll.i; A.139.z.ll.i;
A.140.z.11.i;
A.141.z.ll.i; A.142.z.ll.i; A.143.z.ll.i; A.144.z.11.i; A.145.z.ll.i;
A.146.z.11.i;
A.147.z.ll.i; A.148.z.ll.i; A.149.z.ll.i; A.150.z.ll.i; A.151.z.ll.i;
A.152.z.ll.i;
A.153.z.ll.i; A.154.z.11.i; A.155.z.ll.i; A.156.z.ll.i; A.157.z.ll.i;
A.158.z.11.i;
A.159.z.ll.i; A.160.z.ll.i; A.161.z.ll.i; A.162.z.11.i; A.163.z.ll.i;
A.164.z.11.i;
A.165.z.ll.i; A.166.z.ll.i; A.167.z.lLi; A.168.z.ll.i; A.169.z.11.i;
A.170.z.ll.i;
A.171.z.ll.i; A.172.z.11.i; A.173.z.ll.i; A.174.z.11.i; A.175.z.ll.i;
A.176.z.ll.i;
A.177.z.11.i; A.178.z.ll.i; A.179.z.11.i; A.180.z.11.i; A.181.z.ll.i;
A.182.z.11.i;
A.183.z.ll.i; A.184.z.ll.i; A.185.z.11.i; A.186.z.11.i; A.187.z.ll.i;
A.188.z.ll.i;
A.189.z.ll.i; A.190.z.ll.i; A.191.z.ll.i; A.192.z.11.i; A.193.z.ll.i;
A.194.z.11.i;
A.195.z.ll.i; A.196.z.11.i; A.197.z.ll.i; A.198.z.11.i; A.199.z.ll.i;
A.200.z.11.i;
A.201.z.ll.i; A.202.z.11.i; A.203.z.ll.i; A.204.z.11.i; A.205.z.ll.i;
A.206.z.ll.i;
A.207.z.ll.i; A.208.z.ll.i; A.209.z.ll.i; A.210.z.11.i; A.211.z.11.i;
A.212.z.ll.i;
A.213.z.ll.i; A.214.z.ll.i; A.215.z.ll.i; A.216.z.ll.i; A.217.z.ll.i;
A.218.z.11.i;
A.219.z.ll.i; A.220.z.ll.i; A.221.z.ll.i; A.222.z.ll.i; A.223.z.11.i;
A.224.z.ll.i;
A.225.z.11.i; A.226.z.11.i; A.227.z.11.i; A.228.z.ll.i; A.229.z.11.i;
A.230.z.ll.i;
A.231.z.ll.i; A.232.z.11.i; A.233.z.ll.i; A.234.z.ll.i; A.235.z.ll.i;
A.236.z.ll.i;
A.237.z.ll.i; A.238.z.ll.i; A.239.z.ll.i; A.240.z.ll.i; A.241.z.ll.i;
A.242.z.11.i;
A.243.z.ll.i; A.244.z.ll.i; A.245.z.ll.i; A.246.z.Il.i; A.247.z.ll.i;
A.248.z.ll.i;
A.249.z.11.i; A.250.z.ll.i; A.251.z.ll.i; A.252.z.Il.i; A.253.z.ll.i;
A.254.z.ll.i;
A.255.z.ll.i; A.256.z.11.i; A.257.z.ll.i; A.258.z.11.i; A.259.z.ll.i;
A.260.z.11.i;
A.261.z.ll.i; A.262.z.ll.i; A.263.z.ll.i; A.264.z.ll.i; A.265.z.11.i;
A.266.z.ll.i;
A.267.z.11.i; A.268.z.11.i; A.269.z.11.i; A.270.z.ll.i; A.271.z.11.i;
A.272.z.11.i;
A.273.z.ll.i; A.274.z.ll.i; A.275.z.ll.i; A.276.z.11.i; A.277.z.ll.i;
A.278.z.ll.i;
A.279.z.11.i; A.280.z.ll.i; A.281.z.ll.i; A.282.z.11.i; A.283.z.11.i;
A.284.z.ll.i;
A.285.z.11.i; A.286.z.ll.i; A.287.z.11.i; A.288.z.11.i; A.289.z.11.i;
A.290.z.ll.i;
A.291.z.ll.i; A.292.z.ll.i; A.293.z.ll.i; A.294.z.11.i; A.295.z.ll.i;
A.296.z.ll.i;
A.297.z.ll.i; A.298.z.ll.i; A.299.z.ll.i; A.300.z.11.i; A.301.z.11.i;
A.302.z.ll.i;
A.303.z.ll.i; A.304.z.11.i; A.305.z.11.i; A.306.z.ll.i; A.307.z.11.i;
A.308.z.11.i;
A.309.z.ll.i; A.310.z.ll.i; A.311.z.11.i; A.312.z.ll.i; A.313.z.11.i;
A.314.z.11.i;
A.315.z.ll.i; A.316.z.11.i; A.317.z.ll.i; A.318.z.11.i; A.319.z.ll.i;
A.320.z.11.i;
A.321.z.11.i; A.323.z.11.i; A.324.z.ll.i; A.325.z.ll.i; A.326.z.ll.i;
A.327.z.ll.i;

A.328.z.ll.i; A.329.z.ll.i; A.330.z.11.i; A.331.z.ll.i; A.332.z.11.i;
A.333.z.ll.i;
A.334.z.ll.i; A.335.z.11.i; A.336.z.ll.i; A.337.z,ll.i; A.338.z.ll.i;
A.339.z.ll.i;
A.340.z.ll.i; A.341.z.ll.i; A.342.z.ll.i; A.343.z.ll.i; A.344.z.11.i;
A.345.z.ll.i;
A.346.z.ll.i; A.347.z.ll.i; A.348.z.ll.i; A.349.z.ll.i; A.350.z.ll.i;
A.351.z.ll.i;
A.352.z.ll.i; A.353.z.ll.i; A.354.z.ll.i; A.355.z.11.i; A.356.z.ll.i;
A.357.z.ll.i;
A.358.z.ll.i; A.359.z.11.i; A.360.z.11.i; A.361.z.ll.i; A.362.z.11.i;
A.363.z.ll.i;
A.364.z.ll.i; A.365.z.ll.i; A.366.z.11.i; A.367.z.ll.i; A.368.z.ll.i;
A.369.z.11.i;
A.370.z.ll.i; A.371.z.ll.i; A.372.z.ll.i; A.373.z.ll.i; A.374.z.ll.i;
A.375.z.ll.i;
A.376.z.ll.i; A.377.z.ll.i; A.378.z.11.i; A.379.z.ll.i; A.380.z.ll.i;
A.381.z.ll.i;
A.382.z.ll.i; A.383.z.ll.i; A.384.z.11.i; A.385.z.ll.i; A.386.z.11.i;
A.387.z.ll.i;
A.388.z.ll.i; A.389.z.ll.i; A.390.z.ll.i; A.391.z.11.i; A.392.z.ll.i;
A.393.z.ll.i;
A.394.z.ll.i; A.395.z.ll.i; A.396.z.ll.i; A.397.z.ll.i; A.398.z.ll.i;
A.399.z.ll.i;
A.400.z.ll.i; A.401.z.ll.i; A.402.z.ll.i; A.403.z.ll.i; A.404.z.ll.i;
A.405.z.ll.i;
A.406.z.11.i; A.407.z.ll.i; A.408.z.ll.i; A.409.z.11.i; A.410.z.ll.i;
A.411.z.ll.i;
A.412.z.11.i; A.413.z.ll.i; A.414.z.11.i; A.415.z.ll.i; A.416.z.11.i;
A.417.z.ll.i;
A.418.z.ll.i; A.419.z.ll.i; A.420.z.ll.i; A.421.z.ll.i; A.422.z.ll.i;
A.423.z.ll.i;
A.424.z.ll.i; A.425.z.ll.i; A.426.z.11.i; A.427.z.ll.i; A.428.z.ll.i;
A.429.z.ll.i;
A.430.z.ll.i; A.431.z.ll:i; A.432.z.ll.i; A.433.z.ll.i; A.434.z.11.i;
A.435.z.11.i;
A.436.z.Il.i; A.437.z.11.i; A.438.z.ll.i; A.439.z.ll.i; A.440.z.ll.i;
A.441.z.ll.i;
A.442.z.ll.i; A.443.z.ll.i; A.444.z.11.i; A.445.z.11.i; A.446.z.ll.i;
A.447.z.ll.i;
A.448.z.ll.i; A.449.z.ll.i; A.450.z.ll.i; A.451.z.ll.i; A.452.z.ll.i;
A.453.z.ll.i;
A.454.z.ll.i; A.455.z.11.i; A.456.z.11.i; A.457.z.ll.i; A.458.z.11.i;
A.459.z.ll.i;
A.460.z.ll.i; A.461.z.11.i; A.462.z.ll.i; A.463.z.ll.i; A.464.z.ll.i;
A.465.z.11.i;
A.466.z.ll.i; A.467.z.ll.i; A.468.z.11.i; A.469.z.ll.i; A.470.z.ll.i;
A.471.z.ll.i;
A.472.z.li.i; A.473.z.11.i; A.474.z.11.i; A.475.z.11.i; A.476.z.11.i;
A.477.z.ll.i;
A.478.z.ll.i; A.479.z.ll.i; A.480,z.ll.i; A.481.z.ll.i; A.482.z.11.i;
A.483.z.ll.i;
A.484.z.ll.i; A.485.z.ll.i; A.486.z.ll.i; A.487.z.ll.i; A.488.z.11.i;
A.489.z.ll.i;
A.490.z.11.i; A.491.z.ll.i; A.492.z.ll.i; A.493.z.ll.i; A.494.z.ll.i;
A.495.z.ll.i;
A.496.z.ll.i; A.497.z.ll.i; A.498.z.11.i; A.499.z.ll.i; A.500.z.11.i;
A.501.z.ll.i;
A.502.z.ll.i; A.503.z.11.i; A.504.z.11.i; A.505.z.ll.i; A.506.z.ll.i;
A.507.z.11.i;
A.508.z.ll.i; A.509.z.ll.i; A.510.z.11.i; A.511.z.11.i; A.512.z.ll.i;
A.512.z.ll.i;
A.513.z.ll.i; A.514.z.ll.i; A.515.z.11.i; A.516.z.ll.i; A.517.z.11.i;
A.518.z.ll.i;
A.519.z.11.i; A.520.z.ll.i; A.521.z.11.i; A.522.z.11.i; A.523.z.ll.i;
A.524.z.ll.i;
A.525.z.ll.i; A.526.z.11.i; A.527.z.ll.i; A.528.z.ll.i; A.529.z.11.i;
A.530.z.ll.i;
A.531.z.ll.i; A.532.z.ll.i; A.533.z.ll.i; A.534.z.11.i; A.535.z.ll.i;
A.536.z.ll.i;
A.537.z.ll.i; A.538.z.11.i; A.539.z.ll.i; A.540.z.11.i; A.541.z.ll.i;
A.542.z.ll.i;
A.543.z.11.i; A.544.z.11.i; A.545.z.ll.i; A.546.z.ll.i; A.547.z.11.i;
A.548.z.ll.i;
A.549.z.ll.i; A.550.z.11.i; A.551.z.11.i; A.552.z.11.i; A.553.z.11.i;
A.554.z.ll.i;
A.555.z.11.i; A.556.z.11.i; A.557.z.ll.i; A.558.z.11.i; A.559.z.11.i;
A.560.z.Il.i;
A.561.z.11.i; A.562.z.ll.i; A.563.z.11.i; A.564.z.11.i; A.565.z.11.i;
A.566.z.ll.i;
A.567.z.ll.i; A.568.z.11.i; A.569.z.11.i; A.570.z.11.i; A.571.z.ll.i;
A.572.z.ll.i;
A.573.z,ll.i; A.574.z.ll.i; A.575.z.ll.i; A.576.z.ll.i; A.577.z.11.i;
A.578.z.11.i;
A.579.z.11.i; A.580.z.11.i; A.581.z.11.i; A.582.z.11.i; A.583.z.11.i;
A.584.z.11.i;
A.585.z.ll.i; A.586.z.ll.i; A.587.z.ll.i; A.588.z.11.i; A.589.z.ll.i;
A.590.z.11.i;
A.591.z.ll.i; A.592.z.11.i; A.593.z.ll.i; A.594.z.ll.i; A.595.z.11.i;
A.596.z.ll.i;
A.597.z.11.i; A.598.z.ll.i; A.599.z.11.i; A.600.z.ll.i; A.601.z.ll.i;
A.602.z.ll.i;
A.603.z.ll.i; A.604.z.ll.i; A.605.z.ll.i; A.606.z.ll.i; A.607.z.ll.i;
A.608.z.11.i;

A.609.z.11.i; A.610.z.ll.i; A.611.z.11.i; A.612.z.ll.i; A.613.z.11.i;
A.6l~.z.ll.i;
A.615.z.ll.i; A.616.z.ll.i; A.617.z.ll.i; A.618.z.ll.i; A.619.z.ll.i;
A.620.z.ll.i;
A.621.z.ll.i; A.622.z.ll.i; A.623.z.ll.i; A.624.z.ll.i; A.625.z.ll.i;
A.626.z.ll.i;
A.627.z.ll.i; A.628.z.11.i; A.629.z.11.i; A.630.z.ll.i; A.631.z.ll.i;
A.632.z.ll.i;
A.633.z.ll.i; A.634.z.11.i; A.635.z.ll.i; A.636.z.11.i; A.637.z.ll.i;
A.638.z.ll.i;
A.639.z.11.i; A.640.z.ll.i; A.641.z.ll.i; A.642.z.11.i; A.643.z.ll.i;
A.644.z.11.i;
A.645.z.ll.i; A.646.z.Il.i; A.647.z.11.i; A.648.z.ll.i; A.649.z.ll.i;
A.650.z.ll.i;
A.651.z.ll.i; A.652.z.ll.i; A.653.z.11.i; A.654.z.ll.i; A.655.z.ll.i;
A.656.z.11.i;
A.657.z.ll.i; A.658.z.ll.i; A.659.z.ll.i; A.660.z.ll.i; A.2.A.4.i; A.3.A.4.i;
A.4.A.4.i; A.5.A.4.i; A.6.A.4.i; A.7.A.4.i; A.9.A.4.i; A.l0.A.4.i; A.15.A.4.i;
A.100.A.4.i; A.lOl.A.4.i; A.102.A.4.i; A.103.A.4.i; A.104.A.4.i; A.205.A.4.i;
A.106.A.4.i; A.107.A.4.i; A.108.A.4.i; A.109.A.4.i; A.110.A.4.i; A.111.A.4.i;
A.112.A.4.i; A.113.A.4.i; A.114.A.4.i; A.115.A.4.i; A.116.A.4.i; A.117.A.4.i;
A.118.A.4.i; A.119.A.4.i; A.120.A.4.i; A.121.A.4.i; A.122.A.4.i; A.123.A.4.i;
A.124.A.4.i; A.125.A.4.i; A.126.A.4.i; A.127.A.4.i; A.128.A.4.i; A.129.A.4.i;
A.130.A.4.i; A.131.A.4.i; A.132.A.4.i; A.133.A.4.i; A.134.A.4.i; A.135.A.4.i;
A.136.A.4.i; A.137.A.4.i; A.138.A.4.i; A.139.A.4.i; A.140.A.4.i; A.141.A.4.i;
A.142.A.4.i; A.143.A.4.i; A.144.A.4.i; A.145.A.4.i; A.146.A.4.i; A.147.A.4.i;
A.148.A.4.i; A.149.A.4.i; A.150.A.4.i; A.151.A.4.i; A.152.A.4.i; A.153.A.4.i;
A.154.A.4.i; A.155.A.4.i; A.156.A.4.i; A.157.A.4.i; A.158.A.4.i; A.159.A.4.i;
A.160.A.4.i; A.161.A.4.i; A.162.A.4.i; A.163.A.4.i; A.164.A.4.i; A.165.A.4.i;
A.166.A.4.i; A.167.A.4.i; A.168.A.4.i; A.169.A.4.i; A.I70.A.4.i; A.171.A.4.i;
A.172.A.4.i; A.173.A.4.i; A.174.A.4.i; A.175.A.4.i; A.176.A.4.i; A.177.A.4.i;
A.178.A.4.i; A.179.A.4.i; A.180.A.4.i; A.181.A.4.i; A.182.A.4.i; A.183.A.4.i;
A.184.A.4.i; A.185.A.4.i; A.186.A.4.i; A.187.A.4.i; A.188.A.4.i; A.189.A.4.i;
A.190.A.4.i; A.191.A.4.i; A.192.A.4.i; A.193.A.4.i; A.194.A.4.i; A.195.A.4.i;
A.196.A.4.i; A.197.A.4.i; A.198.A.4.i; A.199.A.4.i; A.200.A.4.i; A.201.A.4.i;
A.202.A.4.i; A.203.A.4.i; A.204.A.4.i; A.205.A.4.i; A.206.A.4.i; A.207.A.4.i;
A.208.A.4.i; A.209.A.4.i; A.210.A.4.i; A.211.A.4.i; A.212.A.4.i; A.213.A.4.i;
A.214.A.4.i; A.215.A.4.i; A.216.A.4.i; A.217.A.4.i; A.218.A.4.i; A.219.A.4.i;
A.220.A.4.i; A.221.A.4.i; A.222.A.4.i; A.223.A.4.i; A.224.A.4.i; A.225.A.4.i;
A.226.A.4.i; A.227.A.4.i; A.228.A.4.i; A.229.A.4.i; A.230.A.4.i; A.231.A.4.i;
A.232.A.4.i; A.233.A.4.i; A.234.A.4.i; A.235.A.4.i; A.236.A.4.i; A.237.A.4.i;
A.238.A.4.i; A.239.A.4.i; A.240.A.4.i; A.241.A.4.i; A.242.A.4.i; A.243.A.4.i;
A.244.A.4.i; A.245.A.4.i; A.246.A.4.i; A.247.A.4.i; A.248.A.4.i; A.249.A.4.i;
A.250.A.4.i; A.251.A.4.i; A.252.A.4.i; A.253.A.4.i; A.254.A.4.i; A.255.A.4.i;
A.256.A.4.i; A.257.A.4.i; A.258.A.4.i; A.259.A.4.i; A.260.A.4.i; A.261.A.4.i;
A.262.A.4.i; A.263.A.4.i; A.264.A.4.i; A.265.A.4.i; A.266.A.4.i; A.267.A.4.i;
A.268.A.4.i; A.269.A.4.i; A.270.A.4.i; A.271.A.4.i; A.272.A.4.i; A.273.A.4.i;
A.274.A.4.i; A.275.A.4.i; A.276.A.4.i; A.277.A.4.i; A.278.A.4.i; A.279.A.4.i;
A.280.A.4.i; A.281.A.4.i; A.282.A.4.i; A.283.A.4.i; A.284.A.4.i; A.285.A.4.i;
A.286.A.4.i; A.287.A.4.i; A.288.A.4.i; A.289.A.4.i; A.290.A.4.i; A.291.A.4.i;
A.292.A.4.i; A.293.A.4.i; A.294.A.4.i; A.295.A.4.i; A.296.A.4.i; A.297.A.4.i;
A.298.A.4.i; A.299.A.4.i; A.300.A.4.i; A.301.A.4.i; A.302.A.4.i; A.303.A.4.i;
A.304.A.4.i; A.305.A.4.i; A.306.A.4.i; A.307.A.4.i; A.308.A.4.i; A.309.A.4.i;
A.310.A.4.i; A.311.A.4.i; A.312.A.4.i; A.313.A.4.i; A.314.A.4.i; A.315.A.4.i;
A.316.A.4.i; A.317.A.4.i; A.318.A.4.i; A.319.A.4.i; A.320.A.4.i; A.321.A.4.i;

A.323.A.4.i; A.324.A.4.i; A.325.A.4.i; A.326.A.4.i; A.327.A.4.i; A.328.A.4.i;
A.329.A.4.i; A.330.A.4.i; A.331.A.4.i; A.332.A.4.i; A.333.A.4.i; A.334.A.4.i;
A.335.A.4.i; A.336.A.4.i; A.337.A.4.i; A.338.A.4.i; A.339.A.4.i; A.340.A.4.i;
A.341.A.4.i; A.342.A.4.i; A.343.A.4.i; A.344.A.4.i; A.345.A.4.i; A.346.A.4.i;
A.347.A.4.i; A.348.A.4.i; A.349.A.4.i; A.350.A.4.i; A.351.A.4.i; A.352.A.4.i;
A.353.A.4.i; A.354.A.4.i; A.355.A.4.i; A.356.A.4.i; A.357.A.4.i; A.358.A.4.i;
A.359.A.4.i; A.360.A.4.i; A.361.A.4.i; A.362.A.4.i; A.363.A.4.i; A.364.A.4.i;
A.365.A.4.i; A.366.A.4.i; A.367.A.4.i; A.368.A.4.i; A.369.A.4.i; A.370.A.4.i;
A.371.A.4.i; A.372.A.4.i; A.373.A.4.i; A.374.A.4.i; A.375.A.4.i; A.376.A.4.i;
A.377.A.4.i; A.378.A.4.i; A.379.A.4.i; A.380.A.4.i; A.381.A.4.i; A.382.A.4.i;
A.383.A.4.i; A.384.A.4.i; A.385.A.4.i; A.386.A.4.i; A.387.A.4.i; A.388.A.4.i;
A.389.A.4.i; A.390.A.4.i; A.391.A.4.i; A.392.A.4.i; A.393.A.4.i; A.394.A.4.i;
A.395.A.4.i; A.396.A.4.i; A.397.A.4.i; A.398.A.4.i; A.399.A.4.i; A.400.A.4.i;
A.401.A.4.i; A.402.A.4.i; A.403.A.4.i; A.404.A.4.i; A.405.A.4.i; A.406.A.4.i;
A.407.A.4.i; A.408.A.4.i; A.409.A.4.i; A.410.A.4.i; A.411.A.4.i; A.412.A.4.i;
A.413.A.4.i; A.414.A.4.i; A.415.A.4.i; A.416.A.4.i; A.417.A.4.i; A.418.A.4.i;
A.419.A.4.i; A.420.A.4.i; A.421.A.4.i; A.422.A.4.i; A.423.A.4.i; A.424.A.4.i;
A.425.A.4.i; A.426.A.4.i; A.427.A.4.i; A.428.A.4.i; A.429.A.4.i; A.430.A.4.i;
A.431.A.4.i; A.432.A.4.i; A.433.A.4.i; A.434.A.4.i; A.435.A.4.i; A.436.A.4.i;
A.437.A.4.i; A.438.A.4.i; A.439.A.4.i; A.440.A.4.i; A.441.A.4.i; A.442.A.4.i;
A.443.A.4.i; A.444.A.4.i; A.445.A.4.i; A.446.A.4.i; A.447.A.4.i; A.448.A.4.i;
A.449.A.4.i; A.450.A.4.i; A.451.A.4.i; A.452.A.4.i; A.453.A.4.i; A.454.A.4.i;
A.455.A.4.i; A.456.A.4.i; A.457.A.4.i; A.458.A.4.i; A.459.A.4.i; A.460.A.4.i;
A.461.A.4.i; A.462.A.4.i; A.463.A.4.i; A.464.A.4.i; A.465.A.4.i; A.466.A.4.i;
A.467.A.4.i; A.468.A.4.i; A.469.A.4.i; A.470.A.4.i; A.471.A.4.i; A.472.A.4.i;
A.473.A.4.i; A.474.A.4.i; A.475.A.4.i; A.476.A.4.i; A.477.A.4.i; A.478.A.4.i;
A.479.A.4.i; A.480.A.4.i; A.481.A.4.i; A.482.A.4.i; A.483.A.4.i; A.484.A.4.i;
A.485.A.4.i; A.486.A.4.i; A.487.A.4.i; A.488.A.4.i; A.489.A.4.i; A.490.A.4.i;
A.491.A.4.i; A.492.A.4.i; A.493.A.4.i; A.494.A.4.i; A.495.A.4.i; A.496.A.4.i;
A.497.A.4.i; A.498.A.4.i; A.499.A.4.i; A.500.A.4.i; A.501.A.4.i; A.502.A.4.i;
A.503.A.4.i; A.504.A.4.i; A.505.A.4.i; A.506.A.4.i; A.507.A.4.i; A.508.A.4.i;
A.509.A.4.i; A.510.A.4.i; A.511.A.4.i; A.512.A.4.i; A.512.A.4.i; A.513.A.4.i;
A.514.A.4.i; A.515.A.4.i; A.516.A.4.i; A.517.A.4.i; A.518.A.4.i; A.519.A.4.i;
A.520.A.4.i; A.521.A.4.i; A.522.A.4.i; A.523.A.4.i; A.524.A.4.i; A.525.A.4.i;
A.526.A.4.i; A.527.A.4.i; A.528.A.4.i; A.529.A.4.i; A.530.A.4.i; A.531.A.4.i;
A.532.A.4.i; A.533.A.4.i; A.534.A.4.i; A.535.A.4.i; A.536.A.4.i; A.537.A.4.i;
A.538.A.4.i; A.539.A.4.i; A.540.A.4.i; A.541.A.4.i; A.542.A.4.i; A.543.A.4.i;
A.544.A.4.i; A.545.A.4.i; A.546.A.4.i; A.547.A.4.i; A.548.A.4.i; A.549.A.4.i;
A.550.A.4.i; A.551.A.4.i; A.552.A.4.i; A.553.A.4.i; A.554.A.4.i; A.555.A.4.i;
A.556.A.4.i; A.557.A.4.i; A.558.A.4.i; A.559.A.4.i; A.560.A.4.i; A.561.A.4.i;
A.562.A.4.i; A.563.A.4.i; A.564.A.4.i; A.565.A.4.i; A.566.A.4.i; A.567.A.4.i;
A.568.A.4.i; A.569.A.4.i; A.570.A.4.i; A.571.A.4.i; A.572.A.4.i; A.573.A.4.i;
A.574.A.4.i; A.575.A.4.i; A.576.A.4.i; A.577.A.4.i; A.578.A.4.i; A.579.A.4.i;
A.580.A.4.i; A.581.A.4.i; A.582.A.4.i; A.583.A.4.i; A.584.A.4.i; A.585.A.4.i;
A.586.A.4.i; A.587.A.4.i; A.588.A.4.i; A.589.A.4.i; A.590.A.4.i; A.591.A.4.i;
A.592.A.4.i; A.593.A.4.i; A.594.A.4.i; A.595.A.4.i; A.596.A.4.i; A.597.A.4.i;
A.598.A.4.i; A.599.A.4.i; A.600.A.4.i; A.601.A.4.i; A.602.A.4.i; A.603.A.4.i;

A.604.A.4.i; A.605.A.4.i; A.606.A.4.i; A.607.A.4.i; A.608.A.4.i; A.609.A.4.i;
A.610.A.4.i; A.611.A.4.i; A.612.A.4.i; A.613.A.4.i; A.614.A.4.i; A.615.A.4.i;
A.616.A.4.i; A.617.A.4.i; A.618.A.4.i; A.6I9.A.4.i; A.620.A.4.i; A.621.A.4.i;
A.62-2.A.4.i; A.623.A.4.i; A.624.A.4.i; A.625.A.4.i; A.626.A.4.i; A.627.A.4.i;
A.628.A.4.i; A.629.A.4.i; A.630.A.4.i; A.631.A.4.i; A.632.A.4.i; A.633.A.4.i;
A.634.A.4.i; A.635.A.4.i; A.636.A.4.i; A.637.A.4.i; A.638.A.4.i; A.639.A.4.i;
A.640.A.4.i; A.641.A.4.i; A.642.A.4.i; A.643.A.4.i; A.644.A.4.i; A.645.A.4.i;
A.646.A.4.i; A.647.A.4.i; A.648.A.4.i; A.649.A.4.i; A.650.A.4.i; A.651.A.4.i;
A.652.A.4.i; A.653.A.4.i; A.654.A.4.i; A.655.A.4.i; A.656.A.4.i; A.657.A.4.i;
A.658.A.4.i; A.659.A.4.i; A.660.A.4.i; A.2.A.11.i; A.3.A.ll.i; A.4.A.ll.i;
A.S.A.ll.i; A.6.A.11.i; A.7.A.ll.i; A.9.A.ll.i; A.10.A.ll.i; A.15.A.ll.i;
A.100.A.ll.i; A.101.A.ll.i; A.102.A.ll.i; A.103.A.ll.i; A.104.A.ll.i;
A.105.A.11.i; A.106.A.11.i; A.107.A.ll.i; A.108.A.ll.i; A.109.A.ll.i;
A.110.A.11.i; A.111.A.11.i; A.112.A.11.i; A.113.A.ll.i; A.114.A.ll.i;
A.115.A.ll.i; A.116.A.ll.i; A.117.A.11.i; A.118.A.ll.i; A.119.A.11.i;
A.120.A.ll.i; A.121.A.ll.i; A.122.A.ll.i; A.123.A.ll.i; A.124.A.11.i;
A.125.A.ll.i; A.126.A.11.i; A.127.A.11.i; A.128.A.ll.i; A.129.A.ll.i;
A.130.A.ll.i; A.131.A.11.i; A.132.A.ll.i; A.133.A.11.i; A.134.A.11.i;
A.135.A.11.i; A.136.A.11.i; A.137.A.ll.i; A.138.A.ll.i; 'A.139.A.ll.i;
A.140.A.ll.i; A.141.A.ll.i; A.142.A.ll.i; A.143.A.11.i; A.144.A.11.i;
A.145.A.ll.i; A.146.A.ll.i; A.147.A.11.i; A.148.A.11.i; A.149.A.11.i;
A.150.A.11.i; A.151.A.ll.i; A.152.A.11.i; A.153.A.ll.i; A.154.A.ll.i;
A.155.A.ll.i; A.156.A.ll.i; A.157.A.11.i; A.158.A.11.i; A.159.A.ll.i;
A.160.A.ll.i; A.161.A.ll.i; A.162.A.ll.i; A.163.A.ll.i; A.164.A.ll.i;
A.165.A.ll.i; A.166.A.11.i; A.167.A.ll.i; A.168.A.ll.i; A.169.A.ll.i;
A.170.A,11.i; A.171.A.11.i; A.172.A.11.i; A.173.A.11.i; A.174.A.11.i;
A.175.A.ll.i; A.176.A.11.i; A.177.A.11.i; A.178.A.ll.i; A.179.A.ll.i;
A.180.A.11.i; A.181.A.ll.i; A.182.A.ll.i; A.1$3.A.ll.i; A.184.A.ll.i;
A.185.A.ll.i; A.186.A.11.i; A.187.A.11.i; A.188.A.11.i; A.189.A.11.i;
A.190.A.ll.i; A.191.A.ll.i; A.192.A.ll.i; A.193.A.11.i; A.194.A.ll.i;
A.195.A.ll.i; A.196.A.ll.i; A.197.A.11.i; A.198.A.11.i; A.199.A.ll.i;
A.200.A.11.i; A.201.A.11.i; A.202.A.11.i; A.203.A.ll.i; A.204.A.ll.i;
A.205.A.11.i; A.206.A.11.i; A.207.A.ll.i; A.208.A.11.i; A.209.A.ll.i;
A.210.A.11.i; A.211.A.ll.i; A.212.A.11.i; A.213.A.11.i; A.214.A.ll.i;
A.215.A.11.i; A.216.A.11.i; A.217.A.ll.i; A.218.A.ll.i; A.219.A.ll.i;
A.220.A.ll.i; A.221.A.ll.i; A.222.A.ll.i; A.223.A.11.i; A.224.A.ll.i;
A.225.A.ll.i; A.226.A.11.i; A.227.A.ll.i; A.228.A.11.i; A.229.A.Il.i;
A.230.A.11.i; A.231.A.11.i; A.232.A.ll.i; A.233.A.ll.i; A.234.A.ll.i;
A.235.A.ll.i; A.236.A.ll.i; A.237.A.ll.i; A.238.A.ll.i; A.239.A.ll.i;
A.240.A.ll.i; A.241.A.ll.i; A.242.A.11.i; A.243.A.11.i; A.244.A.11.i;
A.245.A.ll.i; A.246.A.11.i; A.247.A.ll.i; A.248.A.11.i; A.249.A.ll.i;
A.250.A.11.i; A.251.A.ll.i; A.252.A.ll.i; A.253.A.11.i; A.254.A.ll.i;
A.255.A.11.i; A.25b.A.ll.i; A.257.A.11.i; A.258.A.11.i; A.259.A.ll.i;
A.260.A.ll.i; A.261.A.11.i; A.262.A.11.i; A.263.A.11.i; A.264.A.ll.i;
A.265.A.11.i; A.266.A.ll.i; A.267.A.ll.i; A.268.A.11.i; A.269.A.ll.i;
A.270.A.ll.i; A.271.A.ll.i; A.272.A.ll.i; A.273.A.ll.i; A.274.A.li.i;
A.275.A.11.i; A.276.A.ll.i; A.277.A.11.i; A.278.A.il.i; A.279.A.ll.i;

WO 99/14185 PC1'/US98/19355 A.280.A.11.i; A.281.A.ll.i; A.282.A.11.i; A.283.A.ll.i; A.284.A.ll.i;
A.285.A.11.i; A.286.A.ll.i; A.287.A.ll.i; A.288.A.lI.i; A.289.A.ll.i;
A.290.A.11.i; A.291.A.ll.i; A.292.A.ll.i; A.293.A.ll.i; A.294.A.li.i;
A.295.A.ll.i; A.296.A.ll.i; A.297.A.ll.i; A.298.A.ll.i; A.299.A.ll.i;
A.300.A.11.i; A.301.A.11.i; A.302.A.11.i; A.303.A.11.i; A.304.A.ll.i;
A.305.A.ll.i; A.306.A.ll.i; A.307.A.ll.i; A.308.A.11.i; A.309.A.ll.i;
A.310.A.11.i; A.311.A.1I.i; A.312.A.11.i; A.313.A.ll.i; A.314.A,ll.i;
A.315.A.ll.i; A.316.A.ll.i; A.317.A.ll.i; A.318.A.11.i; A.319.A.11.i;
A.320.A.11.i; A.321.A.11.i; A.323.A.11.i; A.324.A.11.i; A.325.A.ll.i;
A.326.A.11.i; A.327.A.ll.i; A.328.A.ll.i; A.329.A.11.i; A.330.A.11.i;
A.331.A.11.i; A.332.A.ll.i; A.333.A.ll.i; A.334.A.ll.i; A.335.A.ll.i;
A.336.A.11.i; A.337.A.li.i; A.338.A.ll.i; A.339.A.11.i; A.340.A.ll.i;
A.341.A.ll.i; A.342.A.ll.i; A.343.A.ll.i; A.344.A.ll.i; A.345.A.ll.i;
A.346.A.11.i; A.347.A.ll.i; A.348.A.11.i; A.349.A.ll.i; A.350.A.ll.i;
A.351.A.11.i; A.352.A.11.i; A.353.A.ll.i; A.354.A.ll.i; A.355.A.ll.i;
A.356.A.ll.i; A,357.A.11.i; A.358.A.11.i; A.359.A.11.i; A.360.A.11.i;
A.361.A.ll.i; A.362.A.ll.i; A.363.A.11.i; A.364.A.ll.i; A.365.A.11.i;
A.366.A.11.i; A.367.A.ll.i; A.368.A.ll.i; A.369.A.11.i; A.370.A.ll.i;
A.371.A.11.i; A.372.A.ll.i; A.373.A.11.i; A.374.A.ll.i; A.375.A.ll.i;
A.376.A.11.i; A.377.A.ll.i; A.378.A.ll.i; A.379.A.11.i; A.380.A.ll.i;
A.3$l.A.ll.i; A.382.A.ll.i; A.383.A.ll.i; A.384.A.ll.i; A.385.A.ll.i;
A.386.A.ll.i; A.387.A.ll.i; A.388.A.ll.i; A.389.A.11.i; A.390.A.ll.i;
A.391.A.ll.i; A.392.A.11.i; A.393.A.ll.i; A.394.A.ll.i; A.395.A.ll.i;
A.396.A.11.i; A.397.A.ll.i; A.398.A.ll.i; A.399.A.11.i; A.400.A.ll.i;
A.401.A.ll.i; A.402.A.11.i; A.403.A.ll.i; A.404.A.ll.i; A.405.A.ll.i;
A.406.A.ll.i; A.407.A.11.i; A.408.A.11.i; A.409.A.ll.i; A.410.A.ll.i;
A.411.A.ll.i; A.412.A.ll.i; A.413.A.ll.i; A.414.A.ll.i; A.415.A.11.i;
A.416.A.ll.i; A.417.A.11.i; A.418.A.ll.i; A.419.A.ll.i; A.420.A.11.i;
A.421.A.11.i; A.422.A.Il.i; A.423.A.ll.i; A.424.A.ll.i; A.425.A.11.i;
A.426.A.11.i; A.427.A.ll.i; A.428.A.ll.i; A.429.A.ll.i; A.430.A.ll.i;
A.431.A.ll.i; A.432.A.ll.i; A.433.A.ll.i; A.434.A.ll.i; A.435.A.ll.i;
A.436.A.11.i; A.437.A.ll.i; A.438.A.ll.i; A.439.A.11.i; A.440.A.ll.i;
A.441.A.ll.i; A.442.A.ll.i; A.443.A.11.i; A.444.A.11.i; A.445.A.ll.i;
A.446.A.ll.i; A.447.A.11.i; A.448.A.11.i; A.449.A.ll.i; A.450.A.ll.i;
A.451.A.11.i; A.452.A.ll.i; A.453.A.ll.i; A.454.A.ll.i; A.455.A.ll.i;
A.456.A.11.i; A.457.A.ll.i; A.458.A.11.i; A.459.A.11.i; A.460.A.ll.i;
A.461.A.ll.i; A.462.A.11.i; A.463.A.ll.i; A.4b4.A.ll.i; A.465.A.ll.i;
A.466.A.11.i; A.467.A.ll.i; A.468.A.ll.i; A.469.A.11.i; A.470.A.ll.i;
A.471.A.il.i; A.472.A.ll.i; A.473.A.ll.i; A.474.A.11.i; A.475.A.ll.i;
A.476.A.ll.i; A.477.A.11.i; A.478.A.ll.i; A.479.A.11.i; A.480.A.ll.i;
A.481.A.11.i; A.482.A.11.i; A.483.A.11.i; A.484.A.ll.i; A.485.A.11.i;
A.486.A.11.i; A.487.A.ll.i; A.488.A.11.i; A.489.A.11.i; A.490.A.11.i;
A.491.A.ll.i; A.492.A.ll.i; A.493.A.ll.i; A.494.A.ll.i; A.495.A.ll.i;
A.496.A.ll.i; A.497.A.11.i; A.498.A.ll.i; A.499.A.ll.i; A.500.A.ll.i;
A.501.A.11.i; A.502.A.11.i; A.503.A.ll.i; A.504.A.ll.i; A.505.A.11.i;
A.506.A.11.i; A.507.A.ll.i; A.508.A.ll.i; A.509.A.11.i; A.510.A.ll.i;
A.511.A.11.i; A.512.A.ll.i; A.512.A.ll.i; A.513.A.11.i; A.514.A.11.i;

A.515.A.11.i; A.516.A.11.i; A.517.A.11.i; A.518.A.11.i; A.519.A.11.i;
A.520.A.ll.i; A.521.A.11.i; A.522.A.ll.i; A.523.A.11.i; A.524.A.ll.i;
A.525.A.11.i; A.526.A.ll.i; A.527.A.ll.i; A.528.A.11.i; A.529.A.ll.i;
A.530.A.ll.i; A.531.A.11.i; A.532.A.11.i; A.533.A.11.i; A.534.A.ll.i;
A.535.A.ll.i; A.536.A.11.i; A.537.A.11.i; A.538.A.11.i; A.539.A.11.i;
A.540.A.11.i; A.541.A.ll.i; A.542.A.ll.i; A.543.A.11.i; A.544.A.ll.i;
A.545.A.ll.i; A.546.A.ll.i; A.547.A.11.i; A.548.A.11.i; A.549.A.ll.i;
A.550.A.11.i; A.551.A.ll.i; A.552.A.ll.i; A.553.A.ll.i; A.554.A.ll.i;
A.555.A.ll.i; A.556.A.ll.i; A.557.A.ll.i; A.558.A.ll.i; A.559.A.11.i;
A.560.A.11.i; A.561.A.ll.i; A.562.A.ll.i; A.563.A.11.i; A.564.A.ll.i;
A.565.A.11.i; A.566.A.ll.i; A.567.A.ll.i; A.568.A.ll.i; A.569.A.ll.i;
A.570.A.ll.i; A.571.A.11.i; A.572.A.ll.i; A.573.A.ll.i; A.574.A.11.i;
A.575.A.11.i; A.576.A.11.i; A.577.A.ll.i; A.578.A.ll.i; A.579.A.ll.i;
A.580.A.ll.i; A.581.A.11.i; A.582.A.11.i; A.583.A.ll.i; A.584.A.ll.i;
A.585.A.11.i; A.586.A.ll.i; A.587.A.ll.i; A.588.A.ll.i; A.589.A.ll.i;
A.590.A.ll.i; A.591.A.ll.i; A.592.A.ll.i; A.593.A.ll.i; A.594.A.ll.i;
A.595.A.11.i; A.596.A.ll.i; A.597.A.11.i; A.598.A.11.i; A.599.A.1Li;
A.600.A.ll.i; A.601.A.ll.i; A.602.A.ll.i; A.603.A.1Li; A.604.A.ll.i;
A.605.A.11.i; A.606.A.11.i; A.607.A.ll.i; A.608.A.11.i; A.609.A.ll.i;
A.610.A.11.i; A.611.A.11.i; A.612.A.11.i; A.613.A.11.i; A.614.A.11.i;
A.615.A.ll.i; A.616.A.ll.i; A.617.A.ll.i; A.618.A.ll.i; A.619.A.ll.i;
A.620.A.ll.i; A.621.A.11.i; A.622.A.ll.i; A.623.A.11.i; A.624.A.11.i;
A.625.A.ll.i; A.626.A.11.i; A.627.A.11.i; A.628.A.ll.i; A.629.A.11.i;
A.630.A.11.i; A.631.A.ll.i; A.632.A.11.i; A.633.A.ll.i; A.634.A.11.i;
A.635.A.11.i; A.636.A.ll.i; A.637.A.ll.i; A.638.A.ll.i; A.639.A.11.i;
A.640.A.ll.i; A.641.A.11.i; A.642.A.ll.i; A.643.A.ll.i; A.644.A.ll.i;
A.645.A.11.i; A.646.A.ll.i; A.647.A.ll.i; A.648.A.ll.i; A.649.A.11.i;
A.650.A.11.i; A.651.A.11.i; A.652.A.ll.i; A.653.A.ll.i; A.654.A.ll.i;
A.655.A.ll.i; A.656.A.ll.i; A.657.A.ll.i; A.658.A.11.i; A.659.A.ll.i;
A.660.A.11.i; A.2.B.4.i; A.3.B.4.i; A.4.B.4.i; A.5.B.4.i; A.6.B.4.i;
A.7.B.4.i;
A.9.B.4.i; A.l0.B.4.i; A.15.B.4.i; A.100.B.4.i; A.101.B.4.i; A.102.B.4.i;
A.103.B.4.i;
A.104.B.4.i; A.105.B.4.i; A.106.B.4.i; A.107.B.4.i; A.108.B.4.i; A.109.B.4.i;
A.110.B.4.i; A.111.B.4.i; A.112.B.4.i; A.113.B.4.i; A.114.B.4.i; A.115.B.4.i;
A.116.B.4.i; A.117.B.4.i; A.118.B.4.i; A.119.B.4.i; A.120.B.4.i; A.121.B.4.i;
A.122.B.4.i; A.123.B.4.i; A.124.B.4.i; A.125.B.4.i; A.126.B.4.i; A.127.B.4.i;
A.128.B.4.i; A.129.B.4.i; A.130.B.4.i; A.131.B.4.i; A.132.B.4.i; A.133.B.4.i;
A.134.B.4.i; A.135.B.4.i; A.136.B.4.i; A.137.B.4.i; A.138.B.4.i; A.139.B.4.i;
A.140.B.4.i; A.141.B.4.i; A.142.B.4.i; A.143.B.4.i; A.144.B.4.i; A.145.B.4.i;
A.146.B.4.i; A.147.B.4.i; A.148.B.4.i; A.149.B.4.i; A.150.B.4.i; A.151.B.4.i;
A.152.B.4.i; A.153.B.4.i; A.154.B.4.i; A.155.B.4.i; A.156.B.4.i; A.157.B.4.i;
A.158.B.4.i; A.159.B.4.i; A.160.B:4.i; A.161.B.4.i; A.162.B.4.i; A.163.B.4.i;
A.164.B.4.i; A.165.B.4.i; A.166.B.4.i; A.167.B.4.i; A.168.B.4.i; A.169.B.4.i;
A.170.B.4.i; A.171.B.4.i; A.172.B.4.i; A.173.B.4.i; A.174.B.4.i; A.I75.B.4.i;
A.176.B.4.i; A.177.B.4.i; A.178.B.4.i; A.179.B.4.i; A.180.B.4.i; A.181.B.4.i;
A.182.B.4.i; A.183.B.4.i; A.184.B.4.i; A.185.B.4.i; A.186.B.4.i; A.187.B.4.i;
A.188.B.4.i; A.189.B.4.i; A.190.B.4.i; A.191.B.4.i; A.192.B.4.i; A.193.B.4.i;
A.194.B.4.i; A.195.B.4.i; A.196.B.4.i; A.197.B.4.i; A.198.B.4.i; A.199.B.4.i;

A.200.B.4.i; A.201.B.4.i; A.202.B.4.i; A.203.B.4.i; A.204.B.4.i; A.205.B.4.i;
A.206.B.4.i; A.207.B.4.i; A.208.B.4.i; A.209.B.4.i; A.210.B.4.i; A.211.B.4.i;
A.212.B.4.i; A.213.B.4.i; A.214.B.4.i; A.215.B.4.i; A.216.B.4.i; A.217.B.4.i;
A.218.B.4.i; A.219.B.4.i; A.220.B.4.i; A.221.B.4.i; A.222.B.4.i; A.223.B.4.i;
A.224.B.4.i; A.225.B.4.i; A.226.B.4.i; A.227.B.4.i; A.228.B.4.i; A.229.B.4.i;
A.230.B.4.i; A.231.B.4.i; A.232.B.4.i; A.233.B.4.i; A.234.B.4.i; A.235.B.4.i;
A.236.B.4.i; A.237.B.4.i; A.238.B.4.i; A.239.B.4.i; A.240.B.4.i; A.241.B.4.i;
A.242.B.4.i; A.243.B.4.i; A.244.B.4.i; A.245.B.4.i; A.246.B.4.i; A.247.B.4.i;
A.248.B.4.i; A.249.B.4.i; A.250.B.4.i; A.251.B.4.i; A.252.B.4.i; A.253.B.4.i;
A.254.B.4.i; A.255.B.4.i; A.256.B.4.i; A.257.B.4.i; A.258.B.4.i; A.259.B.4.i;
A.260.B.4.i; A.261.B.4.i; A.262.B.4.i; A.263.B.4.i; A.264.B.4.i; A.265.B.4.i;
A.266.B.4.i; A.267.B.4.i; A.268.B.4.i; A.269.B.4.i; A.270.B.4.i; A.271.B.4.i;
A.272.B.4.i; A.273.B.4.i; A.274.B.4.i; A.275.B.4.i; A.276.B.4.i; A.277.B.4.i;
A.278.B.4.i; A.279.B.4.i; A.280.B.4.i; A.281.B.4.i; A.282.B.4.i; A.2$3.B.4.i;
A.284.B.4.i; A.285.B.4.i; A.286.B.4.i; A.287.B.4.i; A.288.B.4.i; A.289.B.4.i;
A.290.B.4.i; A.291.B.4.i; A.292.B.4.i; A.293.B.4.i; A.294.B.4.i; A.295.B.4.i;
A.296.B.4.i; A.297.B.4.i; A.298.B.4.i; A.299.B.4.i; A.300.B.4.i; A.301.B.4.i;
A.302.B.4.i; A.303.B.4.i; A.304.B.4.i; A.305.B.4.i; A.306.B.4.i; A.307.B.4.i;
A.308.B.4.i; A.309.B.4.i; A.310.B.4.i; A.311.B.4.i; A.312.B.4.i; A.313.B.4.i;
A.314.B.4.i; A.315.B.4.i; A.316.B.4.i; A.317.B.4.i; A.318.B.4.i; A.319.B.4.i;
A.320.B.4.i; A.321.B.4.i; A.323.B.4.i; A.324.B.4.i; A.325.B.4.i; A.326.B.4.i;
A.327.B.4.i; A.328.B.4.i; A.329.B.4.i; A.330.B.4.i; A.331.B.4.i; A.332.B.4.i;
A.333.B.4.i; A.334.B.4.i; A.335.B.4.i; A.336.B.4.i; A.337.B.4.i; A.338.B.4.i;
A.339.B.4.i; A.340.B.4.i; A.341.B.4.i; A.342.B.4.i; A.343.B.4.i; A.344.B.4.i;
A.345.B.4.i; A.346.B.4.i; A.347.B.4.i; A.348.B.4.i; A.349.B.4.i; A.350.B.4.i;
A.351.B.4.i; A.352.B.4.i; A.353.B.4.i; A.354.B.4.i; A.355.B.4.i; A.356.B.4.i;
A.357.B.4.i; A.358.B.4.i; A.359.B.4.i; A.360.B.4.i; A.361.B.4.i; A.362.B.4.i;
A.363.B.4.i; A.364.B.4.i; A.365.B.4.i; A.366.B.4.i; A.367.B.4.i; A.368.B.4.i;
A.369.B.4.i; A.370.B.4.i; A.371.B.4.i; A.372.B.4.i; A.373.B.4.i; A.374.B.4.i;
A.375.B.4.i; A.376.B.4.i; A.377.B.4.i; A.378.B.4.i; A.379.B.4.i; A.380.B.4.i;
A.381.B.4.i; A.382.B.4.i; A.383.B.4.i; A.384.B.4.i; A.385.B.4.i; A.386.B.4.i;
A.387.B.4.i; A.388.B.4.i; A.389.B.4.i; A.390.B.4.i; A.391.B.4.i; A.392.B.4.i;
A.393.B.4.i; A.394.B.4.i; A.395.B.4.i; A.396.B.4.i; A.397.B.4.i; A.398.B.4.i;
A.399.B.4.i; A.400.B.4.i; A.401.B.4.i; A.402.B.4.i; A.403.B.4.i; A.404.B.4.i;
A.405.B.4.i; A.406.B.4.i; A.407.B.4.i; A.408.B.4.i; A.409.B.4.i; A.410.B.4.i;
A.411.B.4.i; A.412.B.4.i; A.413.B.4.i; A.414.B.4.i; A.415.B.4.i; A.416.B.4.i;
A.417.B.4.i; A.418.B.4.i; A.419.B.4.i; A.420.B.4.i; A.421.B.4.i; A.422.B.4.i;
A.423.B.4.i; A.424.B.4.i; A.425.B.4.i; A.426.B.4.i; A.427.B.4.i; A.428.B.4.i;
A.429.B.4.i; A.430.B.4.i; A.431.B.4.i; A.432.B.4.i; A.433.B.4.i; A.434.B.4.i;
A.435.B.4.i; A.436.B.4.i; A.437.B.4.i; A.438.B.4.i; A.439.B.4.i; A.440.B.4.i;
A.441.B.4.i; A.442.B.4.i; A.443.B.4.i; A.444.B.4.i; A.445.B.4.i; A.446.B.4.i;
A.447.B.4.i; A.448.B.4.i; A.449.B.4.i; A.450.B.4.i; A.451.B.4.i; A.452.B.4.i;
A.453.B.4.i; A.454.B.4.i; A.455.B.4.i; A.456.B.4.i; A.457.B.4.i; A.458.B.4.i;
A.459.B.4.i; A.460.B.4.i; A.461.B.4.i; A.462.B.4.i; A.463.B.4.i; A.464.B.4.i;
A.465.B.4.i; A.466.B.4.i; A.467.B.4.i; A.468.B.4.i; A.469.B.4.i; A.470.B.4.i;
A.471.B.4.i; A.472.B.4.i; A.473.B.4.i; A.474.B.4.i; A.475.B.4.i; A.476.B.4.i;
A.477.B.4.i; A.478.B.4.i; A.479.B.4.i; A.480.B.4.i; A.481.B.4.i; A.482.B.4.i;

A.483.B.4.i; A.484.B.4.i; A.485.B.4.i; A.486.B.4.i; A.487.B.4.i; A.488.B.4.i;
A.489.B.4.i; A.490.B.4.i; A.491.B.4.i; A.492.B.4.i; A.493.B.4.i; A.494.B.4.i;
A.495.B.4.i; A.496.B.4.i; A.497.B.4.i; A.498.B.4.i; A.499.B.4.i; A.500.B.4.i;
A.50.1.B.4.i; A.502.B.4.i; A.503.B.4.i; A.504.B.4.i; A.505.B.4.i; A.506.B.4.i;
A.507.B.4.i; A.508.B.4.i; A.509.B,4.i; A.510.B.4.i; A.511.B.4.i; A.512.B.4.i;
A.512.B.4.i; A.513.B.4.i; A.514.B.4.i; A.515.B.4.i; A.516.B.4.i; A.517.B.4.i;
A.518.B.4.i; A.519.B.4.i; A.520.B.4.i; A.521.B.4.i; A.522.B.4.i; A.523.B.4.i;
A.524.B.4.i; A.525.B.4.i; A.526.B.4.i; A.527.B.4.i; A.528.B.4.i; A.529.B.4.i;
A.530.B.4.i; A.531.B.4.i; A.532.B.4.i; A.533.B.4.i; A.534.B.4.i; A.535.B.4.i;
A.536.B.4.i; A.537.B.4.i; A.538.B.4.i; A.539.B.4.i; A.540.B.4.i; A.541.B.4.i;
A.542.B.4.i; A.543.B.4.i; A.544.B.4.i; A.545.B.4.i; A.546.B.4.i; A.547.B.4.i;
A.548.B.4.i; A.549.B.4.i; A.550.B.4.i; A.551.B.4.i; A.552.B.4.i; A.553.B.4.i;
A.554.B.4.i; A.555.B.4.i; A.556.B.4.i; A.557.B.4.i; A.558.B.4.i; A.559.B.4.i;
A.560.B.4.i; A.561.B.4.i; A.562.B.4.i; A.563.B.4.i; A.564.B.4.i; A.565.B.4.i;
A.566.B.4.i; A.567.B.4.i; A.568.B.4.i; A.569.B.4.i; A.570.B.4.i; A.571.B.4.i;
A.572.B.4.i; A.573.B.4.i; A.574.B.4.i; A.575.B.4.i; A.576.B.4.i; A.577.B.4.i;
A.578.B.4.i; A.579.B.4.i; A.580.B.4.i; A.581.B.4.i; A.582.B.4.i; A.583.B.4.i;
A.584.B.4.i; A.585.B.4.i; A.586.B.4:i; A.587.B.4.i; A.588.B.4.i; A.589.B.4.i;
A.590.B.4.i; A.591.B.4.i; A.592.B.4.i; A.593.B.4:i; A.594.B.4.i; A.595.B.4.i;
A.596.B.4.i; A.597.B.4.i; A.598.B.4.i; A.599.B.4.i; A.600.B.4.i; A.601.B.4.i;
A.602.B.4.i; A.603.B.4.i; A.604.B.4.i; A.605.B.4.i; A.606.B.4.i; A.607.B.4.i;
A.608.B.4.i; A.609.B.4.i; A.610.B.4.i; A.61I.B.4.i; A.612.B.4.i; A.613.B.4.i;
A.614.B.4.i; A.615.B.4.i; A.616.B.4.i; A.617.B.4.i; A.618.B.4.i; A.619.B.4.i;
A.620.B.4.i; A.621.B.4.i; A.622.B.4.i; A.623.B.4.i; A.624.B.4.i; A.625.B.4.i;
A.626.B.4.i; A.627.B.4.i; A.628.B.4.i; A.629.B.4.i; A.630.B.4.i; A.631.B.4.i;
A.632.B.4.i; A.633.B.4.i; A.634.B.4.i; A.635.B.4.i; A.636.B.4.i; A.637.B.4.i;
A.638.B.4.i; A.639.B.4.i; A.640.B.4.i; A.641.B.4.i; A.642.B.4.i; A.643.B.4.i;
A.644.B.4.i; A.645.B.4.i; A.646.B.4.i; A.647.B.4.i; A.648.B.4.i; A.649.B.4.i;
A.650.B.4.i; A.651.B.4.i; A.652.B.4.i; A.653.B.4.i; A.654.B.4.i; A.655.B.4.i;
A.656.B.4.i; A.657.B.4.i; A.658.B.4.i; A.659.B.4.i; A.660.B.4.i; A.2.B.11.i;
A.3.B.11.i; A.4.B.11.i; A.5.B.11.i; A.6.B.ll.i; A.7.B.11.i; A.9.B.ll.i;
A.l0.B.11.i;
A.15.B.ll.i; A.100.B.11.i; A.101.B.11.i; A.102.B.11.i; A.103.B.11.i;
A.104.B.11.i;
A.105.B.ll.i; A.106.B.11.i; A.107.B.ll.i; A.108.B.ll.i; A.109.B.ll.i;
A.110.B.ll.i;
A.111.B.11.i; A.112.B.ll.i; A.113.B.11.i; A.114.B.ll.i; A.115.B.11.i;
A.116.B.ll.i;
A.117.B.11.i; A.118.B.ll.i; A.119.B.ll.i; A.120.B.ll.i; A.121.B.ll.i;
A.122.B.11.i;
A.123.B.11.i; A.124.B.ll.i; A.125.B.ll.i; A.126.B.ll.i; A.127.B.ll.i;
A.128.B.11.i;
A.129.B.ll.i; A.130.B.ll.i; A.131.B.11.i; A.132.B.ll.i; A.133.B.ll.i;
A.134.B.11.i;
A.I35.B.11.i; A.136.8.11.i; A.137.B.ll.i; A.138.B.11.i; A.139.B.ll.i;
A.140.B.ll.i;
A.141.B.11.i; A.142.B.ll.i; A.143.B.11.i; A.144.B.ll.i; A.145.B.11.i;
A.146.B.11.i;
A.147.B.ll.i; A.148.B.11.i; A.149.B.11.i; A.150.B.ll.i; A.151.B.11.i;
A.152.B.ll.i;
A.153.B.11.i; A.154.B.ll.i; A.I55.B.ll.i; A.156.B.11.i; A.157.B.ll.i;
A.158.B.11.i;
A.159.B.ll.i; A.160.B.ll.i; A.161.B.ll.i; A.162.B.11.i; A.163.B.ll.i;
A.164.B.11.i;
A.165.B.ll.i; A.166.B.11.i; A.167.B.ll.i; A.168.B.ll,i; A.169.B.ll.i;
A.170.B.11.i;
A.171.B.11.i; A.172.B.ll.i; A.173.B.ll.i; A.174.B.ll.i; A.175.B.11.i;
A.176.B.11.i;
A.177.B.11.i; A.178.B.ll.i; A.179.B.11.i; A.180.B.11.i; A.181.B.ll.i;
A.182.B.ll.i;
A.183.B.11.i; A.184.B.11.i; A.185.B.ll.i; A.186.B.ll.i; A.187.B.ll.i;
A.188.B.11.i;
A.189.B.ll.i; A.190.B.21.i; A.191.B.11.i; A.192.B.11.i; A.193.B.ll.i;
A.194.B.ll.i;

A.195.B.ll.i; A.196.B.ll.i; A.197.B.ll.i; A.198.B.ll.i; A.199.B.ll.i;
A.200.B.ll.i;
A.201.B.ll.i; A.202.B.ll.i; A.203.B.ll.i; A.204.B.11.i; A.205.B.ll.i;
A.206.B.11.i;
A.207.B.ll.i; A.208.B.ll.i; A.209.B.ll.i; A.210.B.ll.i; A.211.B.11.i;
A.212.B.ll.i;
A.213.B.ll.i; A.214.B.ll.i; A.215.B.ll.i; A.216.B.11.i; A.217.B.ll.i;
A.218.B.11.i;
A.219.B.ll.i; A.220.B.ll.i; A.221.B.ll.i; A.222.B.11.i; A.223.B.11.i;
A.224.B.11.i;
A.225.B.ll.i; A.226.8.11.i; A.227.B.11.i; A.228.B.ll.i; A.229.B.ll.i;
A.230.B.ll.i;
A.231.B.ll.i; A.232.B.ll.i; A.233.B.ll.i; A.234.B.11.i; A.235.B.Il.i;
A.236.B.ll.i;
A.237.B.11.i; A.238.B.ll.i; A.239.B.ll.i; A.240.B.ll.i; A.241.B.11.i;
A.242.B.ll.i;
A.243.B.11.i; A.244.B.11.i; A.245.B.ll.i; A.246.B.ll.i; A.247.B.11.i;
A.248.B.11.i;
A.249.B.ll.i; A.250.B.ll.i; A.251.B.ll.i; A.252.B.ll.i; A.253.B.ll.i;
A.254.B.ll.i;
A.255.B.ll.i; A.256.B.ll.i; A.257.B.11.i; A.258.B.11.i; A.259.B.ll.i;
A.260.B.11.i;
A.261.B.ll.i; A.262.B.ll.i; A.263.B.11.i; A.264.B.ll.i; A.265.B.ll.i;
A.266.B.ll.i;
A.267.B.ll.i; A.268.B.11.i; A.269.B.ll.i; A.270.B.ll.i; A.271.B.ll.i;
A.272.B.ll.i;
A.273.B.11.i; A.274.B.ll.i; A.275.B.11.i; A.276.B.ll.i; A.277.B.ll.i;
A.278.B.ll.i;
A.279.B.11.i; A.280.B.11.i; A.281.B.ll.i; A.282.B.11.i; A.283.B.ll.i;
A.284.B.ll.i;
A.285.B.ll.i; A.286.B.11.i; A.287.B.ll.i; A.288.B.ll.i; A.289.B.ll.i;
A.290.B.11.i;
A.291.B.ll.i; A.292.B.11.i; A.293.B.ll.i; A.294.B.ll.i; A.295.B.ll.i;
A.296.B.ll.i;
A.297.B.11.i; A.298.B.ll.i; A.299.B.11.i; A.300.B.ll.i; A.301.B.11.i;
A.302.B.ll.i;
A.303.B.ll.i; A.304.B.1I.i; A.305.B.ll.i; A.306.B.ll.i; A.307.B.ll.i;
A.308.B.ll.i;
A.309.B.ll.i; A.310.B.11.i; A.311.B.ll.i; A.312.B.ll.i; A.313.B.11.i;
A.314.B.ll.i;
A.315.B.ll.i; A.316.B.ll.i; A.317.B.ll.i; A.318.B.ll.i; A.319.B.ll.i;
A.320.B.ll.i;
A.321.B.ll.i; A.323.8.11.i; A.324.B.11.i; A.325.B.11.i; A.326.B.ll.i;
A.327.B.ll.i;
A.328.B.11.i; A.329.B.ll.i; A.330.B.ll.i; A.331.B.ll.i; A.332.B.ll.i;
A.333.B.ll.i;
A.334.B.ll.i; A.335.B.11.i; A.336.B.ll.i; A.337.B.11.i; A.338.B.11.i;
A.339.B.11.i;
A.340.B.ll.i; A.341.B.11.i; A.342.B.11.i; A.343.B.ll.i; A.344.B.11.i;
A.345.B.ll.i;
A.346.B.ll.i; A.347.B.ll.i; A.348.B.11.i; A.349.B.ll.i; A.350.B.ll.i;
A.351.B.ll.i;
A.352.B.11.i; A.353.B.ll.i; A.354.B.ll.i; A.355.B.ll.i; A.356.B.ll.i;
A.357.B.ll.i;
A.358.B.11.i; A.359.B.ll.i; A.360.B.ll.i; A.361.B.ll.i; A.362.B.ll.i;
A.363.B.11.i;
A.364.B.ll.i; A.365.B.ll.i; A.366.B.ll.i; A.367.B.11.i; A.368.B.Il.i;
A.369.B.ll.i;
A.370.B.11.i; A.371.B.11.i; A.372.B.ll.i; A.373.B.ll.i; A.374.B.ll.i;
A.375.B.ll.i;
A.376.B.ll.i; A.377.B.ll.i; A.378.B.ll.i; A.379.B.ll.i; A.380.B.11.i;
A.381.B.ll.i;
A.382.B.11.i; A.383.B.ll.i; A.384.B.ll.i; A.385.B.ll.i; A.386.B.ll.i;
A.387.B.ll.i;
A.388.B.11.i; A.389.B.ll.i; A.390.B.ll.i; A.391:B.11.i; A.392.B.ll.i;
A.393.B.11.i;
A.394.B.ll.i; A.395.B.11.i; A.396.B.ll.i; A.397.8.11.i; A.398.B.ll.i;
A.399.B.ll.i;
A.400.B.11.i; A.401.B.ll.i; A.402.B.ll.i; A.403.B.11.i; A.404.B.ll.i;
A.405.B.Il.i;
A.406.B.ll.i; A.407.B.11.i; A.408.B.ll.i; A.409.B.ll.i; A.410.B.ll.i;
A.411.B.ll.i;
A.412.B.ll.i; A.413.B.ll.i; A.414.B.ll.i; A.415.B.11.i; A.416.B.ll.i;
A.417.B.11.i;
A.418.B.ll.i; A.419.B.ll.i; A.420.B.ll.i; A.421.B.ll.i; A.422.B.ll.i;
A.423.B.ll.i;
A.424.B.11.i; A.425.B.11.i; A.426.B.ll.i; A.427.B.11.i; A.428.B.ll.i;
A.429.B.ll.i;
A.430.B.ll.i; A.431.B.ll.i; A.432.B.11.i; A.433.B.ll.i; A.434.B.11.i;
A.435.B.ll.i;
A.436.B.ll.i; A.437.B.11.i; A.438.B.11.i; A.439.B.ll:i; A.440.B.ll.i;
A.441.B.ll.i;
A.442.B.ll.i; A.443.B.ll.i; A.444.B.ll.i; A.445.B.ll.i; A.446.B.ll.i;
A.447.B.ll.i;
A.448.B.ll.i; A.449.B.ll.i; A.450.B.ll.i; A.451.B.ll.i; A.452.B.ll.i;
A.453.B.11.i;
A.454.B.ll.i; A.455.B.ll.i; A.456.B.ll.i; A.457.B.11.i; A.458.B.ll.i;
A.459.B.ll.i;
A.460.B.ll.i; A.461.B.11.i; A.462.B.11.i; A.463.B.ll.i; A.464.B.ll.i;
A.465.B.ll.i;
A.466.B.11.i; A.467.B.11.i; A.468.B.ll.i; A.469.B.ll.i; A.470.B.11.i;
A.471.B.11.i;
A.472.B.ll.i; A.473.B.ll.i; A.474.B.ll.i; A.475.B.11.i; A.476.B.ll.i;
A.477.B.11.i;

A.478.B.ll.i; A.479.B.11.i; A.480.B.ll.i; A.481.B.ll.i; A.482.B.ll.i;
A.483.B.11.i;
A.484.B.11.i; A.485.B.ll.i; A.486.B.11.i; A.487.B.ll.i; A.488.B.ll.i;
A.489.B.ll.i;
A.490.B.ll.i; A.491.B.ll.i; A.492.B.ll.i; A.493.B.ll.i; A.494.B.ll.i;
A.495.B.11.i;
A.496.B.11.i; A.497.B.ll.i; A.498.B.li.i; A.499.B.ll.i; A.500.B.ll.i;
A.501.B.ll.i;
A.502.B.ll.i; A.503.B.11.i; A.504.B.ll.i; A.505.B.ll.i; A.506.B.Il.i;
A.507.B.ll.i;
A.508.B.ll.i; A.509.B.ll.i; A.510.B.11.i; A.511.B.ll.i; A.512.B.ll.i;
A.512.B.ll.i;
A.513.B.ll.i; A.514.B.ll.i; A.515.B.ll.i; A.516.B.ll.i; A.517.B.ll.i;
A.518.B.ll.i;
A.519.B.ll.i; A.520.B.11.i; A.521.B.ll.i; A.522.B.ll.i; A.523.B.ll.i;
A.524.B.ll.i;
A.525.B.ll.i; A.526.B.ll.i; A.527.B.ll.i; A.528.B.ll.i; A.529.B.ll.i;
A.530.B.ll.i;
A.531.B.ll.i; A.532.B.ll.i; A.533.B.ll.i; A.534.B.ll.i; A.535.B.ll.i;
A.536.B.ll.i;
A.537.B.ll.i; A.538.B.11.i; A.539.B.11.i; A.540.B.ll.i; A.541.B.ll.i;
A.542.B.ll.i;
A.543.B.ll.i; A.544.B.ll.i; A.545.B.11.i; A.546.B.ll.i; A.547.B.ll.i;
A.548.B.ll.i;
A.549.B.ll.i; A.550.B.ll.i; A.551.B.lLi; A.552.B.ll.i; A.553.B.ll.i;
A.554.B.11.i;
A.555.B.ll.i; A.556.B.ll.i; A.557.B.ll.i; A.S58.B.11.i; A.559.B.ll.i;
A.S60.B.ll.i;
A.561.B.11.i; A.562.B.11.i; A.563.B.11.i; A.564.B.11.i; A.565.B.ll.i;
A.566.B.ll.i;
A.567.B.ll.i; A.568.B.11.i; A.569.B.ll.i; A.570.B.ll.i; A.571.B.ll.i;
A.572.B.11.i;
A.573.B.11.i; A.574.B.11.i; A.575.B.ll.i; A.576.B.11.i; A.577.B.ll.i;
A.578.B.11.i;
A.579.B.ll.i; A.580.B.ll.i; A.581.B.ll.i; A.582.B.ll.i; A.583.B.ll.i;
A.584.B.ll.i;
A.585.B.ll.i; A.586.B.ll.i; A.587.B.ll.i; A.588.B.11.i; A.589.B.ll.i;
A.590.B.ll.i;
A.591.B.ll.i; A.592.B.ll.i; A.593.B.ll.i; A.594.B.ll.i; A.595.B.ll.i;
A.596.B.11.i;
A.597.B.ll.i; A.598.B.ll.i; A.599.B.ll.i; A.600.B.ll.i; A.601.B.ll.i;
A.602.B.ll.i;
A.603.B.ll.i; A.604.B.ll.i; A.605.B.11.i; A.606.B.11.i; A.607.B.11.i;
A.608.B.11.i;
A.609.B.ll.i; A.610.B.ll.i; A.611.B.ll.i; A.612.B.ll.i; A.613.B.ll.i;
A.614.B.11.i;
A.615.B.ll.i; A.616.B.ll.i; A.617.B.ll.i; A.618.B.ll.i; A.619.B.ll.i;
A.620.B.ll.i;
A.621.B.ll.i; A.622.B.ll.i; A.623.B.11.i; A.b24.B.11.i; A.625.B.ll.i;
A.626.B.11.i;
A.627.B.ll.i; A.628.B.ll.i; A.629.B.11.i; A.630.B.Il.i; A.631.B.ll.i;
A.632.B.ll.i;
A.633.B.ll.i; A.634.B.11.i; A.635.B.ll.i; A.636.B.11.i; A.637.B.11.i;
A.638.B.ll.i;
A.639.B.Il.i; A.640.B.ll.i; A.641.B.ll.i; A.642.B.11.i; A.643.B.ll.i;
A.644.B.11.i;
A.645.B.ll.i; A.646.B.ll.i; A.647.B.ll.i; A.648.B.11.i; A.649.B.ll.i;
A.650.B.ll.i;
A.65LB.ll.i; A.652.B.ll.i; A.653.B.ll.i; A.654.B.ll.i; A.655.B.ll.i;
A.656.B.ll.i;
A.657.B.ll.i; A.658.B.ll.i; A.659.B.ll.i; A.660.8.11.i; A.2.C.4.i; A.3.C.4.i;
A.4.C.4.i; A.5.C.4.i; A.6.C.4.i; A.7.C.4.i; A.9.C.4.i; A.l0.C.4.i; A.15.C.4.i;
A.100.C.4.i; A.lOl.C.4.i; A.102.C.4.i; A.103.C.4.i; A.104.C.4.i; A.105.C.4.i;
A.106.C.4.i; A.107.C.4.i; A.108.C.4.i; A.109.C.4.i; A.110.C.4.i; A.111.C.4.i;
A.112.C.4.i; A.113.C.4.i; A.114.C.4.i; A.115.C.4.i; A.116.C.4.i; A.117.C.4.i;
A.118.C.4.i; A.119.C.4.i; A.120.C.4.i; A.121.C.4.i; A.122.C.4.i; A.123.C.4.i;
A.124.C.4.i; A.125.C.4.i; A.126.C.4.i; A.127.C.4.i; A.128.C.4.i; A.129.C.4.i;
A.130.C.4.i; A.131.C.4.i; A.132.C.4.i; A.133.C.4.i; A.134.C.4.i; A.135.C.4.i;
A.136.C.4.i; A.137.C.4.i; A.138.C.4.i; A.139.C.4.i; A.140.C.4.i; A.141.C.4.i;
A.142.C.4:i; A.143.C.4.i; A.144.C.4.i; A.145.C.4.i; A.146.C.4.i; A.147.C.4.i;
A.148.C.4.i; A.149.C.4.i; A.150.C.4.i; A.151.C.4.i; A.152.C.4.i; A.153.C.4.i;
A.154.C.4.i; A.155.C.4.i; A.156.C.4.i; A.157.C.4.i; A.158.C.4.i; A.159.C.4.i;
A.160.C.4.i; A.161.C.4.i; A.162.C.4.i; A.163.C.4.i; A.164.C.4.i; A.165.C.4.i;
A.166.C.4.i; A.167.C.4.i; A.168.C.4.i; A.169.C.4.i; A.170.C.4.i; A.171.C.4.i;
A.172.C.4.i; A.173.C.4.i; A.174.C.4.i; A.175.C.4.i; A.176.C.4.i; A.177.C.4.i;
A.178.C.4.i; A.179.C.4.i; A.180.C.4.i; A.181.C.4.i; A.182.C.4.i; A.183.C.4.i;
A.184.C.4.i; A.185.C.4.i; A.186.C.4.i; A.187.C.4.i; A.188.C.4.i; A.189.C.4.i;

A.190.C.4.i; A.191.C.4.i; A.192.C.4.i; A.193.C.4.i; A.194.C.4.i; A.195.C.4.i;
A.196.C.4.i; A.197.C.4.i; A.198.C.4.i; A.199.C.4.i; A.200.C.4.i; A.201.C.4.i;
A.202.C.4.i; A.203.C.4.i; A.204.C.4.i; A.205.C.4.i; A.206.C.4.i; A.207.C.4.i;
A.208.C.4.i; A.209.C.4.i; A.210.C.4.i; A.211.C.4.i; A.212.C.4.i; A.213.C.4.i;
A.214.C.4.i; A.2i5.C.4.i; A.216.C.4.i; A.217.C.4.i; A.218.C.4.i; A.219.C.4.i;
A.220.C.4.i; A.221.C.4.i; A.222.C.4.i; A.223.C.4.i; A.224.C.4.i; A.225.C.4.i;
A.226.C.4.i; A.227.C.4.i; A.228.C.4.i; A.229.C.4.i; A.230.C.4.i; A.231.C.4.i;
A.232.C.4.i; A.233.C.4.i; A.234.C.4.i; A.235.C.4.i; A.236.C.4.i; A.237.C.4.i;
A.238.C.4.i; A.239.C.4.i; A.240.C.4.i; A.241.C.4.i; A.242.C.4.i; A.243.C.4.i;
A.244.C.4.i; A.245.C.4.i; A.246.C.4.i; A.247.C.4.i; A.248.C.4.i; A.249.C.4.i;
A.250.C.4.i; A.251.C.4.i; A.252.C.4.i; A.253.C.4.i; A.254.C.4.i; A.255.C.4.i;
A.256.C.4.i; A.257.C.4.i; A.258.C.4.i; A.259.C.4.i; A.260.C.4.i; A.261.C.4.i;
A.262.C.4.i; A.263.C.4.i; A.264.C.4.i; A.265.C.4.i; A.266.C.4.i; A.267.C.4.i;
A.268.C.4.i; A.269.C.4.i; A.270.C.4.i; A.271.C.4.i; A.272.C.4.i; A.273.C.4.i;
A.274.C.4.i; A.275.C.4.i; A.276.C.4.i; A.277.C.4.i; A.278.C.4.i; A.279.C.4.i;
A.280.C.4.i; A.281.C.4.i; A.282.C.4.i; A.283.C.4.i; A.284.C.4.i; A.285.C.4.i;
A.286.C.4.i; A.287.C.4.i; A,288.C.4.i; A.289.C.4.i; A.290.C.4.i; A.291.C.4.i;
A.292.C.4.i; A.293.C.4.i; A.294.C.4.i; A.295.C.4.i; A.296.C.4.i; A.297.C.4.i;
A.298.C.4.i; A.299.C.4.i; A.300.C.4.i; A.301.C.4.i; A.302.C.4.i; A.303.C.4.i;
A.304.C.4.i; A.305.C.4.i; A.306.C.4.i; A.307.C.4.i; A.308.C.4.i; A.309.C.4.i;
A.310.C.4.i; A.311.C.4.i; A.312.C.4.i; A.313.C.4.i; A.314.C.4.i; A.315.C.4.i;
A.316.C.4.i; A.317.C.4.i; A.318.C.4.i; A.319.C.4.i; A.320.C.4.i; A.321.C.4.i;
A.323.C.4.i; A.324.C.4.i; A.325.C.4.i; A.326.C.4.i; A.327.C.4.i; A.328.C.4.i;
A.329.C.4.i; A.330.C.4.i; A.331.C.4.i; A.332.C.4.i; A.333.C.4.i; A.334.C.4.i;
A.335.C.4.i; A.336.C.4.i; A.337.C.4.i; A.338.C.4.i; A.339.C.4.i; A.340.C.4.i;
A.341.C.4.i; A.342.C.4.i; A.343.C.4.i; A.344.C.4.i; A.345.C.4.i; A.346.C.4.i;
A.347.C.4.i; A.348.C.4.i; A.349.C.4.i; A.350.C.4.i; A.351.C.4.i; A.352.C.4.i;
A.353.C.4.i; A.354.C.4.i; A.355.C.4.i; A.356.C.4.i; A.357.C.4.i; A.358.C.4.i;
A.359.C.4.i; A.360.C.4.i; A.361.C.4.i; A.362.C.4.i; A.363.C.4.i; A.364.C.4.i;
A.365.C.4.i; A.366.C.4.i; A.367.C.4.i; A.368.C.4.i; A.369.C.4.i; A.370.C.4.i;
A.371.C.4.i; A.372.C.4.i; A.373.C.4.i; A.374.C.4.i; A.375.C.4.i; A.376.C.4.i;
A.377.C.4.i; A.378.C.4.i; A.379.C.4.i; A.380.C.4.i; A.381.C.4.i; A.382.C.4.i;
A.383.C.4.i; A.384.C.4.i; A.385.C.4.i; A.386.C.4.i; A.387.C.4.i; A.388.C.4.i;
A.389.C.4.i; A.390.C.4.i; A.391.C.4.i; A.392.C.4.i; A.393.C.4.i; A.394.C.4.i;
A.395.C.4.i; A.396.C.4.i; A.397.C.4.i; A.398.C.4.i; A.399.C.4.i; A.400.C.4.i;
A.401.C.4.i; A.402.C.4.i; A.403.C.4.i; A.404.C.4.i; A.405.C.4.i; A.406.C.4.i;
A.407.C.4.i; A.408.C.4.i; A.409.C.4.i; A.410.C.4.i; A.411.C.4.i; A.412.C.4.i;
A.413.C.4.i; A.414.C.4.i; A.415.C.4.i; A.416.C.4.i; A.417.C.4.i; A.418.C.4.i;
A.419.C.4.i; A.420.C.4.i; A.421.C.4.i; A.422.C.4.i; A.423.C.4.i; A.424.C.4.i;
A.425.C.4.i; A.426.C.4.i; A.427.C.4.i; A.428.C.4.i; A.429.C.4.i; A.430.C.4.i;
A.431.C.4.i; A.432.C.4.i; A.433.C.4.i; A.434.C.4.i; A.435.C.4.i; A.436.C.4.i;
A.437.C.4.i; A.438.C.4.i; A.439.C.4.i; A.440.C.4.i; A.441.C.4.i; A.442.C.4.i;
A.443.C.4.i; A.444.C.4.i; A.445.C.4.i; A.446.C.4.i; A.447.C.4.i; A.448.C.4.i;
A.449.C.4.i; A.450.C.4.i; A.451.C.4.i; A.452.C.4.i; A.453.C.4.i; A.454.C.4.i;
A.455.C.4.i; A.456.C.4.i; A.457.C.4.i; A.458.C.4.i; A.459.C.4.i; A.460.C.4.i;
A.461.C.4.i; A.462.C.4.i; A.463.C.4.i; A.464.C.4.i; A.465.C.4.i; A.466.C.4.i;
A.467.C.4.i; A.468.C.4.i; A.469.C.4.i; A.470.C.4.i; A.471.C.4.i; A.472.C.4.i;

A.473.C.4.i; A.474.C.4.i; A.475.C.4.i; A.476.C.4.i; A.477.C.4.i; A.478.C.4.i;
A.479.C.4.i; A.480.C.4.i; A.481.C.4.i; A.482.C.4.i; A.483.C.4.i; A.484.C.4.i;
A.485.C.4.i; A.486.C.4.i; A.487.C.4.i; A.488.C.4.i; A.489.C.4.i; A.490.C.4.i;
A.491.C.4.i; A.492.C.4.i; A.493.C.4.i; A.494.C.4.i; A.495.C.4.i; A.496.C.4.i;
A.497.C.4.i; A.498.C.4.i; A.499.C.4.i; A.500.C.4.i; A.501.C.4.i; A.502.C.4.i;
A.503.C.4.i; A.504.C.4.i; A.505.C.4.i; A.506.C.4.i; A.507.C.4.i; A.508.C.4.i;
A.509.C.4.i; A.510.C.4.i; A.511.C.4.i; A.512.C.4.i; A.512.C.4.i; A.513.C.4.i;
A.514.C.4.i; A.515.C.4.i; A.516.C.4.i; A.517.C.4.i; A.518.C.4.i; A.519.C.4.i;
A.520.C.4.i; A.521.C.4.i; A.522.C.4.i; A.523.C.4.i; A.524.C.4.i; A.525.C.4.i;
A.526.C.4.i; A.527.C.4.i; A.528.C.4.i; A.529.C.4.i; A.530.C.4.i; A.531.C.4.i;
A.532.C.4.i; A.533.C.4.i; A.534.C.4.i; A.535.C.4.i; A.536.C.4.i; A.537.C.4.i;
A.538.C.4.i; A.539.C.4.i; A.540.C.4.i; A.541.C.4.i; A.542.C.4.i; A.543.C.4.i;
A.544.C.4.i; A.545.C.4.i; A.546.C.4.i; A.547.C.4.i; A.548.C.4.i; A.549.C.4.i;
A.550.C.4.i; A.551.C.4.i; A.552.C.4.i; A.553.C.4.i; A.554.C.4.i; A.555.C.4.i;
A.556.C.4.i; A.557.C.4.i; A.558.C.4.i; A.559.C.4.i; A.560.C.4.i; A.561.C.4.i;
A.562.C.4.i; A.563.C.4.i; A.564.C.4.i; A.565.C.4.i; A.566.C.4.i; A.567.C.4.i;
A.568.C.4.i; A.569.C.4.i; A.570.C.4.i; A.571.C.4.i; A.572.C.4.i; A.573.C.4.i;
A.574.C.4.i; A.575.C.4.i; A.576.C.4.i; A.577.C.4.i; A.578.C.4.i; A.579.C.4.i;
A.580.C.4.i; A.581.C.4.i; A.582.C.4.i; A.583.C.4.i; A.584.C.4.i; A.585.C.4.i;
A.586.C.4.i; A.587.C.4.i; A.588.C.4.i; A.589.C.4.i; A.590.C.4.i; A.591.C.4.i;
A.592.C.4.i; A.593.C.4.i; A.594.C.4.i; A.595.C.4.i; A.596.C.4.i; A.597.C.4.i;
A.598.C.4.i; A.599.C.4.i; A.600.C.4.i; A.601.C.4.i; A.602.C.4.i; A.603.C.4.i;
A.604.C.4.i; A.605.C.4.i; A.606.C.4.i; A.607.C.4.i; A.608.C.4.i; A.609.C.4.i;
A.610.C.4.i; A.611.C.4.i; A.612.C.4.i; A.613.C.4.i; A.614.C.4.i; A.615.C.4.i;
A.616.C.4.i; A.617.C.4.i; A.618.C.4.i; A.619.C.4.i; A.620.C.4.i; A.621.C.4.i;
A.622.C.4.i; A.623.C.4.i; A.624.C.4.i; A.625.C.4.i; A.626.C.4.i; A.627.C.4.i;
A.628.C.4.i; A.629.C.4.i; A.630.C.4.i; A.631.C.4.i; A.632.C.4.i; A.633.C.4.i;
A.634.C.4.i; A.635.C.4.i; A.636.C.4.i; A.637.C.4.i; A.638.C.4.i; A.639.C.4.i;
A.640.C.4.i; A.641.C.4.i; A.642.C.4.i; A.643.C.4.i; A.644.C.4.i; A.645.C.4.i;
A.646.C.4.i; A.647.C.4.i; A.648.C.4.i; A.649.C.4.i; A.650.C.4.i; A.651.C.4.i;
A.652.C.4.i; A.653.C.4.i; A.654.C.4.i; A.655.C.4.i; A.656.C.4.i; A.657.C.4.i;
A.658.C.4.i; A.659.C.4.i; A.660.C.4.i; A.2.C.ll.i; A.3.C.11.i; A.4.C.ll.i;
A.S.C.ll.i;
A.6.C.11.i; A.7.C.ll.i; A.9.C.11.i; A.lO.C.ll.i; A.15.C.11.i; A.100.C.ll.i;
A.lOl.C.ll.i; A.102.C.11.i; A.103.C.ll.i; A.104.C.ll.i; A.105.C.11.i;
A.106.C.ll.i;
A.107.C.11.i; A.108.C.11.i; A.109.C.ll.i; A.110.C.ll.i; A.111.C.ll.i;
A.112.C.ll.i;
A.113.C.11.i; A.114.C.11.i; A.115.C.11.i; A.116.C.ll.i; A.117.C.11.i;
A.118.C.ll.i;
A.119.C.ll.i; A.120.C.11.i; A.121.C.11.i; A.122.C.ll.i; A.123.C.11.i;
A.124.C.ll.i;
A.125.C.11.i; A.126.C.ll.i; A.127.C.ll.i; A.128.C.11.i; A.129.C.11.i;
A.130.C.ll.i;
A.131.C.ll.i; A.132.C.ll.i; A.133.C.ll.i; A.134.C.ll.i; A.135.C.ll.i;
A.136.C.ll.i;
A.137.C.11.i; A.138.C.11.i; A.139.C.ll.i; A.140.C.11.i; A.141.C.11.i;
A.142.C.ll.i;
A.143.C.ll.i; A.144.C.11.i; A.145.C.ll.i; A.146.C.11.i; A.147.C.ll.i;
A.148.C.11.i;
A.149.C.11.i; A.150.C.ll.i; A.151.C.ll.i; A.152.C.11.i; A.153.C.11.i;
A.154.C.11.i;
A.155.C.ll.i; A.156.C.ll.i; A.157.C.ll.i; A.158.C.11.i; A.159.C.11.i;
A.160.C.ll.i;
A.161.C.11.i; A.162.C.ll.i; A.163.C.11.i; A.164.C.11.i; A.165.C.11.i;
A.166.C.11.i;
A.167.C.ll.i; A.168.C.ll.i; A.169.C.11.i; A.170.C.ll.i; A.171.C.ll.i;
A.172.C.ll.i;
A.173.C.11.i; A.174.C.ll.i; A.175.C.ll.i; A.176.C.11.i; A.177.C.11.i;
A.178.C.ll.i;
A.179.C.11.i; A.180.C.ll.i; A.181.C.ll.i; A.182.C.11.i; A.183.C.11.i;
A.184.C.11.i;

A.185.C.ll.i; A.186.C.ll.i; A.187.C.11.i; A.188.C.11.i; A.189.C.ll.i;
A.190.C.ll.i;
A.191.C.ll.i; A.192.C.ll.i; A.193.C.ll.i; A.194.C.11.i; A.195.C.ll.i;
A.196.C.ll.i;
A.197.C.ll.i; A.198.C.11.i; A.199.C.ll.i; A.200.C.11.i; A.201.C.11.i;
A.202.C.ll.i;
A.203.C.11.i; A.204.C.ll.i; A.205.C.ll.i; A.206.C.11.i; A.207.C.ll.i;
A.208.C.ll.i;
A.209.C.ll.i; A.210.C.11.i; A.211.C.ll.i; A.212.C.ll.i; A.213.C.ll.i;
A.214.C.11.i;
A.215.C.ll.i; A.216.C.11.i; A.217.C.11.i; A.218.C.11.i; A.219.C.Il.i;
A.220.C.ll.i;
A.221.C.ll.i; A.222.C.11.i; A.223.C.ll.i; A.224.C.11.i; A.225.C.ll.i;
A.226.C.ll.i;
A.227.C.ll.i; A.228.C.11.i; A.229.C.ll.i; A.230.C.11.i; A.231.C.ll.i;
A.232.C.ll.i;
A.233.C.ll.i; A.234.C.11.i; A.235.C.ll.i; A.236.C.ll.i; A.237.C.ll.i;
A.238.C.11.i;
A.239.C.ll.i; A.240.C.ll.i; A.241.C.11.i; A.242.C.ll.i; A.243.C.lLi;
A.244.C.11.i;
A.245.C.ll.i; A.246.C.ll.i; A.247.C.li.i; A.248.C.11.i; A.249.C.ll.i;
A.250.C.ll.i;
A.251.C.ll.i; A.252.C.ll.i; A.253.C.ll.i; A.254.C.ll.i; A.255.C.ll.i;
A.256.C.ll.i;
A.257.C.ll.i; A.258.C.ll.i; A.259.C.ll.i; A.260.C.11.i; A.261.C.11.i;
A.262.C.ll.i;
A.263.C.11,i; A.264.C.ll.i; A.265.C.11.i; A.266.C.11.i; A.267.C.ll.i;
A.268.C.ll.i;
A.269.C.11.i; A.270.C.11.i; A.271.C, l l.i; A.272.C.11.i; A.273.C.ll.i;
A.274.C.11.i;
A.275.C.ll.i; A.276.C.ll.i; A.277.C.11.i; A.278.C.ll.i; A.279.C.ll.i;
A.280.C.ll.i;
A.281.C.~ll.i; A.282.C.ll.i; A.283.C.ll.i; A.284.C.ll.i; A.285.C.Il.i;
A.286.C.ll.i;
A.287.C.ll.i; A.288.C.12.i; A.289.C.11.i; A.290.C.ll.i; A.291.C.ll.i;
A.292.C.ll.i;
A.293.C.ll.i; A.294.C.ll.i; A.295.C.ll.i; A.296.C.11.i; A.297.C.ll.i;
A.298.C.11.i;
A.299.C.ll.i; A.300.C.11.i; A.301.C.ll.i; A.302.C.ll.i; A.303.C.ll.i;
A.304.C.11.i;
A.305.C.11.i; A.306.C.11.i; A.307.C.ll.i; A.308.C.ll.i; A.309.C.ll.i;
A.310.C.ll.i;
A.311.C.11.i; A.312.C.11.i; A.313.C.11.i; A.314.C.ll.i; A.315.C.ll.i;
A.316.C.ll.i;
A.317.C.ll.i; A.318.C.ll.i; A.319.C.ll.i; A.320.C.ll.i; A.321.C.ll.i;
A.323.C.ll.i;
A.324.C.11.i; A.325.C.ll.i; A.326.C.ll.i; A.327.C.ll.i; A.328.C.ll.i;
A.329,C.ll.i;
A.330.C.ll.i; A.331.C.ll.i; A.332.C.11.i; A.333.C.11.i; A.334.C.ll.i;
A.335.C.ll.i;
A.336.C.Il.i; A.337.C.ll.i; A.338.C.11.i; A.339.C.11.i; A.340.C.12.i;
A.341.C.ll.i;
A.342.C.ll.i; A.343.C.ll.i; A.344.C.ll.i; A.345.C.ll.i; A.346.C.ll.i;
A.347.C.ll.i;
A.348.C.ll.i; A.349.C.ll.i; A.350.C.ll.i; A.351.C.ll.i; A.352.C.ll.i;
A.353.C.ll.i;
A.354.C.ll.i; A.355.C.11.i; A.356.C.ll.i; A.357.C.11.i; A.358.C.ll.i;
A.359.C.ll.i;
A.360.C.ll.i; A.361.C.11.i; A.362.C.11.i; A.363.C.ll.i; A.364.C.ll.i;
A.365.C.11.i;
A.366.C.ll.i; A.367.C.ll.i; A.368.C.ll.i; A.369.C.ll.i; A.370.C.11.i;
A.371.C.ll.i;
A.372.C.ll.i; A.373.C.11.i; A.374.C.ll.i; A.375.C.11.i; A.376.C.11.i;
A.377.C.ll.i;
A.378.C.ll.i; A.379.C.11.i; A.380.C.ll.i; A.381.C.ll.i; A.382.C.ll.i;
A.383.C.ll.i;
A.384.C.11.i; A.385.C.ll.i; A.386.C.ll.i; A.387.C.11.i; A.388.C.ll.i;
A.389.C.ll.i;
A.390.C.lLi; A.391.C.11.i; A.392.C.ll.i; A.393.C.11.i; A.394.C.11.i;
A.395.C.ll.i;
A.396.C.ll.i; A.397.C.ll.i; A.398.C.ll.i; A.399.C.11.i; A.400.C.ll.i;
A.401.C.ll.i;
A.402.C.ll.i; A.403.C.ll.i; A.404.C.ll.i; A.405.C.ll.i; A.406.C.ll.i;
A.407.C.ll.i;
A.408.C.11.i; A.409.C.11.i; A.410.C.ll.i; A.411.C.11.i; A.412.C.ll.i;
A.413.C.ll.i;
A.414.C.ll.i; A.415.C.ll.i; A.416.C.11.i; A.417.C.ll.i; A.418.C.ll.i;
A.419.C.ll.i;
A.420.C.ll.i; A.421.C.ll.i; A.422.C.ll.i; A.423.C.ll.i; A.424.C.11.i;
A.425.C.Il.i;
A.426.C.11.i; A.427.C.11.i; A.428.C.ll.i; A.429.C.ll.i; A.430.C.ll.i;
A.431.C.ll.i;
A.432.C.ll.i; A.433.C.ll.i; A.434.C.11.i; A.435.C.ll.i; A.436.C.11.i;
A.437.C.11.i;
A.438.C.ll.i; A.439.C.11.i; A.440.C.ll.i; A.441.C.ll.i; A.442.C.ll.i;
A.443.C.Il.i;
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A.449.C.ll.i;
A.450.C.ll.i; A.451.C.11.i; A.452.C.ll.i; A.453.C.ll.i; A.454.C.ll.i;
A.455.C.11.i;
A.456.C.ll.i; A.457.C.ll.i; A.458.C.ll.i; A.459.C.11.i; A.460.C.ll.i;
A.461.C.11.i;
A.462.C.11.i; A.463.C.11.i; A.464.C.ll.i; A.465.C.11.i; A.466.C.11.i;
A.467.C.11.i;

WO 99/14185 PC1'/US98/19355 A.468.C.11.i; A.469.C.ll.i; A.470.C.ll.i; A.471.C.ll.i; A.472.C.ll.i;
A.473.C.11.i;
A.474.C.ll.i; A.475.C.ll.i; A.476.C.ll.i; A.477.C.11.i; A.478.C.11.i;
A.479.C.11.i;
A.480.C.ll.i; A.481.C.11.i; A.482.C.ll.i; A.483.C.11.i; A.484.C.ll.i;
A.485.C.11.i;
A.486.C.ll.i; A.487.C.ll.i; A.488.C.11.i; A.489.C.11.i; A.490.C.11.i;
A.491.C.11.i;
A.492.C.ll.i; A.493.C.ll.i; A.494.C.ll.i; A.495.C.ll.i; A.496.C.11.i;
A.497.C.ll.i;
A.498.C.ll.i; A.499.C.ll.i; A.500.C.ll.i; A.501.C.Il.i; A.502.C.11.i;
A.503.C.ll.i;
A.504.C.11.i; A.505.C.ll.i; A.506.C.11.i; A.507.C.ll.i; A.508.C.11.i;
A.509.C.ll.i;
A.510.C.11.i; A.511.C.ll.i; A.512.C.ll.i; A.512.C.lLi; A.513.C.ll.i;
A.514.C.11.i;
A.515.C.11.i; A.516.C.11.i; A.517.C.ll.i; A.518.C.ll.i; A.519.C.ll.i;
A.520.C.ll.i;
A.521.C.ll.i; A.522.C.ll.i; A.523.C.ll.i; A.524.C.11.i; A.525.C.ll.i;
A.526.C.11.i;
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A.532.C.11.i;
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A.538.C.11.i;
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A.545.C.ll.i; A.546.C.ll.i; A.547.C.ll.i; A.548.C.11.i; A.549.C.ll.i;
A.550.C.ll.i;
A.551.C.11.i; A.552.C.11.i; A.553.C.ll.i; A.554.C.ll.i; A.555.C.11.i;
A.556.C.ll.i;
A.557.C.11.i; A.558.C.ll.i; A.559.C.ll.i; A.560.C.ll.i; A.561.C.ll.i;
A.562.C.ll.i;
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A.568.C.11.i;
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A.574.C.ll.i;
A.575.C.ll.i; A.576.C.ll.i; A.577.C.ll.i; A.578.C.ll.i; A.579.C.ll.i;
A.580.C.ll.i;
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A.586.C.11.i;
A.587.C.ll.i; A.588.C.11.i; A.589.C.ll.i; A.590.C.ll.i; A.591.C.ll.i;
A.592.C.11.i;
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A.598.C.ll.i;
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A.604.C.ll.i;
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A.616.C.ll.i;
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A.623.C.11.i; A.624.C.ll.i; A.625.C.ll.i; A.626.C.11.i; A.627.C.ll.i;
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A.629.C.ll.i; A.630.C.ll.i; A.631.C.ll.i; A.632.C.ll.i; A.633.C.ll.i;
A.634.C.ll.i;
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A.109.D.4.i; A.110.D.4.i; A.111.D.4.i; A.112.D.4.i; A.113.D.4.i; A.114.D.4.i;
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A.121.D.4.i; A.122.D.4.i; A.123.D.4.i; A.124.D.4.i; A.125.D.4.i; A.126.D.4.i;
A.127.D.4.i; A.128.D.4.i; A.129.D.4.i; A.130.D.4.i; A.131.D.4.i; A.132.D.4.i;
A.133.D.4.i; A.134.D.4.i; A.135.D.4.i; A.136.D.4.i; A.137.D.4.i; A.138.D.4.i;
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A.145.D.4.i; A.146.D.4.i; A.147.D.4.i; A.148.D.4.i; A.149.D.4.i; A.150.D.4.i;
A.151.D.4.i; A.152.D.4.i; A.153.D.4.i; A.154.D.4.i; A.155.D.4.i; A.156.D.4.i;
A.157.D.4.i; A.158.D.4.i; A.159.D.4.i; A.160.D.4.i; A.161.D.4.i; A.162.D.4.i;
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A.169.D.4.i; A.170.D.4.i; A.171.D.4.i; A.172.D.4.i; A.173.D.4.i; A.174.D.4.i;
A.175.D.4.i; A.176.D.4.i; A.177.D.4.i; A.178.D.4.i; A.179.D.4.i; A.180.D,4.i;

WO 99/14185 PCT/US9$/19355 A.181.D.4.i; A.182.D.4.i; A.183.D.4.i; A.184.D.4.i; A.185.D.4.i; A.186.D.4.i;
A.187.D.4.i; A.188.D.4.i; A.189.D.4.i; A.190.D.4.i; A.191.D.4.i; A.192.D.4.i;
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A.211.D.4.i; A.212.D.4.i; A.213.D.4.i; A.214.D.4.i; A.215.D.4.i; A.216.D.4.i;
A.217.D.4.i; A.218.D.4.i; A.219.D.4.i; A.220.D.4.i; A.221.D.4.i; A.222.D.4.i;
A.223.D.4.i; A.224.D.4.i; A.225.D.4.i; A.226.D.4.i; A.227.D.4.i; A.228.D.4.i;
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A.241.D.4.i; A.242.D.4.i; A.243.D.4.i; A.244.D.4.i; A.245.D.4.i; A.246.D.4.i;
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A.277.D.4.i; A.278.D.4.i; A.279.D.4.i; A.280.D.4.i; A.281.D.4.i; A.282.D.4.i;
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A.631.D.4.i; A.632.D.4.i; A.633.D.4.i; A.634.D.4.i; A.635.D.4.i; A.636.D.4.i;
A.637.D.4.i; A.638.D.4.i; A.639.D.4.i; A.640.D.4.i; A.641.D.4.i; A.642.D.4.i;
A.643.D.4.i; A.644.D.4.i; A.645.D.4.i; A.646.D.4.i; A.647.D.4.i; A.648.D.4.i;
A.649.D.4.i; A.650.D.4.i; A.651.D.4.i; A.652.D.4.i; A.653.D.4.i; A.654.D.4.i;
A.655.D.4.i; A.656.D.4.i; A.657.D.4.i; A.658.D.4.i; A.659.D.4.i; A.660.D.4.i;
A.2.D.ll.i; A.3.D.11.i; A.4.D.ll.i; A.5.D.ll.i; A.6.D.11.i; A.7.D.11.i;
A.9.D.11.i;
A.lO.D.ll.i; A.15.D.ll.i; A.100.D.11.i; A.lOl.D.ll.i; A.102.D.ll.i;
A.103.D.11.i;
A.104.D.11.i; A.105.D.ll.i; A.106.D.ll.i; A.107.D.ll.i; A.108.D.11.i;
A.109.D.ll.i;
A.110.D.ll.i; A.111.D.ll.i; A.112.D.ll.i; A.113.D.ll.i; A.114.D.11.i;
A.115.D.ll.i;
A.116.D.ll.i; A.lI7.D.11.i; A.118.D.11.i; A.119.D.11.i; A.120.D.11.i;
A.121.D.11.i;
A.122.D.ll.i; A.123.D.ll.i; A.124.D.11.i; A.125.D.11.i; A.126.D.ll.i;
A.127.D.ll.i;
A.128.D.ll.i; A.129.D.11.i; A.130.D.11.i; A.131.D.11.i; A.132.D.11.i;
A.133.D.11.i;
A.134.D.11.i; A.135.D.ll.i; A.136.D.Il.i; A.137.D.ll.i; A.138.D.ll.i;
A.139.D.11.i;
A.140.D.11.i; A.141.D.ll.i; A.142.D.11.i; A.143.D.ll.i; A.144.D.11.i;
A.145.D.ll.i;
A.146.D.11.i; A.147.D.11.i; A.148.D.ll.i; A.149.D.11.i; A.150.D.ll.i;
A.151.D.ll.i;
A.152.D.11.i; A.153.D.11.i; A.154.D.ll.i; A.155.D.11.i; A.156.D.11.i;
A.157.D.ll.i;
A.158.D.ll.i; A.159.D.Il.i; A.160.D.ll.i; A.161.D.11.i; A.162.D.ll.i;
A.163.D.ll.i;
A.164.D.ll.i; A.165.D.ll.i; A.166.D.ll.i; A.167.D.ll.i; A.168.D.ll.i;
A.169.D.ll.i;
A.170.D.11.i; A.171.D.ll.i; A.172.D.11.i; A.173.D.ll.i; A.174.D.ll.i;
A.175.D.ll.i;

A.176.D.11.i; A.177.D.11.i; A.178.D.ll.i; A.179.D.11.i; A.180.D.ll.i;
A.181.D.ll.i;
A.182.D.ll.i; A.183.D.ll.i; A.184.D.ll.i; A.185.D.11.i; A.186.D.ll.i;
A.187.D.ll.i;
A.188.D.11.i; A.189.D.11.i; A.190.D.ll.i; A.191.D.11.i; A.192.D.11.i;
A.193.D.ll.i;
A.194.D.11.i; A.195.D.11.i; A.196.D.ll.i; A.197.D.11.i; A.198.D.ll.i;
A.199.D.11.i;
A.200.D.11,i; A.201.D.ll.i; A.202.D.ll.i; A.203.D.ll.i; A.204.D.ll.i;
A.205:D.ll.i;
A.206.D.ll.i; A.207.D.11.i; A.208.D.11.i; A.209.D.ll.i; A.210.D.ll.i;
A.211.D.ll.i;
A.212.D.ll.i; A.213.D.11.i; A.214.D.ll.i; A.215.D.11.i; A.216.D.11.i;
A.217.D.11.i;
A.218.D.ll.i; A.219.D.11.i; A.220.D.ll.i; A.221.D.11.i; A.222.D.11.i;
A.223.D.11.i;
A.224.D.ll.i; A.225.D.ll.i; A.226.D.ll.i; A.227.D.ll.i; A.228.D.11.i;
A.229.D.11.i;
A.230.D.11.i; A.231.D.11.i; A.232.D.11.i; A.233.D.ll.i; A.234.D.ll.i;
A.235.D.ll.i;
A.236.D.ll.i; A.237.D.ll.i; A.238.D.ll.i; A.239.D.ll.i; A.240.D.ll.i;
A.241.D.ll.i;
A.242.D.ll.i; A.243.D.ll.i; A.244.D.ll,i; A.245.D.11.i; A.246.D.ll.i;
A.247.D.ll.i;
A.248.D.ll.i; A.249.D.ll.i; A.250.D.ll.i; A.251.D.ll.i; A.252.D.ll.i;
A.253.D.11.i;
A.254.D.ll.i; A.255.D.11.i; A.256.D.ll.i; A.257.D.ll.i; A.258.D.ll.i;
A.259.D.ll.i;
A.260.D.ll.i; A.261.D.11.i; A.262.D.ll.i; A.263.D.ll.i; A.264.D.11.i;
A.265.D.ll.i;
A.266.D.ll.i; A.267.D.11.i; A.268.D.ll.i; A.269.D.ll.i; A.270.D.ll.i;
A.271.D.ll.i;
A.272.D.ll.i; A.273.D.ll.i; A.274.D.ll.i; A.275.D.ll.i; A.276.D.ll.i;
A.277.D.ll.i;
A.278.D.11.i; A.279.D.ll.i; A.280.D.ll.i; A.281.D.ll.i; A.282.D.11.i;
A.283.D.ll.i;
A.284.D.ll.i; A.285.D.ll.i; A.286.D.ll.i; A.287.D.ll.i; A.288.D.ll.i;
A.289.D.11.i;
A.290.D.ll.i; A.291.D.ll.i; A.292.D.11.i; A.293.D.ll.i; A.294.D.ll.i;
A.295.D.ll.i;
A.296.D.ll.i; A.297.D.11.i; A.298.D.ll.i; A.299.D.ll.i; A.300.D.ll.i;
A.301.D.ll.i;
A.302.D.ll.i; A.303.D.11.i; A.304.D.11.i; A.305.D.ll.i; A.306.D.11.i;
A.307.D.11.i;
A.308.D.ll.i; A.309.D.ll.i; A.310.D.11.i; A.311.D.11.i; A.312.D.ll.i;
A.313.D.ll.i;
A.314.D.11.i; A.315.D.ll.i; A.316.D.ll.i; A.317.D.ll.i; A.318.D.ll.i;
A.319.D.11.i;
A.320.D.ll.i; A.321.D.11.i; A.323.D.11.i; A.324.D.ll.i; A.325.D.ll.i;
A.326.D.11.i;
A.327.D.ll.i; A.328.D.11.i; A.329.D.ll.i; A.330.D.ll.i; A.331.D.11.i;
A.332.D.11.i;
A.333.D.11.i; A.334.D.11.i; A.335.D.11.i; A.336.D.11.i; A.337.D.11.i;
A.338.D.ll.i;
A.339.D.11.i; A.340.D.11.i; A.341.D.ll.i; A.342.D.11.i; A.343.D.ll.i;
A.344.D.ll.i;
A.345.D.ll.i; A.346.D.ll.i; A.347.D.ll.i; A.348.D.ll.i; A.349.D.11.i;
A.350.D.ll.i;
A.351.D.ll.i; A.352.D.11.i; A.353.D.ll.i; A.354.D.11.i; A.355.D.ll.i;
A.356.D.ll.i;
A.357.D.11.i; A.358.D.11.i; A.359.D.ll.i; A.360.D.ll.i; A.361.D.11.i;
A.362.D.ll.i;
A.363.D.ll.i; A.364.D.11.i; A.365.D.11.i; A.366.D.11.i; A.367.D.ll.i;
A.368.D.ll.i;
A.369.D.11.i; A.370.D.11.i; A.371.D.11.i; A.372.D.11.i; A.373.D.11.i;
A.374.D.ll.i;
A.375.D.ll.i; A.376.D.ll.i; A.377.D.11.i; A.378.D.Il.i; A.379.D.ll.i;
A.380.D.ll.i;
A.381.D.11.i; A.382.D.11.i; A.383.D.ll.i; A.384.D.ll.i; A.385.D.11.i;
A.386.D.ll.i;
A.387.D.ll.i; A.388.D.ll.i; A.389.D.11.i; A.390.D.ll.i; A.391.D.11.i;
A.392.D.ll.i;
A.393.D.ll.i; A.394.D.11.i; A.395.D.11.i; A.396.D.11.i; A.397.D.11.i;
A.398.D.ll.i;
A.399.D.ll.i; A.400.D.11.i; A.401.D.ll.i; A.402.D.11.i; A.403.D.ll.i;
A.404.D.ll.i;
A.405.D.ll.i; A.406.D.ll.i; A.407.D.ll.i; A.408.D.11.i; A.409.D.ll.i;
A.410.D.ll.i;
A.411.D.ll.i; A.412.D.ll.i; A.413.D.11.i; A.414.D.ll.i; A.415.D.ll.i;
A.416.D.ll.i;
A.417.D.ll.i; A.418.D.ll.i; A.419.D.ll.i; A.420.D.ll.i; A.421.D.ll.i;
A.422.D.ll.i;
A.423.D.ll.i; A.424.D.ll.i; A.425.D.ll.i; A.426.D.ll.i; A.427.D.ll.i;
A.428.D.ll.i;
A.429.D.ll.i; A.430.D.ll.i; A.431.D.ll.i; A.432.D.11.i; A.433.D.ll.i;
A.434.D.ll.i;
A.435.D.Il.i; A.436.D.11.i; A.437.D.ll.i; A.438.D.11.i; A.439.D.ll.i;
A.440.D.ll.i;
A.441.D.11.i; A.442.D.11.i; A.443.D.ll.i; A.444.D.11.i; A.445.D.11.i;
A.446.D.11.i;
A.447.D.ll.i; A.448.D.ll.i; A.449.D.11.i; A.450.D.ll.i; A.45i.D.ll.i;
A.452.D.11.i;
A.453.D.11.i; A.454.D.11.i; A.455.D.11.i; A.456.D.ll.i; A.457.D.ll.i;
A.458.D.11.i;

A.459.D.ll.i; A.460.D.ll.i; A.461.D.ll.i; A.462.D.11.i; A.463.D.ll.i;
A.464.D.11.i;
A.465.D.ll.i; A.466.D.ll.i; A.467.D.ll.i; A.468.D.11.i; A.469.D.ll.i;
A.470.D.ll.i;
A.471.D.11.i; A.472.D.11.i; A.473.D.ll.i; A.474.D.11.i; A.475.D.11.i;
A.476.D.ll.i;
A.477.D.ll.i; A.478.D.ll.i; A.479.D.11.i; A.480.D.11.i; A.481.D.11.i;
A.482.D.11.i;
A.483.D.ll.i; A.484.D.11.i; A.485.D.ll.i; A.486.D.ll.i; A.487.D.11.i;
A.488.D.ll.i;
A.489.D.ll.i; A.490.D.ll.i; A.491.D.ll.i; A.492.D.ll.i; A.493.D.ll.i;
A.494.D.ll.i;
A.495.D.ll.i; A.496.D.11.i; A.497.D.11.i; A.498.D.ll.i; A.499.D.ll.i;
A.500.D.ll.i;
A.501.D.11.i; A.502.D.11.i; A.503.D.ll.i; A.504.D.11.i; A.505.D.ll.i;
A.506.D.11.i;
A.507.D.ll.i; A.508.D.ll.i; A.509.D.11.i; A.510.D.ll.i; A.511.D.ll.i;
A.512.D.11.i;
A.512.D.11.i; A.513.D.ll.i; A.514.D.11.i; A.515.D.ll.i; A.516.D.11.i;
A.517.D.11.i;
A.518.D.ll.i; A.519.D.11.i; A.520.D.11.i; A.521.D.ll.i; A.522.D.11.i;
A.523.D.ll.i;
A.524.D.11.i; A.525.D.ll.i; A.526.D.11.i; A.527.D.11.i; A.528.D.ll.i;
A.529.D.11.i;
A.530.D.ll.i; A.531.D.ll.i; A.532.D.ll.i; A.533.D.11.i; A.534.D.ll.i;
A.535.D.11.i;
A.536.D.11.i; A.537.D.ll.i; A.538.D.ll.i; A.539.D.ll.i; A.540.D.ll.i;
A.541.D.ll.i;
A.542.D.11.i; A.543.D.ll.i; A.544.D.ll.i; A.545.D.11.i; A.546.D.ll.i;
A.547.D.11.i;
A.548.D.11.i; A.549.D.11.i; A.550.D.11.i; A.551.D.11.i; A.552.D.ll.i;
A.553.D.ll.i;
A.554.D.ll.i; A.555.D.11.i; A.556.D.11.i; A.557.D.11.i; A.558.D.ll.i;
A.559.D.11.i;
A.560.D.ll.i; A.561.D.11.i; A.562.D.ll.i; A.563.D.ll.i; A.564.D.ll.i;
A.565.D.11.i;
A.566.D.ll.i; A.567.D.ll.i; A.568.D.11.i; A.569.D.ll.i; A.570.D.11.i;
A.571.D.11.i;
A.572.D.ll.i; A.573.D.ll.i; A.574.D.ll.i; A.575.D.ll.i; A.576.D.ll.i;
A.577.D.ll.i;
A.578.D.ll.i; A.579.D.11.i; A.580.D.11.i; A.581.D.11.i; A.582.D.11.i;
A.583.D.ll.i;
A.584.D.11.i; A.585.D.11.i; A.586.D.11.i; A.587.D.ll.i; A.588.D.11.i;
A.589.D.ll.i;
A.590.D.ll.i; A.591.D.11.i; A.592.D.ll.i; A.593.D.ll.i; A.594.D.11.i;
A.595.D.ll.i;
A.596.D.11.i; A.597.D.ll.i; A.598.D.11.i; A.599.D.Il.i; A.600.D.ll.i;
A.601.D.11.i;
A.602.D.ll.i; A.603.D.11.i; A.604.D.11.i; A.605.D.ll.i; A.606.D.ll.i;
A.607.D.ll.i;
A.608.D.ll.i; A.609.D.ll.i; A.610.D.ll.i; A.611.D.ll.i; A.612.D.ll.i;
A.613.D.ll.i;
A.614.D.ll.i; A.615.D.ll.i; A.616.D.ll.i; A.617.D.ll.i; A.618.D.ll.i;
A.619.D.11.i;
A.620.D.ll.i; A.621.D.ll.i; A.622.D.ll.i; A.623.D.11.i; A.624.D.ll.i;
A.625.D.ll.i;
A.626.D.ll.i; A.627.D.ll.i; A.628.D.11.i; A.629.D.11.i; A.630.D.11.i;
A.631.D.ll.i;
A.632.D.11.i; A.633.D.ll.i; A.634.D.ll.i; A.635.D.11.i; A.636.D.ll.i;
A.637.D.ll.i;
A.638.D.ll.i; A.639.D.11.i; A.640.D.ll.i; A.641.D.ll.i; A.642.D.11.i;
A.643.D.ll.i;
A.644.D.11.i; A.645.D.ll.i; A.646.D.11.i; A.647.D.ll.i; A.648.D.11.i;
A.649.D.ll.i;
A.650.D.11.i; A.651.D.ll.i; A.652.D.ll.i; A.653.D.11.i; A.654.D.ll.i;
A.655.D.11.i;
A.656.D.ll.i; A.657.D.11.i; A.658.D.ll.i; A.659.D.11.i; A.660.D.ll.i;
A.2.E.4.i;
A.3.E.4.i; A.4.E.4.i; A.5.E.4.i; A.6.E.4.i; A.7.E.4.i; A.9.E.4.i; A.l0.E.4.i;
A.15.E.4.i;
A.100.E.4.i; A.101.E.4.i; A.102.E.4.i; A.103.E.4.i; A.104.E.4.i; A.105.E.4.i;
A.106.E.4.i; A.107.E.4.i; A.108.E.4.i; A.109.E.4.i; A.110.E.4.i; A.111.E.4.i;
A.112.E.4.i; A.113.E.4.i; A.114.E.4.i; A.115.E.4.i; A.116.E.4.i; A.117.E.4.i;
A.118.E.4.i; A.119.E.4.i; A.120.E.4.i; A.121.E.4.i; A.122.E.4.i; A.123.E.4.i;
A.124.E.4.i; A.125.E.4.i; A.126.E.4.i; A.127.E.4.i; A.128.E.4.i; A.129.E.4.i;
A.130.E.4.i; A.131.E.4.i; A.132.E.4.i; A.133.E.4.i; A.134.E.4.i; A.135.E.4.i;
A.136.E.4.i; A.137.E.4.i; A.138.E.4.i; A.139.E.4.i; A.140.E.4.i; A.141.E.4.i;
A.142.E.4.i; A.143.E.4.i; A.144.E.4.i; A.145.E.4.i; A.146.E.4.i; A.147.E.4.i;
A.148.E.4.i; A.149.E.4.i; A.150.E.4.i; A.151.E.4.i; A.152.E.4.i; A.153.E.4.i;
A.154.E.4.i; A.155.E.4.i; A.156.E.4.i; A.157.E.4.i; A.158.E.4.i; A.159.E.4.i;
A.160.E.4.i; A.161.E.4.i; A.162.E.4.i; A.163.E.4.i; A.164.E.4.i; A.165.E.4.i;
A.166.E.4.i; A.167.E.4.i; A.168.E.4.i; A.169.E.4.i; A.170.E.4.i; A.171.E.4.i;

A.172.E.4.i; A.173.E.4.i; A.174.E.4.i; A.175.E.4.i; A.176.E.4.i; A.177.E.4.i;
A.178.E.4.i; A.179.E.4.i; A.180.E.4.i; A.181.E.4.i; A.182.E.4.i; A.183.E.4.i;
A.184.E.4.i; A.185.E.4.i; A.186.E.4.i; A.187.E.4.i; A.188.E.4.i; A.189.E.4.i;
A.190.E.4.i; A.191.E.4.i; A.192.E.4.i; A.193.E.4.i; A.194.E.4.i; A.195.E.4.i;
A.196.E.4.i; A.197.E.4.i; A.198.E.4.i; A.199.E.4.i; A.200.E.4.i; A.201.E.4.i;
A.202.E.4.i; A.203.E.4.i; A.204.E.4.i; A.205.E.4.i; A.206.E.4.i; A.207.E.4.i;
A.208.E.4.i; A.209.E.4.i; A.210.E.4.i; A.211.E.4.i; A.212.E.4.i; A.213.E.4.i;
A.214.E.4.i; A.215.E.4.i; A.216.E.4.i; A.217.E.4.i; A.218.E.4.i; A.219.E.4.i;
A.220.E.4.i; A.221.E.4.i; A.222.E.4.i; A.223.E.4.i; A.224.E.4.i; A.225.E.4.i;
A.226.E.4.i; A.227.E.4.i; A.228.E.4.i; A.229.E.4.i; A.230.E.4.i; A.231.E.4.i;
A.232.E.4.i; A.233.E.4.i; A.234.E.4.i; A.235.E.4.i; A.236.E.4.i; A.237.E.4.i;
A.238.E.4.i; A.239.E.4.i; A.240.E.4.i; A.241.E.4.i; A.242.E.4.i; A.243.E.4.i;
A.244.E.4.i; A.245.E.4.i; A.246.E.4.i; A.247.E.4.i; A.248.E.4.i; A.249.E.4.i;
A.250.E.4.i; A.251.E.4.i; A.252.E.4.i; A.253.E.4.i; A.254.E.4.i; A.255.E.4.i;
A.256.E.4.i; A.257.E.4.i; A.258.E.4.i; A.259.E.4.i; A.260.E.4.i; A.261.E.4.i;
A.262.E.4.i; A.263.E.4.i; A.264.E.4.i; A.265.E.4.i; A.266.E.4.i; A.267.E.4.i;
A.268.E.4.i; A.269.E.4.i; A.270.E.4.i; A.271.E.4.i; A.272.E.4.i; A.273.E.4.i;
A.274.E.4.i; A.275.E.4.i; A.276.E.4.i; A.277.E.4.i; A.278.E.4.i; A.279.E.4.i;
A.280.E.4.i; A.281.E.4.i; A.282.E.4.i; A.283.E.4.i; A.2$4.E.4.i; A.285.E.4.i;
A.286.E.4.i; A.287.E.4.i; A.288.E.4.i; A.289.E.4.i; A.290.E.4.i; A.291.E.4.i;
A.292.E.4.i; A.293.E.4.i; A.294.E.4.i; A.295.E.4.i; A.296.E.4.i; A.297.E.4.i;
A.298.E.4.i; A.299.E.4.i; A.300.E.4.i; A.301.E.4.i; A.302.E.4.i; A.303.E.4.i;
A.304.E.4.i; A.305.E.4.i; A.306.E.4.i; A.307.E.4.i; A.308.E.4.i; A.309.E.4.i;
A.310.E.4.i; A.311.E.4.i; A.312.E.4.i; A.313.E.4.i; A.314.E.4.i; A.315.E.4.i;
A.316.E.4.i; A.317.E.4.i; A.318.E.4.i; A.319.E.4.i; A.320.E.4.i; A.321.E.4.i;
A.323.E.4.i; A.324.E.4.i; A.325.E.4.i; A.326.E.4.i; A.327.E.4.i; A.328.E.4.i;
A.329.E.4.i; A.330.E.4.i; A.331.E.4.i; A.332.E.4.i; A.333.E.4.i; A.334.E.4.i;
A.335.E.4.i; A.336.E.4.i; A.337.E.4.i; A.338.E.4.i; A.339.E.4.i; A.340.E.4.i;
A.341.E.4.i; A.342.E.4.i; A.343.E.4.i; A.344.E.4.i; A.345.E.4.i; A.346.E.4.i;
A.347.E.4.i; A.348.E.4.i; A.349.E.4.i; A.350.E.4.i; A.351.E.4.i; A.352.E.4.i;
A.353.E.4.i; A.354.E.4.i; A.355.E.4.i; A.356.E.4.i; A.357.E.4.i; A.358.E.4.i;
A.359.E.4.i; A.360.E.4.i; A.361.E.4.i; A.362.E.4.i; A.363.E.4.i; A.364.E.4.i;
A.365.E.4.i; A.366.E.4.i; A.367.E.4.i; A.368.E.4.i; A.369.E.4.i; A.370.E.4.i;
A.371.E.4.i; A.372.E.4.i; A.373.E.4.i; A.374.E.4.i; A.375.E.4.i; A.376.E.4.i;
A.377.E.4.i; A.378.E.4.i; A.379.E.4.i; A.380.E.4.i; A.381.E.4.i; A.382.E.4.i;
A.383.E.4.i; A.384.E.4.i; A.385.E.4.i; A.386.E.4.i; A.387.E.4.i; A.388.E.4.i;
A.389.E.4.i; A.390.E.4.i; A.391.E.4.i; A.392.E.4.i; A.393.E.4.i; A.394.E.4.i;
A.395.E.4.i; A.396.E.4.i; A.397.E.4.i; A.398.E.4.i; A.399.E.4.i; A.400.E.4.i;
A.401.E.4.i; A.402.E.4.i; A.403.E.4.i; A.404.E.4.i; A.405.E.4.i; A.406.E.4.i;
A.407.E.4.i; A.408.E.4.i; A.409.E.4.i; A.410.E.4.i; A.411.E.4.i; A.412.E.4.i;
A.413.E.4.i; A.414.E.4.i; A.415.E.4.i; A.416.E.4.i; A.417.E.4.i; A.418.E.4.i;
A.419.E.4.i; A.420.E.4.i; A.421.E.4.i; A.422.E.4.i; A.423.E.4.i; A.424.E.4.i;
A.425.E.4.i; A.426.E.4.i; A.427.E.4.i; A.428.E.4.i; A.429.E.4.i; A.430.E.4.i;
A.431.E.4.i; A.432.E.4.i; A.433.E.4.i; A.434.E.4.i; A.435.E.4.i; A.436.E.4.i;
A.437.E.4.i; A.438.E.4.i; A.439.E.4.i; A.440.E.4.i; A.441.E.4.i; A.442.E.4.i;
A.443.E.4.i; A.444.E.4.i; A.445.E.4.i; A.446.E.4.i; A.447.E.4.i; A.448.E.4.i;
A.449.E.4.i; A.450.E.4.i; A.451.E.4.i; A.452.E.4.i; A.453.E.4.i; A.454.E.4.i;

A.455.E.4.i; A.456.E.4.i; A.457.E.4.i; A.458.E.4.i; A.459.E.4.i; A.460.E.4.i;
A.461.E.4.i; A.462.E.4.i; A.463.E.4.i; A.464.E.4.i; A.465.E.4.i; A.466.E.4.i;
A.467.E.4.i; A.468.E.4.i; A.469.E.4.i; A.470.E.4.i; A.471.E.4.i; A.472.E.4.i;
A.473.E.4.i; A.474.E.4.i; A.475.E.4.i; A.476.E.4.i; A.477.E.4.i; A.478.E.4.i;
A.479.E.4.i; A.480.E.4.i; A.481.E.4.i; A.482.E.4.i; A.483.E.4.i; A.484.E.4.i;
A.485.E.4.i; A.486.E.4.i; A.487.E.4.i; A.488.E.4.i; A.489.E.4.i; A.490.E.4.i;
A.491.E.4.i; A.492.E.4.i; A.493.E.4.i; A.494.E.4.i; A.495.E.4.i; A.496.E.4.i;
A.497.E.4.i; A.498.E.4.i; A.499.E.4.i; A.500.E.4.i; A.501.E.4.i; A.502.E.4.i;
A.503.E.4.i; A.504.E.4.i; A.505.E.4.i; A.506.E.4.i; A.507.E.4.i; A.508.E.4.i;
A.509.E.4.i; A.510.E.4.i; A.511.E.4.i; A.512.E.4.i; A.512.E.4.i; A.513.E.4.i;
A.514.E.4.i; A.515.E.4.i; A.516.E.4.i; A.517.E.4.i; A.518.E.4.i; A.519.E.4.i;
A.520.E.4.i; A.521.E.4.i; A.522.E.4.i; A.523.E.4.i; A.524.E.4.i; A.525.E.4.i;
A.526.E.4.i; A.527.E.4.i; A.528.E.4.i; A.529.E.4.i; A.530.E.4.i; A.531.E.4.i;
A.532.E.4.i; A.533.E.4.i; A.534.E.4.i; A.535.E.4.i; A.536.E.4.i; A.537.E.4.i;
A.538.E.4.i; A.539.E.4.i; A.540.E.4.i; A.541.E.4.i; A.542.E.4.i; A.543.E.4.i;
A.544.E.4.i; A.545.E.4.i; A.546.E.4.i; A.547.E.4.i; A.548.E.4.i; A.549.E.4.i;
A.550.E.4.i; A.551.E.4.i; A.552.E.4.i; A.553.E.4.i; A.554.E.4.i; A.555.E.4.i;
A.556.E.4.i; A.557.E.4.i; A.558.E.4.i; A.559.E.4.i; A.560.E.4.i; A.561.E.4.i;
A.562.E.4.i; A.563.E.4.i; A.564.E.4.i; A.565.E.4.i; A.566.E.4.i; A.567.E.4.i;
A.568.E.4.i; A.569.E.4.i; A.570.E.4.i; A.571.E.4.i; A.572.E.4.i; A.573.E.4.i;
A.574.E.4.i; A.575.E.4.i; A.576.E.4.i; A.577.E.4.i; A.578.E.4.i; A.579.E.4.i;
A.580.E.4.i; A.581.E.4.i; A.582.E.4.i; A.583.E.4.i; A.584.E.4.i; A.585.E.4.i;
A.586.E.4.i; A.587.E.4.i; A.588.E.4.i; A.589.E.4.i; A.590.E.4.i; A.591.E.4.i;
A.592.E.4.i; A.593.E.4.i; A.594.E.4.i; A.595.E.4.i; A.596.E.4.i; A.597.E.4.i;
A.598.E.4.i; A.599.E.4.i; A.600.E.4.i; A.601.E.4.i; A.602.E.4.i; A.603.E.4.i;
A.604.E.4.i; A.605.E.4.i; A.606.E.4.i; A.607.E.4.i; A.608.E.4.i; A.609.E.4.i;
A.610.E.4.i; A.611.E.4.i; A.612.E.4.i; A.613.E.4.i; A.614.E.4.i; A.615.E.4.i;
A.616.E.4.i; A.617.E.4.i; A.618.E.4.i; A.619.E.4.i; A.620.E.4.i; A.621.E.4.i;
A.622.E.4.i; A.623.E.4.i; A.624.E.4.i; A.625.E.4.i; A.626.E.4.i; A.627.E.4.i;
A.628.E.4.i; A.629.E.4.i; A.630.E.4.i; A.631.E.4.i; A.632.E.4.i; A.633.E.4.i;
A.634.E.4.i; A.635.E.4.i; A.636.E.4.i; A.637.E.4.i; A.638.E.4.i; A.639.E.4.i;
A.640.E.4.i; A.641.E.4.i; A.642.E.4.i; A.643.E.4.i; A.644.E.4.i; A.645.E.4.i;
A.646.E.4.i; A.647.E.4.i; A.648.E.4.i; A.649.E.4.i; A.650.E.4.i; A.651.E.4.i;
A.652.E.4.i; A.653.E.4.i; A.654.E.4.i; A.655.E.4.i; A.656.E.4.i; A.657.E.4.i;
A.658.E.4.i; A.659.E.4.i; A.660.E.4.i; A.2.E.ll.i; A.3.E.11.i; A.4.E.ll.i;
A.5.E.11.i;
A.6.E.ll.i; A.7.E.11.i; A.9.E.ll.i; A.lO.E.Il.i; A.15.E.11.i; A.100.E.ll.i;
A.lOl.E.ll.i; A.102.E.11.i; A.103.E.11.i; A.104.E.11.i; A.105.E.11.i;
A.106.E.ll.i;
A.107.E.ll.i; A.108.E.ll.i; A.109.E.ll.i; A.110.E.ll.i; A.111.E.11.i;
A.112.E.11.i;
A.113.E.ll.i; A.114.E.ll.i; A.115.E.11.i; A.116.E.ll.i; A.117.E.ll.i;
A.118.E.ll.i;
A.119.E.ll.i; A.120.E.ll.i; A.121.E.ll.i; A.122.E.ll.i; A.123.E.ll.i;
A.124.E.ll.i;
A.125.E.ll.i; A.126.E.ll.i; A.127.E.ll.i; A.128.E.11.i; A.129.E.ll.i;
A.130.E.ll.i;
A.131.E.11.i; A.132.E.11.i; A.133.E.11.i; A.134.E.11.i; A.135.E.ll.i;
A.136.E.ll.i;
A.137.E.ll.i; A.138.E.11.i; A.139.E.11.i; A.140.E.ll.i; A.141.E.11.i;
A.142.E.ll.i;
A.143.E.11.i; A.144.E.11.i; A.145.E.11.i; A.146.E.11.i; A.147.E.ll.i;
A.148.E.ll.i;
A.149.E.11.i; A.150.E.ll.i; A.151.E.11.i; A.152.E.ll.i; A.153.E.11.i;
A.154.E.ll.i;
A.155.E.11.i; A.156.E.11.i; A.157.E.ll.i; A.158.E.11.i; A.159.E.11.i;
A.160.E.ll.i;
A.161.E.11.i; A.162.E.11.i; A.163.E.11.i; A.164.E.ll.i; A.165.E.ll.i;
A.166.E.ll.i;

A.167.E.11.i; A.168.E.11.i; A.169.E.11.i; A.170.E.ll.i; A.171.E.ll.i;
A.172.E.11.i;
A.173.E.11.i; A.174.E.ll.i; A.175.E.ll.i; A.176.E.ll.i; A.177.E.ll.i;
A.178.E.ll.i;
A.179.E.ll.i; A.180.E.ll.i; A.181.E.11.i; A.I82.E.ll.i; A.183.E.ll.i;
A.184.E.ll.i;
A.185.E.11.i; A.186.E.ll.i; A.187.E.11.i; A.188.E.11.i; A.189.E.ll.i;
A.190.E.ll.i;
A.191.E.ll.i; A.192.E.ll.i; A.193.E.ll.i; A.194.E.ll.i; A.I95.E.ll.i;
A.196.E.ll.i;
A.197.E.ll.i; A.198.E.ll.i; A.199.E.11.i; A.200.E.ll.i; A.201.E.11.i;
A.202.E.ll.i;
A.203.E.11.i; A.204.E.ll.i; A.205.E.ll.i; A.206.E.ll.i; A.207.E.11.i;
A.208.E.ll.i;
A.209.E.11.i; A.210.E.ll.i; A.211.E.11.i; A.212.E.11.i; A.213.E.ll.i;
A.214.E.ll.i;
A.215.E.ll.i; A.216.E.11.i; A.217.E.ll.i; A.218.E.11.i; A.219.E.ll.i;
A.220.E.11.i;
A.221.E.ll.i; A.222.E.ll.i; A.223.E.11.i; A.224.E.11.i; A.225.E.ll.i;
A.226.E.ll.i;
A.227.E.11.i; A.228.E.ll.i; A.229.E.ll.i; A.230.E.ll.i; A.231.E.11.i;
A.232.E.ll.i;
A.233.E.ll.i; A.234.E.11.i; A.235.E.ll.i; A.236.E.ll.i; A.237.E.ll.i;
A.238.E.11.i;
A.239.E.ll.i; A.240.E.ll.i; A.241.E.ll.i; A.242.E.ll.i; A.243.E.ll.i;
A.244.E.11.i;
A.245.E.ll.i; A.246.E.ll.i; A.247.E.ll.i; A.248.E.ll.i; A.249.E.ll.i;
A.250.E.11.i;
A.251.E.ll.i; A.252.E.ll.i; A.253.E.ll.i; A.254.E.Il.i; A.255.E.ll.i;
A.256.E.ll.i;
A.257.E.11.i; A.258.E.ll.i; A.259.E.ll.i; A.260.E.11.i; A.261.E.ll.i;
A.262.E.ll.i;
A.263.E.ll.i; A.264.E.ll.i; A.265.E.ll.i; A.266.E.11.i; A.267.E.ll.i;
A.268.E.lI.i;
A.269.E.ll.i; A.270.E.ll.i; A.271.E.ll.i; A.272.E.ll.i; A.273.E.ll.i;
A.274.E.ll.i;
A.275.E.ll.i; A.276.E.ll.i; A.277.E.11.i; A.278.E.ll.i; A.279.E.11.i;
A.280.E.ll.i;
A.281.E.ll.i; A.282.E.il.i; A.283.E.11.i; A.284.E.ll.i; A.285.E.11.i;
A.286.E.ll.i;
A.287.E.ll.i; A.288.E.ll.i; A.289.E.ll.i; A.290.E.11.i; A.291.E.ll.i;
A.292.E.11.i;
A.293.E.ll.i; A.294.E.11.i; A.295.E.Il.i; A.296.E.11.i; A.297.E.11.i;
A.298.E.ll.i;
A.299.E.ll.i; A.300.E.ll.i; A.301.E.11.i; A.302.E.ll.i; A.303.E.11.i;
A.304.E.ll.i;
A.305.E.ll.i; A.306.E.ll.i; A.307.E.11.i; A.308.E.ll.i; A.309.E.ll.i;
A.310.E.ll.i;
A.311.E.ll.i; A.312.E.ll.i; A.313.E.ll.i; A.314.E.ll.i; A.315.E.ll.i;
A.316.E.ll.i;
A.317.E.11.i; A.318.E.11.i; A.319.E.ll.i; A.320.E.ll.i; A.321.E.ll.i;
A.323.E.ll.i;
A.324.E.ll.i; A.325.E.11.i; A.326.E.11.i; A.327.E.ll.i; A.328.E.ll.i;
A.329.E.ll.i;
A.330.E.ll.i; A.331.E.11.i; A.332.E.ll.i; A.333.E.Il.i; A.334.E.11.i;
A.335.E.ll.i;
A.336.E.ll.i; A.337.E.ll.i; A.338.E.ll.i; A.339.E.ll.i; A.340.E.Il.i;
A.341.E.ll.i;
A.342.E.11.i; A.343.E.ll.i; A.344.E.11.i; A.345.E.ll.i; A.346.E.ll.i;
A.347.E.ll.i;
A.348.E.ll.i; A.349.E.ll.i; A.350.E.11.i; A.351.E.ll.i; A.352.E.li.i;
A.353.E.11.i;
A.354.E.11.i; A.355.E.ll.i; A.356.E.ll.i; A.357.E.ll.i; A.358.E.11.i;
A.359.E.11.i;
A.360.E.ll.i; A.361.E.11.i; A.362.E.ll.i; A.363.E.11.i; A.364.E.ll.i;
A.365.E.11.i;
A.366.E.11.i; A.367.E.ll.i; A.368.E.ll.i; A.369.E.11.i; A.370.E.11.i;
A.371.E.ll.i;
A.372.E.11.i; A.373.E.ll.i; A.374.E.ll.i; A.375.E.ll.i; A.376.E.11.i;
A.377.E.11.i;
A.378.E.ll.i; A.379.E.ll.i; A.380.E.11.i; A.381.E.ll.i; A.382.E.11.i;
A.383.E.ll.i;
A.384.E.ll.i; A.385.E.ll.i; A.386.E.ll.i; A.387.E.ll.i; A.388.E.ll.i;
A.389.E.ll.i;
A.390.E.11.i; A.391.E.ll.i; A.392.E.ll.i; A.393.E.11.i; A.394.E.11.i;
A.395.E.ll.i;
A.396.E.il.i; A.397.E.11.i; A.398.E.11.i; A.399.E.ll.i; A.400.E.ll.i;
A.401.E.ll.i;
A.402.E.ll.i; A.403.E.11.i; A.404.E.ll.i; A.405.E.ll.i; A.406.E.ll.i;
A.407.E.ll.i;
A.408.E.ll.i; A.409.E.ll.i; A.410.E.ll.i; A.411.E.11.i; A.412.E.ll.i;
A.413.E.ll.i;
A.414.E.ll.i; A.415.E.ll.i; A.416.E.11.i; A.417.E.11.i; A.418.E.ll.i;
A.419.E.ll.i;
A.420.E.ll.i; A.421.E.ll.i; A.422.E.11.i; A.423.E.ll.i; A.424.E.ll.i;
A.425.E.11.i;
A.426.E.11.i; A.427.E.11.i; A.428.E.ll.i; A.429.E.ll.i; A.430.E.11.i;
A.431.E.ll.i;
A.432.E.11.i; A.433.E.11.i; A.434.E.11.i; A.435.E.11.i; A.436.E.11.i;
A.437.E.11.i;
A.438.E.11.i; A.439.E.ll.i; A.440.E.ll.i; A.441.E.11.i; A.442.E.ll.i;
A.443.E.ll.i;
A.444.E.ll.i; A.445.E.ll.i; A.446.E.ll.i; A.447.E.11.i; A.448.E.ll.i;
A.449.E.11.i;

A.450.E.11.i; A.451.E.11.i; A.452.E.11.i; A.453.E.ll.i; A.454.E.ll.i;
A.455.E.ll.i;
A.456.E.11.i; A.457.E.ll.i; A.458.E.ll.i; A.459.E.11.i; A.460.E.ll.i;
A.461.E.ll.i;
A.462.E.11.i; A.463.E.11.i; A.464.E.ll.i; A.465.E.ll.i; A.466.E.ll.i;
A.467.E.ll.i;
A.468.E.ll.i; A.469.E.11.i; A.470.E.ll.i; A.471.E.11.i; A.472.E.ll.i;
A.473.E.ll.i;
A.474.E.11.i; A.475.E.ll.i; A.476.E.ll.i; A.477.E.ll.i; A.478.E.ll.i;
A.479.E.ll.i;
A.480.E.ll.i; A.481.E.ll.i; A.482.E.ll.i; A.483.E.ll.i; A.484.E.ll.i;
A.485.E.ll.i;
A.486.E.11.i; A.487.E.11.i; A.488.E.11.i; A.489.E.11.i; A.490.E.11.i;
A.491.E.ll.i;
A.492.E.11.i; A.493.E.11.i; A.494.E.ll.i; A.495.E.11.i; A.496.E.11.i;
A.497.E.ll.i;
A.498.E.ll.i; A.499.E.11.i; A.500.E.11.i; A.501.E.ll.i; A.502.E.ll.i;
A.503.E.ll.i;
A.504.E.ll.i; A.505.E.ll.i; A.506.E.ll.i; A.507.E.ll.i; A.508.E.ll.i;
A.509.E.ll.i;
A.510.E.ll.i; A.511.E.ll.i; A.512.E.ll.i; A.512.E.ll.i; A.513.E.ll.i;
A.514.E.ll.i;
A.515.E.ll.i; A.516.E.11.i; A.517.E.11.i; A.518.E.11.i; A.519.E.ll.i;
A.520.E.ll.i;
A.521.E.11.i; A.522.E.11.i; A.523.E.ll.i; A.524.E.ll.i; A.525.E.ll.i;
A.526.E.ll.i;
A.527.E.ll.i; A.528.E.ll.i; A.529.E.ll.i; A.530.E.ll.i; A.531.E.11.i;
A.532.E.11.i;
A.533.E.11.i; A.534.E.ll.i; A.535.E.ll.i; A.536.E.ll.i; A.537.E.11.i;
A.538.E.ll.i;
A.539.E.ll.i; A.540.E.ll.i; A.541.E.ll.i; A.542.E.ll.i; A.543.E.ll.i;
A.544.E.ll.i;
A.545.E.11.i; A.546.E.11.i; A.547.E.ll.i; A.548.E.ll.i; A.549.E.11.i;
A.550.E.ll.i;
A.551.E.ll.i; A.552.E.11.i; A.553.E.11.i; A.554.E.ll.i; A.555.E.ll.i;
A.556.E.ll.i;
A.557.E.11.i; A.558.E.ll.i; A.559.E.ll.i; A.560.E.ll.i; A.561.E.ll.i;
A.562.E.ll.i;
A.563.E.11.i; A.564.E.11.i; A.565.E.11.i; A.566.E.ll.i; A.567.E.ll.i;
A.568.E.ll.i;
A.569.E.ll.i; A.570.E.11.i; A.571.E.11.i; A.572.E.ll.i; A.573.E.ll.i;
A.574.E.ll.i;
A.575.E.11.i; A.576.E.ll.i; A.577.E.11.i; A.578.E.ll.i; A.579.E.ll.i;
A.580.E.11.i;
A.581.E.11.i; A.582.E.11.i; A.583.E.ll.i; A.5&4.E.11.i; A.585.E.ll.i;
A.586.E.ll.i;
A.587.E.ll.i; A.588.E.ll.i; A.589.E.ll.i; A.590.E.ll.i; A.591.E.ll.i;
A.592.E.ll.i;
A.593.E.ll.i; A.594.E.ll.i; A.595.E.ll.i; A.596.E.Il.i; A.597.E.11.i;
A.598.E.Il.i;
A.599.E.ll.i; A.600.E.ll.i; A.601.E.ll.i; A.602.E.ll.i; A.603.E.ll.i;
A.604.E.11.i;
A.605.E.ll.i; A.606.E.ll.i; A.607.E.11.i; A.608.E.11.i; A.609.E.ll.i;
A.610.E.11.i;
A.611.E.11.i; A.612.E.11.i; A.613.E.11.i; A.614.E.ll.i; A.615.E.ll.i;
A.616.E.ll.i;
A.617.E.ll.i; A.618.E.ll.i; A.619.E.ll.i; A.620.E.11.i; A.621.E.ll.i;
A.622.E.ll.i;
A.623.E.ll.i; A.624.E.11.i; A.625.E.ll.i; A.626.E.11.i; A.627.E.ll.i;
A.62$.E.ll.i;
A.629.E.ll.i; A.630.E.ll.i; A.631.E.ll.i; A.632.E.ll.i; A.633.E.ll.i;
A.634.E.11.i;
A.635.E.ll.i; A.636.E.11.i; A.637.E.ll.i; A.638.E.ll.i; A.639.E.ll.i;
A.640.E.ll.i;
A.641.E.ll.i; A.642.E.ll.i; A.643.E.11.i; A.644.E.ll.i; A.645.E.ll.i;
A.646.E.ll.i;
A.647.E.ll.i; A.648.E.ll.i; A.649.E.ll.i; A.650.E.11.i; A.651.E.ll.i;
A.652.E.ll.i;
A.653.E.11.i; A.654.E.ll.i; A.655.E.ll.i; A.656.E.ll.i; A.657.E.ll.i;
A.658.E.11.i;
A.659.E.ll.i; A.660.E.ll.i; A.2.F.4.i; A.3.F.4.i; A.4.F.4.i; A.5.F.4.i;
A.6.F.4.i;
A.7.F.4.i; A.9.F.4.i; A.l0.F.4.i; A.15.F.4.i; A.IOO.F.4.i; A.lOl.F.4.i;
A.102.F.4.i;
A.103.F.4.i; A.104.F.4.i; A.105.F.4.i; A.106.F.4.i; A.107.F.4.i; A.lO8.F.4.i;
A.109.F.4.i; A.110.F.4.i; A.111.F.4.i; A.112.F.4.i; A.113.F.4.i; A.114.F.4.i;
A.115.F.4.i; A.116.F.4.i; A.I17.F.4.i; A.118.F.4.i; A.119.F.4.i; A.120.F.4.i;
A.121.F.4.i; A.122.F.4.i; A.123.F.4.i; A.124.F.4.i; A.125.F.4.i; A.126.F.4.i;
A.127.F.4.i; A.128.F.4.i; A.129.F.4.i; A.130.F.4.i; A.131.F.4.i; A.132.F.4.i;
A.133.F.4.i; A.I34.F.4.i; A.135.F.4.i; A.136.F.4.i; A.137.F.4.i; A.138.F.4.i;
A.139.F.4.i; A.140.F.4.i; A.141.F.4.i; A.142.F.4.i; A.143.F.4.i; A.144.F.4.i;
A.145.F.4.i; A.146.F.4.i; A.147.F.4.i; A.148.F.4.i; A.149.F.4.i; A.150.F.4.i;
A.151.F.4.i; A.152.F.4.i; A.153.F.4.i; A.154.F.4.i; A.155.F.4.i; A.156.F.4.i;
A.157.F.4.i; A.158.F.4.i; A.159.F.4.i; A.160.F.4.i; A.161.F.4.i; A.162.F.4.i;

A.163.F.4.i; A.164.F.4.i; A.165.F.4.i; A.166.F.4.i; A.167.F.4.i; A.168.F.4.i;
A.169.F.4.i; A.170.F.4.i; A.171.F.4.i; A.172.F.4.i; A.173.F.4.i; A.174.F.4.i;
A.175.F.4.i; A.176.F.4.i; A.177.F.4.i; A.178.F.4.i; A.179.F.4.i; A.180.F.4.i;
A.181.F.4.i; A.182.F.4.i; A.183.F.4.i; A.184.F.4.i; A.185.F.4.i; A.186.F.4.i;
A.187.F.4.i; A.188.F.4.i; A.189.F.4.i; A.190.F.4.i; A.191.F.4.i; A.192.F.4.i;
A.193.F.4.i; A.194.F.4.i; A.195.F.4.i; A.196.F.4.i; A.197.F.4.i; A.198.F.4.i;
A.199.F.4.i; A.200.F.4.i; A.201.F.4.i; A.202.F.4.i; A.203.F.4.i; A.204.F.4.i;
A.205.F.4.i; A.206.F.4.i; A.207.F.4.i; A.208.F.4.i; A.209.F.4.i; A.210.F.4.i;
A.211.F.4.i; A.212.F.4.i; A.213.F.4.i; A.214.F.4.i; A.215.F.4.i; A.216.F.4.i;
A.217.F.4.i; A.218.F.4.i; A.219.F.4.i; A.220.F.4.i; A.221.F.4.i; A.222.F.4.i;
A.223.F.4.i; A.224.F.4.i; A.225.F.4.i; A.226.F.4.i; A.227.F.4.i; A.228.F.4.i;
A.229.F.4.i; A.230.F.4.i; A.231.F.4.i; A.232.F.4.i; A.233.F.4.i; A.234.F.4.i;
A.235.F.4.i; A.236.F.4.i; A.237.F.4.i; A.238.F.4.i; A.239.F.4.i; A.240.F.4.i;
A.241.F.4.i; A.242.F.4.i; A.243.F.4.i; A.244.F.4.i; A.245.F.4.i; A.246.F.4.i;
A.247.F.4.i; A.248.F.4.i; A.249.F,4.i; A.250.F.4.i; A.251.F.4.i; A.252.F.4.i;
A.253.F.4.i; A.254.F.4.i; A.255.F.4.i; A.256.F.4.i; A.257.F.4.i; A.258.F.4.i;
A.259.F.4.i; A.260.F.4.i; A.261.F.4.i; A.262.F.4.i; A.263.F.4.i; A.264.F.4.i;
A.265.F.4.i; A.266.F.4.i; A.267.F.4.i; A.268.F.4.i; A.269.F.4.i; A.270.F.4.i;
A.271.F.4.i; A.272.F.4.i; A.273.F.4.i; A.274.F.4.i; A.275.F.4.i; A.276.F.4.i;
A.277.F.4.i; A.278.F.4.i; A.279.F.4.i; A.280.F.4.i; A.281.F.4.i; A.282.F.4.i;
A.283.F.4.i; A.284.F.4.i; A.285.F.4.i; A.286.F.4.i; A.287.F.4.i; A.288.F.4.i;
A.289.F.4.i; A.290.F.4.i; A.291.F.4.i; A.292.F.4.i; A.293.F.4.i; A.294.F.4.i;
A.295.F.4.i; A.296.F.4.i; A.297.F.4.i; A.298.F.4.i; A.299.F.4.i; A.300.F.4.i;
A.301.F.4.i; A.302.F.4.i; A.303.F.4.i; A.304.F.4.i; A.305.F.4.i; A.306.F.4.i;
A.307.F.4.i; A.308,F.4.i; A.309.F.4:i; A.310.F.4.i; A.311.F.4.i; A.312.F.4.i;
A.313.F.4.i; A.314.F.4.i; A.315.F.4.i; A.316.F.4.i; A.317.F.4.i; A.328.F.4.i;
A.319.F.4.i; A.320.F.4.i; A.321.F.4.i; A.323.F.4.i; A.324.F.4.i; A.325.F.4.i;
A.326.F.4.i; A.327.F.4.i; A.328.F.4.i; A.329.F.4.i; A.330.F.4.i; A.331.F.4.i;
A.332.F.4.i; A.333.F.4.i; A.334.F.4.i; A.335.F.4.i; A.336.F.4.i; A.337.F.4.i;
A.338.F.4.i; A.339.F.4.i; A.340.F.4.i; A.341.F.4.i; A.342.F.4.i; A.343.F.4.i;
A.344.F.4.i; A.345.F.4.i; A.346.F.4.i; A.347.F.4.i; A.348.F.4.i; A.349.F.4.i;
A.350.F.4.i; A.351.F.4.i; A.352.F.4.i; A.353.F.4.i; A.354.F.4.i; A.355.F.4.i;
A.356.F.4.i; A.357.F.4.i; A.358.F.4.i; A.359.F.4.i; A.360.F.4.i; A.361.F.4.i;
A.362.F.4.i; A.363.F.4.i; A.364.F.4.i; A.365.F.4.i; A.366.F.4.i; A.367.F.4.i;
A.368.F.4.i; A.369.F.4.i; A.370.F.4.i; A.371.F.4.i; A.372.F.4.i; A.373.F.4.i;
A.374.F.4.i; A.375.F.4.i; A.376.F.4.i; A.377.F.4.i; A.378.F.4.i; A.379.F.4.i;
A.380.F.4.i; A.381.F.4.i; A.382.F.4.i; A.3$3.F.4.i; A.384.F.4.i; A.385.F.4.i;
A.386.F.4.i; A.387.F.4.i; A.388.F.4.i; A.389.F.4.i; A.390.F.4.i; A.391.F.4.i;
A.392.F.4.i; A.393.F.4.i; A.394.F.4.i; A.395.F.4.i; A.396.F.4.i; A.397.F.4.i;
A.398.F.4.i; A.399.F.4.i; A.400.F.4.i; A.401.F.4.i; A.402.F.4.i; A.403.F.4.i;
A.404.F.4.i; A.405.F.4.i; A.406.F.4.i; A.407.F.4.i; A.408.F.4.i; A.409.F.4.i;
A.410.F.4.i; A.411.F.4.i; A.412.F.4.i; A.413.F.4.i; A.414.F.4.i; A.415.F.4.i;
A.416.F.4.i; A.417.F.4.i; A.418.F.4.i; A.419.F.4.i; A.420.F.4.i; A.421.F.4.i;
A.422.F.4.i; A.423.F.4.i; A.424.F.4.i; A.425.F.4.i; A.426.F.4.i; A.427.F.4.i;
A.428.F.4.i; A.429.F.4.i; A.430.F.4.i; A.431.F.4.i; A.432.F.4.i; A.433.F.4.i;
A.434.F.4.i; A.435.F.4.i; A.436.F.4.i; A.437.F.4.i; A.438.F.4.i; A.439.F.4.i;
A.440.F.4.i; A.441.F.4.i; A.442.F.4.i; A.443.F.4.i; A.444.F.4.i; A.445.F.4.i;

A.446.F.4.i; A.447.F.4.i; A.448.F.4.i; A.449.F.4.i; A.450.F.4.i; A.451.F.4.i;
A.452.F.4.i; A.453.F.4.i; A.454.F.4.i; A.455.F.4.i; A.456.F.4.i; A.457.F.4.i;
A.458.F.4.i; A.459.F.4.i; A.460.F.4.i; A.461.F.4.i; A.462.F.4.i; A.463.F.4.i;
A.464.F.4.i; A.465.F.4.i; A.466.F.4.i; A.467.F.4.i; A.468.F.4.i; A.469.F.4.i;
A.470.F.4.i; A.471.F.4.i; A.472.F.4.i; A.473.F.4.i; A.474.F.4.i; A.475.F.4.i;
A.476.F.4.i; A.477.F.4.i; A.478.F.4.i; A.479.F.4.i; A.480.F.4.i; A.481.F.4.i;
A.482.F.4.i; A.483.F.4.i; A.484.F.4.i; A.485.F.4.i; A.486.F.4.i; A.487.F.4.i;
A.488.F.4.i; A.489.F.4.i; A.490.F.4.i; A.491.F.4.i; A.492.F.4.i; A.493.F.4.i;
A.494.F.4.i; A.495.F.4.i; A.496.F.4.i; A.497.F.4.i; A.498.F.4.i; A.499.F.4.i;
A.500.F.4.i; A.501.F.4.i; A.502.F.4.i; A.503.F.4.i; A.504.F.4.i; A.505.F.4.i;
A.506.F.4.i; A.507.F.4.i; A.508.F.4.i; A.509.F.4.i; A.510.F.4.i; A.511.F.4.i;
A.512.F.4.i; A.512.F.4.i; A.513.F.4.i; A.514.F.4.i; A.515.F.4.i; A.516.F.4.i;
A.517.F.4.i; A.518.F.4.i; A.519.F.4.i; A.520.F.4.i; A.521.F.4.i; A.522.F.4.i;
A.523.F.4.i; A.524.F.4.i; A.525.F.4.i; A.526.F.4.i; A.527.F.4.i; A.528.F.4.i;
A.529.F.4.i; A.530.F.4.i; A.531.F.4.i; A.532.F.4.i; A.533.F.4.i; A.534.F.4.i;
A.535.F.4.i; A.536.F.4.i; A.537.F.4.i; A.538.F.4.i; A.539.F.4.i; A.540.F.4.i;
A.541.F.4.i; A.542.F.4.i; A.543.F.4.i; A.544.F.4.i; A.545.F.4.i; A.546.F.4.i;
A.547.F.4.i; A.548.F.4.i; A.549.F.4.i; A.550.F.4.i; A.551.F.4.i; A.552.F.4.i;
A.553.F.4.i; A.554.F.4.i; A.555.F.4.i; A.556.F.4.i; A.557.F.4.i; A.558.F.4.i;
A.559.F.4.i; A.560.F.4.i; A.561.F.4.i; A.562.F.4.i; A.563.F.4.i; A.564.F.4.i;
A.565.F.4.i; A.566.F.4.i; A.567.F.4.i; A.568.F.4.i; A.569.F.4.i; A.570.F.4.i;
A.571.F.4.i; A.572.F.4.i; A.573.F.4.i; A.574.F.4.i; A.575.F.4.i; A.576.F.4.i;
A.577.F.4.i; A.578.F.4.i; A.579.F.4.i; A.580.F.4.i; A.581.F.4.i; A.582.F.4.i;
A.583.F.4.i; A.584.F.4.i; A.585.F.4.i; A.586.F.4.i; A.587.F.4.i; A.588.F.4.i;
A.589.F.4.i; A.590.F.4.i; A.591.F.4.i; A.592.F.4.i; A.593.F.4.i; A.594.F.4.i;
A.595.F.4.i; A.596.F.4.i; A.597.F.4.i; A.598.F.4.i; A.599.F.4.i; A.600.F.4.i;
A.601.F.4.i; A.602.F.4.i; A.603.F.4.i; A.604.F.4.i; A.605.F.4.i; A.606.F.4.i;
A.607.F.4.i; A.608.F.4.i; A.609.F.4.i; A.610.F.4.i; A.611.F.4.i; A.612.F.4.i;
A.bl3.F.4.i; A.614.F.4.i; A.615.F.4.i; A.616.F.4.i; A.617.F.4.i; A.618.F.4.i;
A.619.F.4.i; A.620.F.4.i; A.621.F.4.i; A.622.F.4.i; A.623.F.4.i; A.624.F.4.i;
A.625.F.4.i; A.626.F.4.i; A.627.F.4.i; A.628.F.4.i; A.629.F.4.i; A.630.F.4.i;
A.631.F.4.i; A.632.F.4.i; A.633.F.4.i; A.634.F.4.i; A.635.F.4.i; A.636.F.4.i;
A.637.F.4.i; A.638.F.4.i; A.639.F.4.i; A.640.F.4.i; A.641.F.4.i; A.642.F.4.i;
A.643.F.4.i; A.644.F.4.i; A.645.F.4.i; A.646.F.4.i; A.647.F.4.i; A.648.F.4.i;
A.649.F.4.i; A.650.F.4.i; A.651.F.4.i; A.652.F.4.i; A.653.F.4.i; A.654.F.4.i;
A.655.F.4.i; A.656.F.4.i; A.657.F.4.i; A.658.F.4.i; A.659.F.4.i; A.660.F.4.i;
A.2.F.ll.i; A.3.F.11.i; A.4.F.ll.i; A.S.F.ll.i; A.6.F.11.i; A.7.F.11.i;
A.9.F.ll.i;
A.lO.F.ll.i; A.15.F.ll.i; A.100.F.ll.i; A.lOl.F.ll.i; A.102.F.11.i;
A.103.F.ll.i;
A.104.F.11.i; A.105.F.ll.i; A.106.F.ll.i; A.107.F.ll.i; A.108.F.ll.i;
A.109.F.11.i;
A.110.F.ll.i; A.111.F.ll.i; A.112.F.11.i; A.113.F.ll.i; A.114.F.ll.i;
A.115.F.ll.i;
A.116.F.ll.i; A.117.F.1i.i; A.118.F.11.i; A.119.F.ll.i; A.120.F.ll.i;
A.121.F.ll.i;
A.122.F.ll.i; A.123.F.11.i; A.124.F.ll.i; A.125.F.ll.i; A.126.F.ll.i;
A.127.F.ll.i;
A.128.F.11.i; A.129.F.11.i; A.130.F.ll.i; A.131.F.11.i; A.132.F.ll.i;
A.133.F.11.i;
A.134.F.ll.i; A.135.F.ll.i; A.136.F.11.i; A.137.F.11.i; A.138.F.11.i;
A.139.F.ll.i;
A.140.F.ll.i; A.141.F.11.i; A.142.F.ll.i; A.143.F.11.i; A.144.F.11.i;
A.145.F.ll.i;
A.146.F.ll.i; A.147.F.11.i; A.148.F.11.i; A.149.F.11.i; A.150.F.11.i;
A.151.F.11.i;
A.152.F.ll.i; A.153.F.ll.i; A.154.F.11.i; A.155.F.ll.i; A.156.F.11.i;
A.157.F.ll.i;

A.158.F.ll.i; A.159.F.ll.i; A.160.F.11.i; A.161.F.ll.i; A.162.F.11.i;
A.163.F.ll.i;
A.164.F.ll.i; A.165.F.ll.i; A.166.F.ll.i; A.167.F.11.i; A.168.F.li.i;
A.169.F.ll.i;
A.170.F.11.i; A.171.F.11.i; A.172.F.ll.i; A.173.F.ll.i; A.174.F.ll.i;
A.175.F.ll.i;
A.176.F.ll.i; A.177.F.11.i; A.178.F.ll.i; A.179.F.ll.i; A.180.F.ll.i;
A.181.F.ll.i;
A.182.F.ll.i; A.183.F.ll.i; A.184.F.ll.i; A.185.F.ll.i; A.186.F.ll.i;
A.187.F.ll.i;
A.188.F.11.i; A.189.F.ll.i; A.190.F.ll.i; A.191.F.ll.i; A.192.F.ll.i;
A.193.F.11.i;
A.194.F.11.i; A.195.F.ll.i; A.196.F.11.i; A.197.F.11.i; A.198.F.11.i;
A.199,F.Il.i;
A.200.F.ll.i; A.201.F.11.i; A.202.F.11.i; A.203.F.ll.i; A.204.F.11.i;
A.205.F.11.i;
A.206.F.ll.i; A.207.F.ll.i; A.208.F.ll.i; A.209.F.ll.i; A.210.F.ll.i;
A.211.F.ll.i;
A.212.F.11.i; A.213.F.ll.i; A.214.F.11.i; A.215.F.ll.i; A.216.F.ll.i;
A.217.F.ll.i;
A.218.F.lLi; A.219.F.ll.i; A.220.F.11.i; A.221.F.ll.i; A.222.F.ll.i;
A.223.F.ll.i;
A.224.F.11.i; A.225.F.11.i; A.226.F.ll.i; A.227.F.ll.i; A.228.F.ll.i;
A.229.F.ll.i;
A.230.F.ll.i; A.231.F.ll.i; A.232.F.11.i; A.233.F.ll.i; A.234.F.11.i;
A.235.F.ll.i;
A.236.F.ll.i; A.237.F.ll.i; A.238.F.11.i; A.239.F.ll.i; A.240.F.11.i;
A.241.F.ll.i;
A.242.F.11.i; A.243.F.ll.i; A.244.F.ll.i; A.245.F.ll.i; A.246.F.ll.i;
A.247.F.11.i;
A.248.F.ll.i; A.249.F.11.i; A.250.F.ll.i; A.251.F.ll.i; A.252.F.ll.i;
A.253.F.11.i;
A.254.F.ll.i; A.255.F.ll.i; A.256.F.ll.i; A.257.F.11.i; A.258.F.ll.i;
A.259.F.ll.i;
A.260.F.ll.i; A.261.F.11.i; A.262.F.11.i; A.263.F.ll.i; A.264.F.ll.i;
A.265.F.ll.i;
A.266.F.ll.i; A.267.F.ll.i; A.268.F.ll.i; A.269.F.ll.i; A.270.F.ll.i;
A.271.F.11.i;
A.272.F.ll.i; A.273.F.11.i; A.274.F.ll.i; A.275.F.ll.i; A.276.F.ll.i;
A.277.F.11.i;
A.278.F.ll.i; A.279.F.ll.i; A.280.F.ll.i; A.281.F.ll.i; A.282.F.ll.i;
A.283.F.ll.i;
A.284.F.11.i; A.285.F.11.i; A.286.F.ll.i; A.287.F.ll.i; A.288.F.ll.i;
A.289.F.ll.i;
A.290.F.ll.i; A.291.F.11.i; A.292.F.11.i; A.293.F.11.i; A.294.F.11.i;
A.295.F.ll.i;
A.296.F.ll.i; A.297.F.ll.i; A.298.F.lI.i; A.299.F.ll.i; A.300.F.ll.i;
A.301.F.ll.i;
A.302.F.11.i; A.303.F.ll.i; A.304.F.ll.i; A.305.F.ll.i; A.306.F.ll.i;
A.307.F.ll.i;
A.308.F.ll.i; A.309.F.ll.i; A.310.F.11.i; A.311.F.ll.i; A.312.F.ll.i;
A.313.F.11.i;
A.314.F.11.i; A.315.F.11.i; A.316.F.11.i; A.317.F.ll.i; A.318.F.ll.i;
A.319.F.ll.i;
A.320.F.11.i; A.321.F.ll.i; A.323.F.ll.i; A.324.F.ll.i; A.325.F.11.i;
A.326.F.ll.i;
A.327.F.11.i; A.328.F.11.i; A.329.F.ll.i; A.330.F.ll.i; A.331.F.ll.i;
A.332.F.ll.i;
A.333.F.ll.i; A.334.F.ll.i; A.335.F.ll.i; A.336.F.ll.i; A.337.F.ll.i;
A.338.F.ll.i;
A.339.F.ll.i; A.340.F.11.i; A.341.F.ll.i; A.342.F.ll.i; A.343.F.ll.i;
A.344.F.ll.i;
A.345.F.ll.i; A.346.F.11.i; A.347.F.11.i; A.348.F.ll.i; A.349.F.ll.i;
A.350.F.ll.i;
A.351.F.Il.i; A.352.F.ll.i; A.353.F.ll.i; A.354.F.ll.i; A.355.F.ll.i;
A.356.F.11.i;
A.357.F.11.i; A.358.F.ll.i; A.359.F.ll.i; A.360.F.ll.i; A.361.F.ll.i;
A.362.F.11.i;
A.363.F.ll.i; A.364.F.ll.i; A.365.F.Il.i; A.366.F.ll.i; A.367.F.11.i;
A.368.F.ll.i;
A.369.F.ll.i; A.370.F.11.i; A.371.F.ll.i; A.372.F.ll.i; A.373.F.11.i;
A.374.F.ll.i;
A.375.F.ll.i; A.376.F.ll.i; A.377.F.ll.i; A.378.F.ll.i; A.379.F.ll.i;
A.380.F.ll.i;
A.381.F.ll.i; A.382.F.ll.i; A.383.F.lI.i; A.384.F.ll.i; A.385.F.ll.i;
A.386.F.11.i;
A.387.F.ll.i; A.388.F.ll.i; A.389.F.ll.i; A.390.F.11.i; A.391.F.11.i;
A.392.F.ll.i;
A.393.F.ll.i; A.394.F.ll.i; A.395.F.11.i; A.396.F.11.i; A.397.F.11.i;
A.398.F.11.i;
A.399.F.11.i; A.400.F.ll.i; A.401.F.ll.i; A.402.F.ll.i; A.403.F.ll.i;
A.404.F.11.i;
A.405.F.ll.i; A.406.F.11.i; A.407.F.11.i; A.408.F.ll.i; A.409.F.ll.i;
A.410.F.ll.i;
A.411.F.11.i; A.412.F.ll.i; A.413.F.ll.i; A.414.F.ll.i; A.415.F.11.i;
A.416.F.ll.i;
A.417.F.11.i; A.418.F.ll.i; A.419.F.ll.i; A.420.F.11.i; A.421.F.ll.i;
A.422.F.ll.i;
A.423.F.ll.i; A.424.F.11.i; A.425.F.ll.i; A.426.F.ll.i; A.427.F.ll.i;
A.428.F.ll.i;
A.429.F.11.i; A.430.F.ll.i; A.431.F.ll.i; A.432.F.11.i; A.433.F.ll.i;
A.434.F.11.i;
A.435.F.11.i; A.436.F.ll.i; A.437.F.ll.i; A.438.F.21.i; A.439.F.11.i;
A.440.F.ll.i;

A.441.F.11.i; A.442.F.11.i; A.443.F.ll.i; A.444.F.ll.i; A.445.F.ll.i;
A.446.F.ll.i;
A.447.F.ll.i; A.448.F.11.i; A.449.F.ll.i; A.450.F.11.i; A.451.F.ll.i;
A.452.F.ll.i;
A.453.F.ll.i; A.454.F.ll.i; A.455.F.11.i; A.456.F.ll.i; A.457.F.ll.i;
A.458.F.11.i;
A.459.F.11.i; A.460.F.ll.i; A.461.F.ll.i; A.462.F.ll.i; A.463.F.ll.i;
A.4b4.F.ll.i;
A.465.F.ll.i; A.466.F.ll.i; A.467.F.ll.i; A.468.F.11.i; A.469.F.ll.i;
A.470.F.ll.i;
A.471.F.ll.i; A.472.F.ll.i; A.473.F.11.i; A.474.F.11.i; A.475.F.ll.i;
A.476.F.ll.i;
A.477.F.ll.i; A.478.F.ll.i; A.479.F.ll.i; A.480.F.ll.i; A.481.F.ll.i;
A.482.F.ll.i;
A.483.F.ll.i; A.484.F.ll.i; A.485.F.11.i; A.486.F.11.i; A.487.F.ll.i;
A.488.F.ll.i;
A.489.F.11.i; A.490.F.ll.i; A.491.F.ll.i; A.492.F.ll.i; A.493.F.ll.i;
A.494.F.ll.i;
A.495.F.ll.i; A.496.F.ll.i; A.497.F.11.i; A.498.F.ll.i; A.499.F.11.i;
A.500.F.ll.i;
A.501.F.ll.i; A.502.F.ll.i; A.503.F.ll.i; A.504.F.ll.i; A.505.F.11.i;
A.506.F.ll.i;
A.507.F.11.i; A.508.F.ll.i; A.509.F.ll.i; A.510.F.ll.i; A.511.F.ll.i;
A.512.F.ll.i;
A.512.F.ll.i; A.513.F.ll.i; A.514.F.11.i; A.515.F.ll.i; A.516.F.ll.i;
A.517.F.ll.i;
A.518.F.ll.i; A.519.F.11.i; A.520.F.11.i; A.521.F.ll.i; A.522.F.11.i;
A.523.F.ll.i;
A.524.F.lLi; A.525.F.11.i; A.526.F.ll.i; A.527.F.ll.i; A.528.F.11.i;
A.529.F.ll.i;
A.530.F.ll.i; A.531.F.ll.i; A.532.F.11.i; A.533.F.ll.i; A.534.F.11.i;
A.535.F.ll.i;
A.536.F.11.i; A.537.F.11.i; A.538.F.ll.i; A.539.F.11.i; A.540.F.ll.i;
A.541.F.ll.i;
A.542.F.ll.i; A.543.F.ll.i; A.544.F.ll.i; A.545.F.ll.i; A.546.F.ll.i;
A.547.F.11.i;
A.548.F.ll.i; A.549.F.ll.i; A.550.F.11.i; A.551.F.11.i; A.552.F.ll.i;
A.553.F.ll.i;
A.554.F.ll.i; A.555.F.ll.i; A.556.F.11.i; A.557.F.11.i; A.558.F.ll.i;
A.559.F.11.i;
A.560.F.11.i; A.561.F.11.i; A.562.F.ll.i; A.563.F.ll.i; A.564.F.ll.i;
A.565.F.ll.i;
A.566.F.ll.i; A.567.F.ll.i; A.568.F.11.i; A.569.F.ll.i; A.570.F.ll.i;
A.571.F.ll.i;
A.572.F.11.i; A.573.F.ll.i; A.574.F.ll.i; A.575.F.ll.i; A.576.F.ll.i;
A.577.F.11.i;
A.578.F.11.i; A.579.F.11.i; A.580.F.11.i; A.58LF.11.i; A.582.F.ll.i;
A.583.F.ll.i;
A.584.F.ll.i; A.585.F.11.i; A.586.F.ll.i; A.587.F.ll.i; A.588.F.ll.i;
A.589.F.ll.i;
A.590.F.ll.i; A.591.F.ll.i; A.592.F.ll.i; A.593.F.ll.i; A.594.F.ll.i;
A.595.F.ll.i;
A.596.F.11.i; A.597.F.ll.i; A.59$.F.ll.i; A.599.F.11.i; A.600.F.11.i;
A.601.F.ll.i;
A.602.F.11.i; A.603.F.ll.i; A.604.F.ll.i; A.605.F.ll.i; A.606.F.11.i;
A.607.F.ll.i;
A.608.F.ll.i; A.609.F.ll.i; A.610.F.11.i; A.611.F.ll.i; A.612.F.ll.i;
A.613.F.ll.i;
A.614.F.11.i; A.615.F.11.i; A.616.F.ll.i; A.617.F.11.i; A.618.F.ll.i;
A.619.F.ll.i;
A.620.F.ll.i; A.621.F.11.i; A.622.F.ll.i; A.623.F.11.i; A.624.F.11.i;
A.625.F.11.i;
A.626.F.ll.i; A.627.F.11.i; A.628.F.11.i; A.629.F.11.i; A.630.F.ll.i;
A.631.F.ll.i;
A.632.F.ll.i; A.633.F.11.i; A.634.F.ll.i; A.635.F.ll.i; A.636.F.ll.i;
A.637.F.ll.i;
A.638.F.11.i; A.639.F.ll.i; A.640.F.11.i; A.641.F.ll.i; A.642.F.ll.i;
A.643.F.11.i;
A.644.F.ll.i; A.645.F.ll.i; A.646.F.11.i; A.647.F.ll.i; A.648.F.ll.i;
A.649.F.ll.i;
A.650.F.11.i; A.651.F.ll.i; A.652.F.11.i; A.653.F.ll.i; A.654.F.11.i;
A.655.F.ll.i;
A.656.F.ll.i; A.657.F.11.i; A.658.F.ll.i; A.659.F.ll.i; A.660.F.ll.i;
A.2.a.44.i;
A.3.a.44.i; A.4.a.44.i; A.5.a.44.i; A.9.a.44.i; A.100.a.44.i; A.lOl.a.44.i;
A.102.a.44.i;
A.103.a.44.i; A.104.a.44.i; A.105.a.44.i; A.106.a.44.i; A.107.a.44.i;
A.108.a.44.i;
A.109.a.44.i; A.110.a.44.i; A.111.a.44.i; A.112.a.44.i; A.113.a.44.i;
A.114.a.44.i;
A.115.a.44.i; A.116.a.44.i; A.117.a.44.i; A.118.a.44.i; A.119.a.44.i;
A.120.a.44.i;
A.121.a.44.i; A.122.a.44.i; A.123.a.44.i; A.124.a.44.i; A.125.a.44.i;
A.126.a.44.i;
A.127.a.44.i; A.128.a.44.i; A.129.a.44.i; A.130.a.44.i; A.131.a.44.i;
A.132.a.44.i;
A.133.a.44.i; A.134.a.44.i; A.135.a.44.i; A.136.a.44.i; A.137.a.44.i;
A.138.a.44.i;
A.139.a.44.i; A.140.a.44.i; A.141.a.44.i; A.142.a.44.i; A.143.a.44.i;
A.144.a.44.i;
A.145.a.44.i; A.146.a.44.i; A.i47.a.44.i; A.148.a.44.i; A.149.a.44.i;
A.150.a.44.i;
A.151.a.44.i; A.152.a.44.i; A.153.a.44.i; A.154.a.44.i; A.155.a.44.i;
A.156.a.44.i;

A.157.a.44.i; A.158.a.44.i; A.159.a.44.i; A.160.a.44.i; A.161.a.44.i;
A.162.a.44.i;
A.163.a.44.i; A.164.a.44.i; A.165.a.44.i; A.166.a.44.i; A.167.a.44.i;
A.168.a.44.i;
A.169.a.44.i; A.170.a.44.i; A.171.a.44.i; A.172.a.44.i; A.173.a.44.i;
A.174.a.44.i;
A.l7~.a.44.i; A.176.a.44.i; A.177.a.44.i; A.178.a.44.i; A.179.a.44.i;
A.180.a.44.i;
A.181.a.44.i; A.182.a.44.i; A.183.a.44.i; A.184.a.44.i; A.185.a.44.i;
A.186.a.44.i;
A.187.a.44.i; A.188.a.44.i; A.189.a.44.i; A.190.a.44.i; A.191.a.44.i;
A.192.a.44.i;
A.193.a.44.i; A.194.a.44.i; A.195.a.44.i; A.196.a.44.i; A.197.a.44.i;
A.198.a.44.i;
A.199.a.44.i; A.200.a.44.i; A.201.a.44.i; A.202.a.44.i; A.203.a.44.i;
A.204.a.44.i;
A.205.a.44.i; A.206.a.44.i; A.207.a.44.i; A.208.a.44.i; A.209.a.44.i;
A.210.a.44.i;
A.211.a.44.i; A.212.a.44.i; A.213.a.44.i; A.214.a.44.i; A.215.a.44.i;
A.216.a.44.i;
A.217.a.44.i; A.218.a.44.i; A.219.a.44.i; A.220.a.44.i; A.221.a.44.i;
A.222.a.44.i;
A.223.a.44.i; A.224.a.44.i; A.225.a.44.i; A.226.a.44.i; A.227.a.44.i;
A.228.a.44.i;
A.229.a.44.i; A.230.a.44.i; A.231.a.44.i; A.232.a.44.i; A.233.a.44.i;
A.234.a.44.i;
A.235.a.44.i; A.236.a.44.i; A.237.a.44.i; A.238.a.44.i; A.239.a.44.i;
A.240.a.44.i;
A.241.a.44.i; A.242.a.44.i; A.243.a.44.i; A.244.a.44.i; A.245.a.44.i;
A.246.a.44.i;
A.247.a.44.i; A.248.a.44.i; A.249.a.44.i; A.250.a.44.i; A.251.a.44.i;
A.252.a.44.i;
A.253.a.44.i; A.254.a.44.i; A.255.a.44.i; A.256.a.44.i; A.257.a.44.i;
A.258.a.44.i;
A.259.a.44.i; A.260.a.44.i; A.261.a.44.i; A.262.a.44.i; A.263.a.44.i;
A.264.a.44.i;
A.265.a.44.i; A.266.a.44.i; A.267.a.44.i; A.268.a.44.i; A.269.a.44.i;
A.270.a.44.i;
A.271.a.44.i; A.272.a.44.i; A.273.a.44.i; A.274.a.44.i; A.275.a.44.i;
A.276.a.44.i;
A.277.a.44.i; A.278.a.44.i; A.279.a.44.i; A.280.a.44.i; A.281.a.44.i;
A.282.a.44.i;
A.283.a.44.i; A.284.a.44.i; A.285.a.44.i; A.286.a.44.i; A.287.a.44.i;
A.288.a.44.i;
A.289.a.44.i; A.290.a.44.i; A.291.a.44.i; A.292.a.44.i; A.293.a.44.i;
A.294.a.44.i;
A.295.a.44.i; A.296.a.44.i; A.297.a.44.i; A.298.a.44.i; A.299.a.44.i;
A.300.a.44.i;
A.301.a.44.i; A.302.a.44.i; A.303.a.44.i; A.304.a.44.i; A.305.a.44.i;
A.306.a.44.i;
A.307.a.44.i; A.308.a.44.i; A.309.a.44.i; A.310.a.44.i; A.311.a.44.i;
A.3I2.a.44.i;
A.313.a.44.i; A.314.a.44.i; A.315.a.44.i; A.316.a.44.i; A.317.a.44.i;
A.3I8.a.44.i;
A.319.a.44.i; A.320.a.44.i; A.321.a.44.i; A.322.a.44.i; A.323.a.44.i;
A.324.a.44.i;
A.325.a.44.i; A.326.a.44.i; A.327.a.44.i; A.328.a.44.i; A.329.a.44.i;
A.330.a.44.i;
A.331.a.44.i; A.332.a.44.i; A.333.a.44.i; A.334.a.44.i; A.335.a.44.i;
A.336.a.44.i;
A.337.a.44.i; A.338.a.44.i; A.339.a.44.i; A.340.a.44.i; A.341.a.44.i;
A.342.a.44.i;
A.343.a.44.i; A.344.a.44.i; A.345.a.44.i; A.346.a.44.i; A.347.a.44.i;
A.348.a.44.i;
A.349.a.44.i; A.350.a.44.i; A.351.a.44.i; A.352.a.44.i; A.353.a.44.i;
A.354.a.44.i;
A.355.a.44.i; A.356.a.44.i; A.357.a.44.i; A.358.a.44.i; B.2.a.44.i;
B.3.a.44.i;
B.4.a.44.i; B.5.a.44.i; B.9.a.44.i; B.100.a.44.i; B.101.a.44.i; B.102.a.44.i;
B.103.a.44.i;
B.104.a.44.i; B.105.a.44.i; 8.106.a.44.i; B.107.a.44.i; 8.108.a.44.i;
B.109.a.44.i;
B.110.a.44.i; B.111.a.44.i; B.112.a.44.i; B.113.a.44.i; B.114.a.44.i;
B.115.a.44.i;
B.116.a.44.i; B.117.a.44.i; B.118.a.44.i; B.119.a.44.i; B.120.a.44.i;
B.121.a.44.i;
B.122.a.44.i; B.123.a.44.i; B.124.a.44.i; B.125.a.44.i; B.126.a.44,i;
B.I27.a.44.i;
B.I28.a.44.i; B.129.a.44.i; B.130.a.44.i; B.131.a.44.i; B.132.a.44.i;
B.133.a.44.i;
B.134.a.44.i; B.135.a.44.i; B.136.a.44.i; B.137.a.44.i; B.138.a.44.i;
B.139.a.44.i;
B.140.a.44.i; B.141.a.44.i; B.142.a.44.i; B.143.a.44.i; B.144.a.44.i;
B.145.a.44.i;
B.146.a.44.i; B.147.a.44.i; B.148.a.44.i; B.149.a.44.i; B.150.a.44.i;
B.151.a.44.i;
B.152.a.44.i; B.153.a.44.i; B.154.a.44.i; B.155.a.44.i; B.156.a.44.i;
B.157.a.44.i;
B.158.a.44.i; B.159.a.44.i; B.160.a.44.i; B.161.a.44.i; B.162.a.44.i;
B.163.a.44.i;
B.164.a.44.i; B.165.a.44.i; B.166.a.44.i; B.167.a.44.i; B.168.a.44.i;
B.169.a.44.i;
B.170.a.44.i; B.171.a.44.i; B.172.a.44.i; B.I73.a.44.i; B.174.a.44.i;
B.175.a.44.i;

B.176.a.44.i; B.177.a.44.i; B.178.a.44.i; B.179.a.44.i; B.180.a.44.i;
B.181.a.44.i;
B.182.a.44.i; B.183.a.44.i; B.184.a.44.i; B.185.a.44.i; B.186.a.44.i;
B.187.a.44.i;
B.188.a.44.i; B.189.a.44.i; B.190.a.44.i; B.191.a.44.i; B.192.a.44.i;
B.193.a.44.i;
B.l9~.a.44.i; B.195.a.44.i; B.196.a.44.i; B.197.a.44.i; B.198.a.44.i;
B.199.a.44.i;
B.200.a.44.i; B.201.a.44.i; B.202.a.44.i; B.203.a.44.i; B.204.a.44.i;
B.205.a.44.i;
B.206.a.44.i; B.207.a.44.i; B.208.a.44.i; B.209.a.44.i; B.210.a.44.i;
B.211.a.44.i;
B.212.a.44.i; B.213.a.44.i; B.214.a.44.i; B.215.a.44.i; B.216.a.44.i;
B.217.a.44.i;
B.218.a.44.i; B.219.a.44.i; B.220.a.44.i; B.221.a.44.i; B.222.a.44.i;
B.223.a.44.i;
B.224.a.44.i; B.225.a.44.i; B.226.a.44.i; B.227.a.44.i; B.228.a.44.i;
B.229.a.44.i;
B.230.a.44.i; B.231.a.44.i; B.232.a.44.i; B.233.a.44.i; B.234.a.44.i;
B.235.a.44.i;
B.236.a.44.i; B.237.a.44.i; B.238.a.44.i; B.239.a.44.i; B.240.a.44.i;
B.241.a.44.i;
B.242.a.44.i; B.243.a.44.i; B.244.a.44.i; B.245.a.44.i; B.246.a.44.i;
B.247.a.44.i;
B.248.a.44.i; B.249.a.44.i; B.250.a.44.i; B.251.a.44.i; B.252.a.44.i;
B.253.a.44.i;
8.254.a.44.i; B.255.a.44.i; B.256.a.44.i; B.257.a.44.i; B.258.a.44.i;
B.259.a.44.i;
B.260.a.44.i; B.261.a.44.i; B.262.a.44.i; B.263.a.44.i; B.264.a.44.i;
B.265.a.44.i;
B.266.a.44.i; B.267.a.44.i; B.268.a.44.i; B.269.a.44.i; B.270.a.44.i;
B.271.a.44.i;
B.272.a.44.i; B.273.a.44.i; B.274.a.44.i; B.275.a.44.i; B.276.a.44.i;
B.277.a.44.i;
B.278.a.44.i; B.279.a.44.i; B.280.a.44.i; B.281.a.44.i; B.282.a.44.i;
B.283.a.44.i;
B.284.a.44.i; B.285.a.44.i; B.286.a.44.i; B.287.a.44.i; B.288.a.44.i;
B.289.a.44.i;
B.290.a.44.i; B.291.a.44.i; B.292.a.44.i; B.293.a.44.i; B.294.a.44.i;
B.295.a.44.i;
B.296.a.44.i; B.297.a.44.i; B.298.a.44.i; B.299.a.44.i; B.300.a.44.i;
B.301.a.44.i;
B.302.a.44.i; B.303.a.44.i; B.304.a.44.i; B.305.a.44.i; B.306.a.44.i;
B.307.a.44.i;
B.308.a.44.i; B.309.a.44.i; 8.310.a.44.i; B.311.a.44.i; B.312.a.44.i;
B.313.a.44.i;
B.314.a.44.i; B.315.a.44.i; B.316.a.44.i; B.317.a.44.i; B.318.a.44.i;
B.319.a.44.i;
B.320.a.44.i; B.321.a.44.i; B.322.a.44.i; B.323.a.44.i; B.324.a.44.i;
B.325.a.44.i;
B.326.a.44.i; B.327.a.44.i; B.328.a.44.i; B.329.a.44.i; B.330.a.44.i;
B.331.a.44.i;
B.332.a.44.i; B.333.a.44.i; B.334.a.44.i; B.335.a.44.i; B.336.a.44.i;
8.337.a.44.i;
B.338.a.44.i; B.339.a.44.i; B.340.a.44.i; B.341.a.44.i; B.342.a.44.i;
B.343.a.44.i;
B.344.a.44.i; B.345.a.44.i; B.346.a.44.i; B.347.a.44.i; B.348.a.44.i;
B.349.a.44.i;
B.350.a.44.i; B.351.a.44.i; B.352.a.44.i; B.353.a.44.i; B.354.a.44.i;
B.355.a.44.i;
B.356.a.44.i; B.357.a.44.i; B.358.a.44.i; E.2.a.44.i; E.3.a.44.i; E.4.a.44.i;
E.5.a.44.i;
E.9.a.44.i; E.100.a.44.i; E.101.a.44.i; E.102.a.44.i; E.103.a.44.i;
E.104.a.44.i;
E.105.a.44.i; E.106.a.44.i; E.107.a.44.i; E.108.a.44.i; E.109.a.44.i;
E.110.a.44.i;
E.lll.a.44.i; E.112.a.44.i; E.113.a.44.i; E.114.a.44.i; E.115.a.44.i;
E.116.a.44.i;
E.117.a.44.i; E.118.a.44.i; E.119.a.44.i; E.120.a.44.i; E.121.a.44,i;
E.122.a.44.i;
E.123.a.44.i; E.124.a.44.i; E.125.a.44.i; E.126.a.44.i; E.127.a.44.i;
E.I28.a.44.i;
E.129.a.44.i; E.130.a.44.i; E.131.a.44.i; E.132.a.44.i; E.133.a.44.i;
E.134.a.44.i;
E.135.a.44.i; E.136.a.44.i; E.137.a.44.i; E.138.a.44.i; E.139.a.44.i;
E.140.a.44.i;
E.141.a.44.i; E.142.a.44.i; E.143.a.44.i; E.144.a.44.i; E.145.a.44.i;
E.146.a.44.i;
E.147.a.44.i; E.148.a.44.i; E.149.a.44.i; E.150.a.44.i; E.151.a.44.i;
E.152.a.44.i;
E.153.a.44.i; E.154.a.44.i; E.155.a.44.i; E.156.a.44.i; E.157.a.44.i;
E.158.a.44.i;
E.159.a.44.i; E.160.a.44.i; E.161.a.44.i; E.162.a.44.i; E.163.a.44.i;
E.164.a.44.i;
E.165.a.44.i; E.166.a.44.i; E.267.a.44.i; E.168.a.44.i; E.169.a.44.i;
E.170.a.44.i;
E.171.a.44.i; E.172.a.44.i; E.173.a.44.i; E.174.a.44.i; E.175.a.44.i;
E.176.a.44.i;
E.177.a.44.i; E.178.a.44.i; E.179.a.44.i; E.180.a.44.i; E.181.a.44.i;
E.182.a.44.i;
E.183.a.44.i; E.184.a.44.i; E.185.a.44.i; E.186.a.44.i; E.187.a.44.i;
E.188.a.44.i;
E.189.a.44.i; E.190.a.44.i; E.191.a.44.i; E.192.a.44.i; E.193.a.44.i;
E.194.a.44.i;

E.195.a.44.i; E.196.a.44.i; E.197.a.44.i; E.198.a.44.i; E.199.a.44.i;
E.200.a.44.i;
E.201.a.44.i; E.202.a.44.i; E.203.a.44.i; E.204.a.44.i; E.205.a.44.i;
E.206.a.44.i;
E.207.a.44.i; E.208.a.44.i; E.209.a.44.i; E.210.a.44.i; E.211.a.44.i;
E.212.a.44.i;
E.213.a.44.i; E.214.a.44.i; E.215.a.44.i; E.216.a.44.i; E.217.a.44.i;
E.218.a.44.i;
E.2I9.a.44.i; E.220.a.44.i; E.221.a.44.i; E.222.a.44.i; E.223.a.44.i;
E.224.a.44.i;
E.225.a.44.i; E.226.a.44.i; E.227.a.44.i; E.228.a.44.i; E.229.a.44.i;
E.230.a.44.i;
E.231.a.44.i; E.232.a.44.i; E.233.a.44.i; E.234.a.44.i; E.235.a.44.i;
E.236.a.44.i;
E.237.a.44.i; E.238.a.44.i; E.239.a.44.i; E.240.a.44.i; E,241.a.44.i;
E.242.a.44.i;
E.243.a.44.i; E.244.a.44.i; E.245.a.44.i; E.246.a.44.i; E.247.a.44.i;
E.248.a.44.i;
E.249.a.44.i; E.250.a.44.i; E.251.a.44.i; E.252.a.44.i; E.253.a.44.i;
E.254.a.44.i;
E.255.a.44.i; E.256.a.44.i; E.257.a.44.i; E.258.a.44.i; E.259.a.44.i;
E.260.a.44.i;
E.261.a.44.i; E.262.a.44.i; E.263.a.44.i; E.264.a.44.i; E.265.a.44.i;
E.266.a.44.i;
E.267.a.44.i; E.268.a.44.i; E.269.a.44.i; E.270.a.44.i; E.271.a.44.i;
E.272.a.44.i;
E.273.a.44.i; E.274.a.44.i; E.275.a.44.i; E.276.a.44.i; E.277.a.44.i;
E.278.a.44.i;
E.279.a.44.i; E.280.a.44.i; E.281.a.44.i; E.282.a.44.i; E.283.a.44.i;
E.284.a.44.i;
E.285.a.44.i; E.286.a.44.i; E.287.a.44.i; E.288.a.44.i; E.289.a.44.i;
E.290.a.44.i;
E.291.a.44.i; E.292.a.44.i; E.293.a.44.i; E.294.a.44.i; E.295.a.44.i;
E.296.a.44.i;
E.297.a.44.i; E.298.a.44.i; E.299.a.44.i; E.300.a.44.i; E.301.a.44.i;
E.302.a.44.i;
E.303.a.44.i; E.304.a.44.i; E.305.a.44.i; E.306.a.44.i; E.307.a.44.i;
E.308.a.44.i;
E.309.a.44.i; E.310.a.44.i; E.311.a.44.i; E.312.a.44.i; E.313.a.44.i;
E.314.a.44.i;
E.315.a.44.i; E.316.a.44.i; E.317.a.44.i; E.318.a.44.i; E.319.a.44.i;
E.320.a.44.i;
E.321.a.44.i; E.322.a.44.i; E.323.a.44.i; E.324.a.44.i; E.325.a.44.i;
E.326.a.44.i;
E.327.a.44.i; E.328.a.44.i; E.329.a.44.i; E.330.a.44.i; E.331.a.44.i;
E.332.a.44.i;
E.333.a.44.i; E.334.a.44.i; E.335.a.44.i; E.336.a.44.i; E.337.a.44.i;
E.338.a.44.i;
E.339.a.44.i; E.340.a.44.i; E.341.a.44.i; E.342.a.44.i; E.343.a.44.i;
E.344.a.44.i;
E.345.a.44.i; E.346.a.44.i; E.347.a.44.i; E.348.a.44.i; E.349.a.44.i;
E.350.a.44.i;
E.351.a.44.i; E.352.a.44.i; E.353.a.44.i; E.354.a.44.i; E.355.a.44.i;
E.356.a.44.i;
E.357.a.44.i; E.358.a.44.i; B.2.a.4.i; B.3.a.4.i; B.4.a.4.i; B.5.a.4.i;
B.9.a.4.i;
B.100.a.4.i; B.lOl.a.4.i; B.102.a.4.i; B.103.a.4.i; B.104.a.4.i; B.105.a.4.i;
B.106.a.4.i;
B.107.a.4.i; B.108.a.4.i; 8.109.a.4.i; B.110.a.4.i; B.lll.a.4.i; B.112.a.4.i;
B.113.a.4.i;
B.114.a.4.i; B.115.a.4.i; B.116.a.4.i; B.117.a.4.i; B.118.a.4.i; B.119.a.4.i;
B.120.a.4.i;
B.121.a.4.i; B.122.a.4.i; B.123.a.4.i; B.124.a.4.i; B.125.a.4.i; B.126.a.4.i;
B.127.a.4.i;
B.128.a.4.i; B.129.a.4.i; B.130.a.4.i; B.131.a.4.i; B.132.a.4.i; B.133.a.4.i;
B.134.a.4.i;
B.135.a.4.i; B.136.a.4.i; B.137.a.4.i; B.138.a.4.i; 8.139.a.4.i; B.140.a.4.i;
B.141.a.4.i;
B.142.a.4.i; B.143.a.4.i; 8.144.a.4.i; B.145.a.4.i; B.146.a.4.i; B.147.a.4.i;
B.148.a.4.i;
B.149.a.4.i; B.150.a.4.i; B.151.a.4.i; B.152.a.4.i; B.153.a.4.i; B.154.a.4.i;
B.155.a.4.i;
B.156.a.4.i; B.157.a.4.i; B.158.a.4.i; B.159.a.4.i; B.160.a.4.i; B.161.a.4.i;
B.162.a.4.i;
8.163.a.4.i; B.164.a.4.i; B.165.a.4.i; B.166.a.4.i; B.167.a.4.i; B.168.a.4.i;
B.169.a.4.i;
B.170.a.4.i; B.171.a.4.i; B.172.a.4.i; B.173.a.4.i; B.174.a.4.i; B.175.a.4.i;
B.176.a.4.i;
B.177.a.4.i; B.178.a.4.i; B.179.a.4.i; B.180.a.4.i; B.181.a.4.i; B.182.a.4.i;
B.183.a.4.i;
B.184.a.4.i; B.185.a.4.i; B.186.a.4.i; B.187.a.4.i; B.188.a.4.i; B.189.a.4.i;
B.190.a.4.i;
B.191.a.4.i; B.192.a.4.i; B.193.a.4.i; B.194.a.4.i; B.195.a.4.i; B.196.a.4.i;
B.197.a.4.i;
B.198.a.4.i; B.199.a.4.i; B.200.a.4.i; B.201.a.4.i; B.202.a.4.i; B.203.a.4.i;
B.204.a.4.i;
B.205.a.4.i; B.206.a.4.i; B.207.a.4.i; B.208.a.4.i; B.209.a.4.i; B.210.a.4.i;
B.211.a.4.i;
B.212.a.4.i; B.213.a.4.i; 8.214.a.4.i; B.215.a.4.i; B.216.a.4.i; B.217.a.4.i;
B.218.a.4.i;
B.219.a.4.i; B.220.a.4.i; B.221.a.4.i; B.222.a.4.i; 8.223.a.4.i; B.224.a.4.i;
B.225.a.4.i;
B.226.a.4.i; B.227.a.4.i; B.228.a.4.i; B.229.a.4.i; B.230.a.4.i; B.231.a.4.i;
B.232.a.4.i;

B.233.a.4.i; B.234.a.4.i; B.235.a.4.i; B.236.a.4.i; B.237.a.4.i; 8.238.a.4.i;
B.239.a.4.i;
B.240.a.4.i; 8.241.a.4.i; B.242.a.4.i; B.243.a.4.i; B.244.a.4.i; B.245.a.4.i;
B.246.a.4.i;
B.247.a.4.i; B.248.a.4.i; B.249.a.4.i; B.250.a.4.i; B.251.a.4.i; B.252.a.4.i;
B.253.a.4.i;
B.254.a.4.i; B.255.a.4.i; B.256.a.4.i; B.257.a.4.i; B.258.a.4.i; B.259.a.4.i;
B.260.a.4.i;
B.261.a.4.i; B.262.a.4.i; B.263.a.4.i; B.264.a.4.i; B.265.a.4.i; B.266.a.4.i;
B.267.a.4.i;
B.268.a.4.i; B.269.a.4.i; B.270.a.4.i; B.271.a.4.i; B.272.a.4.i; B.273.a.4.i;
B.274.a.4.i;
8.275.a.4.i; B.276.a.4.i; B.277.a.4.i; B.278.a.4.i; B.279.a.4.i; B.280.a.4.i;
B.281.a.4.i;
B.282.a.4.i; B.283.a.4.i; B.284.a.4.i; B.285.a.4.i; B.286.a.4.i; B.287.a.4.i;
B.288.a.4.i;
B.289.a.4.i; B.290.a.4.i; B.291.a.4.i; B.292.a.4.i; B.293.a.4.i; B.294.a.4.i;
B.295.a.4.i;
B.296.a.4.i; B.297.a.4.i; B.298.a.4.i; B.299.a.4.i; B.300.a.4.i; B.301.a.4.i;
B.302.a.4.i;
B.303.a.4.i; B.304.a.4.i; B.305.a.4.i; B.306.a.4.i; B.307.a.4.i; B.308.a.4.i;
B.309.a.4.i;
B.310.a.4.i; B.311.a.4.i; B.312.a.4.i; B.313.a.4.i; B.314.a.4.i; B.315.a.4.i;
B.316.a.4.i;
B.317.a.4.i; B.318.a.4.i; B.319.a.4.i; B.320.a.4.i; B.321.a.4.i; B.322.a.4.i;
B.323.a.4.i;
B.324.a.4.i; 8.325.a.4.i; B.326.a.4.i; B.327.a.4.i; B.328.a.4.i; B.329.a.4.i;
B.330.a.4.i;
B.331.a.4.i; B.332.a.4.i; B.333.a.4.i; B.334.a.4.i; B.335.a.4.i; B.336.a.4.i;
B.337.a.4.i;
B.338.a.4.i; B.339.a.4.i; B.340.a.4.i; B.341.a.4.i; B.342.a.4.i; B.343.a.4.i;
B.344.a.4.i;
B.345.a.4.i; B.346.a.4.i; B.347.a.4.i; B.348.a.4.i; B.349.a.4.i; B.350.a.4.i;
B.351.a.4.i;
B.352.a.4.i; B.353.a.4.i; B.354.a.4.i; B.355.a.4.i; B.356.a.4.i; B.357.a.4.i;
B.358.a.4.i;
E.2.a.4.i; E.3.a.4.i; E.4.a.4.i; E.5.a.4.i; E.9.a.4.i; E.100.a.4.i;
E.101.a.4.i; E.102.a.4.i;
E.103.a.4.i; E.104.a.4.i; E.105.a.4.i; E.106.a.4.i; E.107.a.4.i; E.108.a.4.i;
E.109:a.4.i;
E.110.a.4.i; E.lll.a.4.i; E.112.a.4.i; E.113.a.4.i; E.114.a.4.i; E.115.a.4.i;
E.116.a.4.i;
E.117.a.4.i; E.118.a.4.i; E.119.a.4.i; E.120.a.4.i; E.121.a.4.i; E.122.a.4.i;
E.123.a.4.i;
E.124.a.4.i; E.125.a.4.i; E.126.a.4.i; E.127.a.4.i; E.128.a.4.i; E.129.a.4.i;
E.130.a.4.i;
E.131.a.4.i; E.I32.a.4.i; E.133.a.4.i; E.134.a.4.i; E.135.a.4.i; E.136.a.4.i;
E.137.a.4.i;
E.138.a.4.i; E.139.a.4.i; E.140.a.4.i; E.141.a.4.i; E.142.a.4.i; E.143.a.4.i;
E.144.a.4.i;
E.145.a.4.i; E.146.a.4.i; E.147.a.4.i; E.148.a.4.i; E.149.a.4.i; E.150.a.4.i;
E.151.a.4.i;
E.152.a.4.i; E.153.a.4.i; E.154.a.4.i; E.155.a.4.i; E.156.a.4.i; E.157.a.4.i;
E.158.a.4.i;
E.159.a.4.i; E.160.a.4.i; E.161.a.4.i; E.162.a.4.i; E.163.a.4.i; E.164.a.4.i;
E.165.a.4.i;
E.166.a.4.i; E.167.a.4.i; E.168.a.4.i; E.169.a.4.i; E.170.a.4.i; E.171.a.4.i;
E.172.a.4.i;
E.173.a.4.i; E.174.a.4.i; E.175.a.4.i; E.176.a.4.i; E.177.a.4.i; E.178.a.4.i;
E.179.a.4.i;
E.180.a.4.i; E.181.a.4.i; E.182.a.4.i; E.183.a.4.i; E.1$4.a.4.i; E.185.a.4.i;
E.186.a.4.i;
E.187.a.4.i; E.188.a.4.i; E.189.a.4.i; E.190.a.4.i; E.191.a.4.i; E.192.a.4.i;
E.193.a.4.i;
E.194.a.4.i; E.195.a.4.i; E.196.a.4.i; E.197.a.4.i; E.198.a.4.i; E.199.a.4.i;
E.200.a.4.i;
E.201.a.4.i; E.202.a.4.i; E.203.a.4.i; E.204.a.4.i; E.205.a.4.i; E.206.a.4.i;
E.207.a.4.i;
E.208.a.4.i; E.209.a.4.i; E.210.a.4.i; E.211.a.4.i; E.212.a.4.i; E.213.a.4.i;
E.214.a.4.i;
E.215.a.4.i; E.216.a.4.i; E.217.a.4.i; E.218.a.4.i; E.219.a.4.i; E.220.a.4.i;
E.221.a.4.i;
E.222.a.4.i; E.223.a.4.i; E.224.a.4.i; E.225.a.4.i; E.226.a.4.i; E.227.a.4.i;
E.228.a.4.i;
E.229.a.4.i; E.230.a.4.i; E.231.a.4.i; E.232.a.4.i; E.233.a.4.i; E.234.a.4.i;
E.235.a.4.i;
E.236.a.4.i; E.237.a.4.i; E.238.a.4.i; E.239.a.4.i; E.240.a.4.i; E.241.a.4.i;
E.242.a.4.i;
E.243.a.4.i; E.244.a.4.i; E.245.a.4.i; E.246.a.4.i; E.247.a.4.i; E.248.a.4.i;
E.249.a.4.i;
E.250.a.4.i; E.251.a.4.i; E.252.a.4.i; E.253.a.4.i; E.254.a.4.i; E.255.a.4.i;
E.256.a.4.i;
E.257.a.4.i; E.258.a.4.i; E.259.a.4.i; E.260.a.4.i; E.261.a.4.i; E.262.a.4.i;
E.263.a.4.i;
E.264.a.4.i; E.265.a.4.i; E.266.a.4.i; E.267.a.4.i; E.268.a.4.i; E.269.a.4.i;
E.270.a.4.i;
E.271.a.4.i; E.272.a.4.i; E.273.a.4.i; E.274.a.4.i; E.275.a.4.i; E.276.a.4.i;
E.277.a.4.i;
E.278.a.4.i; E.279.a.4.i; E.280.a.4.i; E.281.a.4.i; E.282.a.4.i; E.283.a.4.i;
E.284.a.4.i;
E.285.a.4.i; E.286.a.4.i; E.287.a.4.i; E.288.a.4.i; E.289.a.4.i; E.290.a.4.i;
E.291.a.4.i;
E.292.a.4.i; E.293.a.4.i; E.294.a.4.i; E.295.a.4.i; E.296.a.4.i; E.297.a.4.i;
E.298.a.4.i;

WO 99/14185 pCT/US98/19355 E.299.a.4.i; E.300.a.4.i; E.301.a.4.i; E.302.a.4.i; E.303.a.4.i; E.304.a.4.i;
E.305.a.4.i;
E.306.a.4.i; E.307.a.4.i; E.308.a.4.i; E.309.a.4.i; E.310.a.4.i; E.311.a.4.i;
E.312.a.4.i;
E.313.a.4.i; E.314.a.4.i; E.315.a.4.i; E.316.a.4.i; E.317.a.4.i; E.318.a.4.i;
E.319.a.4.i;
E.320.a.4.i; E.321.a.4.i; E.322.a.4.i; E.323.a.4.i; E.324.a.4.i; E.325.a.4.i;
E.326.a.4.i;
E.327.a.4.i; E.328.a.4.i; E.329.a.4.i; E.330.a.4.i; E.331.a.4.i; E.332.a.4.i;
E.333.a.4.i;
E.334.a.4.i; E.335.a.4.i; E.336.a.4.i; E.337.a.4.i; E.338.a.4.i; E.339.a.4.i;
E.340.a.4.i;
E.341.a.4.i; E.342.a.4.i; E.343.a.4.i; E.344.a.4.i; E.345.a.4.i; E.346.a.4.i;
E.347.a.4.i;
E.348.a.4.i; E.349.a.4.i; E.350.a.4.i; E.351.a.4.i; E.352.a.4.i; E.353.a.4.i;
E.354.a.4.i;
E.355.a.4.i; E.356.a.4.i; E.357.a.4.i; E.358.a.4.i; B.2.a.ll.i; B.3.a.ll.i;
B.4.a.Il.i;
B.S.a.ll.i; B.9.a.11.i; B.100.a.11.i; B.101.a.ll.i; B.102.a.11.i;
B.103.a.ll.i;
B.104.a.ll.i; B.105.a.ll.i; B.106.a.11.i; B.107.a.ll.i; B.108.a.ll.i;
B.109.a.ll.i;
B.110.a.11.i; B.111.a.ll.i; B.112.a.ll.i; B.113.a.ll.i; B.114.a.ll.i;
B.115.a.ll.i;
B.116.a.ll.i; B.117.a.11.i; B.118.a.11.i; B.119.a.ll.i; B.120.a.ll.i;
8.121.a.ll.i;
B.122.a.11.i; B.123.a.11.i; B.124.a.11.i; 8.125.a.ll.i; B.126.a.11.i;
B.127.a.ll.i;
B.128.a.11.i; B.129.a.ll.i; B.130.a.ll.i; B.131.a.ll.i; B.132.a.11.i;
B.133.a.11.i;
B.134.a.ll.i; B.135.a.11.i; B.136.a.11.i; B.137.a.ll.i; B.138.a.11.i;
B.139.a.ll.i;
B.140.a.ll.i; B.141.a.ll.i; B.142.a.ll.i; B.143.a.ll.i; B.144.a.ll.i;
B.145.a.ll.i;
B.146.a.ll.i; B.147.a.ll.i; B.148.a.ll.i; B.149.a.ll.i; B.150.a.11.i;
B.151.a.11.i;
B.152.a.ll.i; B.153.a.ll.i; B.154.a.ll.i; B.155.a.ll.i; B.156.a.ll.i;
B.157.a.11.i;
B.158.a.11.i; B.159.a.ll.i; B.160.a.ll.i; B.161.a.11.i; B.162.a.ll.i;
B.163.a.ll.i;
B.164.a.11.i; B.165.a.ll.i; B.166.a.ll.i; B.167.a.ll.i; B.168.a.ll.i;
B.169.a.11.i;
B.170.a.ll.i; B.171.a.ll.i; B.172.a.ll.i; B.173.a.ll.i; B.174.a.ll.i;
B.175.a.11.i;
B.176.a.11.i; B.177.a.11.i; B.178.a.ll.i; B.179.a.11.i; B.180.a.ll.i;
B.181.a.ll.i;
B.182.a.ll.i; B.183.a.ll.i; B.184.a.11.i; B.185.a.ll.i; B.186.a.ll.i;
B.187.a.ll.i;
B.188.a.11.i; B.189.a.ll.i; B.190.a.11.i; B.191.a.ll.i; B.192.a.ll.i;
B.193.a.ll.i;
B.194.a.ll.i; B.195.a.ll.i; B.196.a.ll.i; 8.197.a.ll.i; B.198.a.ll.i;
B.199.a.11.i;
B.200.a.11.i; B.201.a.11.i; B.202.a.11.i; B.203.a.ll.i; B.204.a.ll.i;
8.205.a.ll.i;
B.206.a.ll.i; B.207.a.ll.i; B.208.a.ll.i; B.209.a.ll.i; B.210.a.ll.i;
B.211.a.ll.i;
B.212.a.11.i; B.213.a.11.i; B.214.a.11.i; B.215.a.ll.i; B.216.a.11.i;
B.217.a.ll.i;
B.218.a.ll.i; B.219.a.ll.i; B.220.a.ll.i; B.221.a.ll.i; B.222.a.ll.i;
B.223.a.ll.i;
B.224.a.ll.i; B.225.a.ll.i; B.226.a.11.i; B.227.a.ll.i; B.228.a.ll.i;
B.229.a.ll.i;
8.230.a.ll.i; B.231.a.ll.i; B.232.a.ll.i; B.233.a.ll.i; B.234.a.ll.i;
B.235.a.ll.i;
B.236.a.11.i; B.237.a.ll.i; B.238.a.11.i; B.239.a.11.i; B.240.a.ll.i;
B.241.a.ll.i;
B.242.a.ll.i; B.243.a.ll.i; B.244.a.11.i; B.245.a.ll.i; B.246.a.ll.i;
B.247.a.11.i;
B.248.a.11.i; B.249.a.ll.i; B.250.a.ll.i; B.251.a.ll.i; B.252.a.ll.i;
B.253.a.ll.i;
B.254.a.ll.i; B.255.a.11.i; B.256.a.ll.i; B.257.a.ll.i; B.258.a.ll.i;
B.259.a.ll.i;
B.260.a.ll.i; B.261.a.11.i; B.262.a.11.i; B.263.a.11.i; B.264.a.ll.i;
B.265.a.ll.i;
B.266.a.ll.i; B.267.a.11.i; B.268.a.ll.i; B.269.a.Il.i; B.270.a.ll.i;
B.271.a.11.i;
B.272.a.ll.i; B.273.a.11.i; B.274.a.11.i; 8.275.a.ll.i; B.276.a.ll.i;
B.277.a.ll.i;
B.278.a.ll.i; B.279.a.ll.i; B.280.a.11.i; B.281.a.ll.i; B.282.a.11.i;
B.283.a.ll.i;
B.284.a.11.i; B.285.a.11.i; B.286.a.11.i; B.287.a.ll.i; B.288.a.11.i;
B.289.a.ll.i;
B.290.a.ll.i; B.291.a.ll.i; B.292.a.11.i; B.293.a.11.i; B.294.a.ll.i;
B.295.a.ll.i;
B.296.a.11.i; B.297.a.ll.i; B.298.a.11.i; B.299.a.11.i; B.300.a.ll.i;
B.301.a.11.i;
B.302.a.11.i; B.303.a.ll.i; B.304.a.11.i; B.305.a.ll.i; B.306.a.ll.i;
B.307.a.ll.i;
B.308.a.ll.i; B.309.a.ll.i; B.310.a.ll.i; B.311.a.11.i; B.312.a.11.i;
B.313.a.ll.i;
B.314.a.11.i; B.315.a.ll.i; B.316.a.ll.i; B.317.a.11.i; B.318.a.ll.i;
B.319.a.ll.i;
B.320.a.ll.i; 8.321.a.ll.i; B.322.a.11.i; B.323.a.ll.i; B.324.a.ll.i;
8.325.a.ll.i;

B.326.a.11.i; B.327.a.ll.i; B.328.a.ll.i; B.329.a.ll.i; B.330.a.ll.i;
B.331.a.11.i;
B.332.a.ll.i; B.333.a.ll.i; B.334.a.ll.i; B.335.a.11.i; B.336.a.11.i;
B.337.a.11.i;
B.338.a.11.i; B.339.a.ll.i; B.340.a.11.i; B.341.a.11.i; B.342.a.lLi;
B.343.a.ll.i;
B.344.a.ll.i; B.345.a.ll.i; 8.346.a.11.i; B.347.a.ll.i; B.348.a.11.i;
B.349.a.ll.i;
B.350.a.ll.i; B.351.a.11.i; B.352.a.ll.i; B.353.a.ll.i; B.354.a.ll.i;
B.355.a.ll.i;
B.356.a.ll.i; B.357.a.ll.i; B.358.a.11.i; E.2.a.ll.i; E.3.a.11.i; E.4.a.ll.i;
E.S.a.ll.i;
E.9.a.11.i; E.100.a.ll.i; E.lOl.a.ll.i; E.102.a.ll.i; E.103.a.11.i;
E.104.a.ll.i;
E.105.a.ll.i; E.106.a.ll.i; E.107.a.11.i; E.108.a.11.i; E.109.a.ll.i;
E.110.a.ll.i;
E.111.a.ll.i; E.112.a.ll.i; E.113.a.ll.i; E.114.a.11.i; E.115.a.ll.i;
E.116.a.ll.i;
E.117.a.ll.i; E.118.a.ll.i; E.119.a.ll.i; E.120:a.ll.i; E.121.a.11.i;
E.122.a.11.i;
E.123.a.ll.i; E.124.a.ll.i; E.125.a.11.i; E.126.a.ll.i; E.127.a.11.i;
E.128.a.ll.i;
E.129.a.ll.i; E.130.a.ll.i; E.131.a.ll.i; E.132.a.11.i; E.133.a.11.i;
E.I34.a.11.i;
E.135.a.ll.i; E.136.a.11.i; E.137.a.ll.i; E.138.a.ll.i; E.139.a.ll.i;
E.140.a.11.i;
E.141.a.ll.i; E.142.a.11.i; E.143.a.11.i; E.144.a.ll.i; E.145.a.11.i;
E.146.a.11.i;
E.147.a.11.i; E.148.a.11.i; E.149.a.ll.i; E.150.a.ll.i; E.151.a.ll.i;
E.152.a.ll.i;
E.153.a.ll.i; E.154.a.ll.i; E.155.a.ll.i; E.156.a.ll.i; E.157.a.ll.i;
E.158.a.11.i;
E.159.a.ll.i; E.160.a.ll.i; E.161.a.11.i; E.162.a.ll.i; E.163.a.11.i;
E.164.a.ll.i;
E.165.a.11.i; E.166.a.11.i; E.167.a.ll.i; E.168.a.11.i; E.169.a.11.i;
E.170.a.ll.i;
E.171.a.ll.i; E.172.a.ll.i; E.173.a.11.i; E.174.a.ll.i; E.175.a.ll.i;
E.176.a.11.i;
E.177.a.ll.i; E.178.a.11.i; E.179.a.11.i; E.180.a.11.i; E.181.a.11.i;
E.182.a.11.i;
E.183.a.ll.i; E.1$4.a.11.i; E.185.a.ll.i; E.186.a.ll.i; E.187.a.ll.i;
E.188.a.ll.i;
E.189.a.11.i; E.190.a.11.i; E.191.a.ll.i; E.192.a.11.i; E.193.a.ll.i;
E.194.a.ll.i;
E.195.a.ll.i; E.196.a.ll.i; E.197.a.11.i; E.198.a.ll.i; E.199.a.ll.i;
E.200.a.ll.i;
E.201.a.ll.i; E.202.a.ll.i; E.203.a.11.i; E.204.a.11.i; E.205.a.11.i;
E.206.a.11.i;
E.207.a.ll.i; E.208.a.ll.i; E.209.a.ll.i; E.210.a.ll.i; E.211.a.11.i;
E.212.a.ll.i;
E.213.a.ll.i; E.214.a.ll.i; E.215.a.ll.i; E.216.a.ll.i; E.217.a.11.i;
E.218.a.ll.i;
E.219.a.ll.i; E.220.a.ll.i; E.221.a.11.i; E.222.a.ll.i; E.223.a.ll.i;
E.224.a.11.i;
E.225.a.11.i; E.226.a.11.i; E.227.a.11.i; E.228.a.11.i; E.229.a.ll.i;
E.230.a.11.i;
E.231.a.ll.i; E.232.a.ll.i; E.233.a.11.i; E.234.a.ll.i; E.235.a.ll.i;
E.236.a.11.i;
E.237.a.ll.i; E.238.a.ll.i; E.239.a.ll.i; E.240.a.ll.i; E.241.a.11.i;
E.242.a.11.i;
E.243.a.11.i; E.244.a.11.i; E.245.a.11.i; E.246.a.ll.i; E.247.a.ll.i;
E.248.a.ll.i;
E.249.a.11.i; E.250.a.11.i; E.251.a.ll.i; E.252.a.11.i; E.253.a.ll.i;
E.254.a.ll.i;
E.255.a.ll.i; E.256.a.ll.i; E.257.a.ll.i; E.258.a.Il.i; E.259.a.ll.i;
E.260.a.11.i;
E.261.a.ll.i; E.262.a.ll.i; E.263.a.ll.i; E.264.a.ll.i; E.265.a.ll.i;
E.266.a.ll.i;
E.267.a.ll.i; E.268.a.11.i; E.269.a.ll.i; E.270.a.ll.i; E.271.a.ll.i;
E.272.a.11.i;
E.273.a.ll.i; E.274.a.Il.i; E.275.a.ll.i; E.276.a.11.i; E.277.a.11.i;
E.278.a.ll.i;
E.279.a.ll.i; E.280.a.ll.i; E.281.a.ll.i; E.282.a.ll.i; E.283.a.ll.i;
E.284.a.ll.i;
E.285.a.11.i; E.286.a.11.i; E.287.a.ll.i; E.288.a.11.i; E.289.a.ll.i;
E.290.a.ll.i;
E.291.a.11.i; E.292.a.ll.i; E.293.a.lLi; E.294.a.ll.i; E.295.a.ll.i;
E.296.a.11.i;
E.297.a.ll.i; E.298.a.11.i; E.299.a.11.i; E.300.a.11.i; E.301.a.11.i;
E.302.a.ll.i;
E.303.a.ll.i; E.304.a.ll.i; E.305.a.ll.i; E.306.a.11.i; E.307.a.ll.i;
E.308.a.ll.i;
E.309.a.11.i; E.310.a.ll.i; E.311.a.11.i; E.312.a.ll.i; E.313.a.11.i;
E.314.a.11.i;
E.315.a.11.i; E.316.a.11.i; E.317.a.ll.i; E.318.a.ll.i; E.319.a.11.i;
E.320.a.ll.i;
E.321.a.11.i; E.322.a.11.i; E.323.a.ll.i; E.324.a.11.i; E.325.a.ll.i;
E.326.a.lLi;
E.327.a.ll.i; E.328.a.11.i; E.329.a.ll.i; E.330.a.11.i; E.331.a.ll.i;
E.332.a.ll.i;
E.333.a.11.i; E.334.a.ll.i; E.335.a.11.i; E.336.a.ll.i; E.337.a.11.i;
E.338.a.ll.i;
E.339.a.11.i; E.340.a.11.i; E.341.a.ll.i; E.342.a.ll.i; E.343.a.11.i;
E.344.a.ll.i;

E.345.a.11.i; E.346.a.11.i; E.347.a.11.i; E.348.a.11.i; E.349.a.ll.i;
E.350.a.ll.i;
E.351.a.ll.i; E.352.a.ll.i; E.353.a.ll.i; E.354.a.ll.i; E.355.a.11.i;
E.356.a.11.i;
E.357.a.11.i; E.358.a.ll.i; A.661.a.4.i; A.662.a.4.i; A.663.a.4.i;
A.664.a.4.i;
A.66~.a.4.i; B.661.a.4.i; B.662.a.4.i; B.663.a.4.i; B.664.a.4.i; B.665.a.4.i;
C.661.a.4.i;
C.662.a.4.i; C.663.a.4.i; C.664.a.4.i; C.665.a.4.i; A.661.a.11.i;
A.662.a.11.i;
A.663.a.11.i; A.664.a.ll.i; A.665.a.11.i; B.661.a.ll.i; B.662.a.ll.i;
B.663.a.ll.i;
B.b64.a.ll.i; B.665.a.ll.i; C.661.a.ll.i; C.662.a.11.i; C.663.a.11.i;
C.664.a.ll.i;
C.665.a.11.i; A.661.a.44.i; A.662.a.44.i; A.663.a.44.i; A.664.a.44.i;
A.665.a.44.i;
B.661.a.44.i; B.662.a.44.i; B.663.a.44.i; B.664.a.44.i; B.665.a.44.i;
C.661.a.44.i;
C.662.a.44.i; C.663.a.44.i; C.664.a.44.i; C.665.a.44.i; A.666.a.4.i;
A.666.a.ll.i;
A.666.a.44.i; A.666.b.4.i; A.666.b.ll.i; A.666.b.44.i; A.666.x.4.i;
A.666.x.ll.i;
A.666.x.44.i; A.666.y.4.i; A.666.y.11.i; A.666.y.44.i; A.666.z.4.i;
A.666.z.11.i;
A.666.z.4~4.i; A.666.A.4.i; A.666.A.ll.i; A.666.A.44.i; A.666.B.4.i;
A.666.B.ll.i;
A.666.B.44.i; A.666.C.4.i; A.666.C.ll.i; A.666.C.44.i; A.666.D.4.i;
A.666.D.ll.i;
A.666.D.44.i; A.666.E.4.i; A.666.E.11.i; A.666.E.44.i; A.666.F.4.i;
A.666.F.11.i;
A.666.F.44.i; B.666.a.4.i; B.666.a.ll.i; B.666.a.44.i; B.666.b.4.i;
B.666.b.ll.i;
B.666.b.44.i; B.666.x.4.i; B.666.x.ll.i; B.666.x.44.i; B.666.y.4.i;
B.666.y.ll.i;
B.666.y.44.i; B.666.z.4.i; B.666.z.ll.i; B.666.z.44.i; B.666.B.4.i;
B.666.B.ll.i;
B.666.B.44.i; B.666.B.4.i; B.666.B.11.i; B.666.B.44.i; B.666.C.4.i;
B.666.C.ll.i;
B.666.C.44.i; B.666.D.4.i; 8.666.D.ll.i; B.666.D.44.i; B.666.E.4.i;
B.666.E.ll.i;
B.666.E.44.i; B.666.F.4.i; B.666.F.ll.i; B.666.F.44.i; E.666.a.4.i;
E.666.a.11.i;
E.666.a.44.i; E.666.b.4.i; E.666.b.ll.i; E.666.b.44.i; E.666.x.4.i;
E.666.x.11.i;
E.666.x.44.i; E.666.y.4.i; E.666.y.11.i; E.666.y.44.i; E.666.z.4.i;
E.666.z.ll.i;
E.666.z.44.i; E.666.E.4.i; E.666.E.ll.i; E.666.E.44.i; E.666.B.4.i;
E.666.B.11.i;
E.666.B.44.i; E.666.C.4.i; E.666.C.ll.i; E.666.C.44.i; E.666.D.4.i;
E.666.D.ll.i;
E.666.D.44.i; E.666.E.4.i; E.666.E.ll.i; E.666.E.44.i; E.666.F.4.i;
E.666.F.ll.i;
E.666.F.44.i; A.2.a.46.i; A.3.a.46.i; A.4.a.46.i; A.5.a.46.i; A.7.a.46.i;
A.9.a.46.i;
A.100.a.46.i; A.lOl.a.46.i; A.102.a.46.i; A.103.a.46.i; A.104.a.46.i;
A.105.a.46.i;
A.106.a.46.i; A.107.a.46.i; A.108.a.46.i; A.109.a.46.i; A.110.a.46.i;
A.lll.a.46.i;
A.112.a.46.i; A.113.a.46.i; A.114.a.46.i; A.115.a.46.i; A.116.a.46.i;
A.117.a.46.i;
A.118.a.46.i; A.119.a.46.i; A.120.a.46.i; A.121.a.46.i; A.122.a.46.i;
A.123.a.46.i;
A.124.a.46.i; A.125.a.46.i; A.126.a.46.i; A.127.a.46.i; A.128.a.46.i;
A.129.a.46.i;
A.130.a.46.i; A.131.a.46.i; A.132.a.46.i; A.133.a.46.i; A.134.a.46.i;
A.135.a.46.i;
A.136.a.46.i; A.137.a.46.i; A.138.a.46.i; A.139.a.46.i; A.140.a.46.i;
A.141.a.46.i;
A.2.a.47.i; A.3.a.47.i; A.4.a.47.i; A.5.a.47.i; A.7.a.47.i; A.9.a.47.i;
A.100.a.47.i;
A.101.a.47.i; A.102.a.47.i; A.103.a.47.i; A.104.a.47.i; A.105.a.47.i;
A.106.a.47.i;
A.107.a.47.i; A.108.a.47.i; A.109.a.47.i; A.110.a.47.i; A.lll.a.47.i;
A.112.a.47.i;
A.113.a.47.i; A.114.a.47.i; A.115.a.47.i; A.116.a.47.i; A.117.a.47.i;
A.118.a.47.i;
A.119.a.47.i; A.120.a.47.i; A.121.a.47.i; A.122.a.47.i; A.123.a.47.i;
A.124.a.47.i;
A.125.a.47.i; A.126.a.47.i; A.127.a.47.i; A.128.a.47.i; A.129.a.47.i;
A.130.a.47.i;
A.131.a.47.i; A.132.a.47.i; A.133.a.47.i; A.134.a.47.i; A.135.a.47.i;
A.136.a.47.i;
A.137.a.47.i; A.138.a.47.i; A.139.a.47.i; A.140.a.47.i; A.141.a.47.i;
A.2.a.48.i;
A.3.a.48.i; A.4.a.48.i; A.5.a.48.i; A.7.a.48.i; A.9.a.48.i; A.100.a.48.i;
A.101.a.48.i;
A.102.a.48.i; A.103.a.48.i; A.104.a.48.i; A.105.a.48.i; A.106.a.48.i;
A.107.a.48.i;
A.108.a.48.i; A.109.a.48.i; A.110.a.48.i; A.111.a.48.i; A.112.a.48.i;
A.113.a.48.i;
A.114.a.48.i; A.115.a.48.i; A.116.a.48.i; A.117.a.48.i; A.118.a.48.i;
A.119.a.48.i;
A.120.a.48.i; A.l2I.a.48.i; A.122.a.48.i; A.123.a.48.i; A.124.a.48.i;
A.125.a.48.i;

A.126.a.48.i; A.127.a.48.i; A.128.a.48.i; A.129.a.48.i; A.130.a.48.i;
A.131.a.48.i;
A.132.a.48.i; A.133.a.48.i; A.134.a.48.i; A.135.a.48.i; A.136.a.48.i;
A.137.a.48.i;
A.138.a.48.i; A.139.a.48.i; A.140.a.48.i; A.141.a.48.i; A.2.a.49.i;
A.3.a.49.i;
A.4.a.49.i; A.S.a.49.i; A.7.a.49.i; A.9.a.49.i; A.100.a.49.i; A.101.a.49.i;
A.102.a.49.i;
A.103.a.49.i; A.104.a.49.i; A.105.a.49.i; A.106.a.49.i; A.107.a.49.i;
A.lO8.a.49.i;
A.109.a.49.i; A.110.a.49.i; A.111.a.49.i; A.112.a.49.i; A.113.a.49.i;
A.114.a.49.i;
A.115.a.49.i; A.116.a.49.i; A.117.a.49.i; A.118.a.49.i; A.119.a.49.i;
A.120.a.49.i;
A.121.a.49.i; A.122.a.49.i; A.123.a.49.i; A.124.a.49.i; A.125.a.49.i;
A.126.a.49.i;
A.127.a.49.i; A.128.a.49.i; A.129.a.49.i; A.130.a.49.i; A.131.a.49.i;
A.132.a.49.i;
A.133.a.49.i; A.134.a.49.i; A.135.a.49.i; A.136.a.49.i; A.137.a.49.i;
A.138.a.49.i;
A.139.a.49.i; A.140.a.49.i; A.141.a.49.i; A.2.a.50.i; A.3.a.50.i; A.4.a.50.i;
A.5.a.50.i;
A.7.a.50.i; A.9.a.50.i; A.100.a.50.i; A.lOl.a.50.i; A.102.a.50.i;
A.103.a.50.i;
A.104.a.50.i; A.105.a.50.i; A.106.a.50.i; A.107.a.50.i; A.108.a.50.i;
A.109.a.50.i;
A.110.a.50.i; A.111.a.50.i; A.112.a.50.i; A.113.a.50.i; A.114.a.50.i;
A.115.a.50.i;
A.116.a.50.i; A.117.a.50.i; A.118.a.50.i; A.119.a.50.i; A.120.a.50.i;
A.121.a.50.i;
A.122.a.50.i; A.123.a.50.i; A.124.a.50.i; A.125.a.50.i; A.126.a.50.i;
A.127.a.50.i;
A.128.a.50.i; A.129.a.50.i; A.130.a.50.i; A.131.a.50.i; A.132.a.50.i;
A.133.a.50.i;
A.134.a.50.i; A.135.a.50.i; A.136.a.50.i; A.137.a.50.i; A.138.a.50.i;
A.139.a.50.i;
A.140.a.50.i; A.141.a.50.i; A.2.a.51.i; A.3.a.51.i; A.4.a.51.i; A.S.a.5l.i;
A.7.a.51.i;
A.9.a.51.i; A.100.a.51.i; A.lOl.a.5Li; A.102.a.51.i; A.103.a.51.i;
A.104.a.51.i;
A.105.a.51.i; A.106.a.51.i; A.107.a.51.i; A.108.a.51.i; A.109.a.51.i;
A.110.a.51.i;
A.lll.a.5l.i; A.112.a.51.i; A.113.a.51.i; A.114.a.51.i; A.115.a.51.i;
A.116.a.51.i;
A.117.a.51.i; A.118.a.Sl.i; A.119.a.51.i; A.120.a.51.i; A.121.a.51.i;
A.122.a.51.i;
A.123.a.51.i; A.124.a.51.i; A.125.a.51.i; A.126.a.51.i; A.127.a.51.i;
A.128.a.51.i;
A.129.a.51.i; A.130.a.51.i; A.131.a.51.i; A.132.a.51.i; A.133.a.51.i;
A.134.a.51.i;
A.135.a.51.i; A.136.a.51.i; A.137.a.51.i; A.138.a.51.i; A.139.a.51.i;
A.140.a.51.i;
A.141.a.51.i; A.2.b.46.i; A.3.b.46.i; A.4.b.46.i; A.5.b.46.i; A.7.b.46.i;
A.9.b.46.i;
A.100.b.46.i; A.lOl.b.46.i; A.102.b.46.i; A.103.b.46.i; A.104.b.46.i;
A.105.b.46.i;
A.106.b.46.i; A.107.b.46.i; A.lO8.b.46.i; A.109.b.46.i; A.110.b.46.i;
A.111.b.46.i;
A.112.b.46.i; A.113.b.46.i; A.114.b.46.i; A.llS.b.46.i; A.116.b.46.i;
A.117.b.46.i;
A.118.b.46.i; A.119.b.46.i; A.120.b.46.i; A.121.b.46.i; A.122.b.46.i;
A.123.b.46.i;
A.124.b.46.i; A.125.b.46.i; A.126.b.46.i; A.127.b.46.i; A.128.b.46.i;
A.129.b.46.i;
A.130.b.46.i; A.131.b.46.i; A.132.b.46.i; A.133.b.46.i; A.134.b.46.i;
A.135.b.46.i;
A.136.b.46.i; A.137.b.46.i; A.138.b.46.i; A.139.b.46.i; A.140.b.46.i;
A.141.b.46.i;
A.2.b.47.i; A.3.b.47.i; A.4.b.47.i; A.5.b.47.i; A.7.b.47.i; A.9.b.47.i;
A.100.b.47.i;
A.101.b.47.i; A.102.b.47.i; A.103.b.47.i; A.104.b.47.i; A.105.b.47.i;
A.106.b.47.i;
A.107.b.47.i; A.108.b.47.i; A.109.b.47.i; A.110.b.47.i; A.111.b.47.i;
A.112.b.47.i;
A.113.b.47.i; A.114.b.47.i; A.115.b.47.i; A.116.b.47.i; A.117.b.47.i;
A.118.b.47.i;
A.119.b.47.i; A.120.b.47.i; A.121.b.47.i; A.122.b.47.i; A.123.b.47.i;
A.124.b.47.i;
A.125.b.47.i; A.126.b.47.i; A.127.b.47.i; A.128.b.47.i; A.129.b.47.i;
A.130.b.47.i;
A.131.b.47.i; A.132.b.47.i; A.133.b.47.i; A.134.b.47.i; A.135.b.47.i;
A.136.b.47.i;
A.137.b.47.i; A.138.b.47.i; A.139.b.47.i; A.140.b.47.i; A.141.b.47.i;
A.2.b.48.i;
A.3.b.48.i; A.4.b.48.i; A.5.b.48.i; A.7.b.48.i; A.9.b.48.i; A.100.b.48.i;
A.lOl.b.48.i;
A.102.b.48.i; A.103.b.48.i; A.104.b.48.i; A.105.b.48.i; A.106.b.48.i;
A.107.b.48.i;
A.108.b.48.i; A.109.b.48.i; A.110.b.48.i; A.111.b.48.i; A.112.b.48.i;
A.113.b.48.i;
A.114.b.48.i; A.115.b.48.i; A.116.b.48.i; A.lI7.b.48.i; A.118.b.48.i;
A.119.b.48.i;
A.120.b.48.i; A.121.b.48.i; A.122.b.48.i; A.123.b.48.i; A.124.b.48.i;
A.125.b.48.i;

A.126.b.48.i; A.127.b.48.i; A.128.b.48.i; A.129.b.48.i; A.130.b.48.i;
A.131.b.48.i;
A.132.b.48.i; A.133.b.48.i; A.134.b.48.i; A.135.b.48.i; A.136.b.48.i;
A.137.b.48.i;
A.138.b.48.i; A.139.b.48.i; A.140.b.48.i; A.141.b.48.i; A.2.b.49.i;
A.3.b.49.i;
A.4.b.49.i; A.5.b.49.i; A.7.b.49.i; A.9.b.49.i; A.100.b.49.i; A.101.b.49.i;
A.102.b.49.i;
A.103.b.49.i; A.104.b.49.i; A.105.b.49.i; A.106.b.49.i; A.107.b.49.i;
A.lO8.b.49.i;
A.109.b.49.i; A.110.b.49.i; A.111.b.49.i; A.112.b.49.i; A.113.b.49.i;
A.114.b.49.i;
A.115.b.49.i; A.116.b.49.i; A.117.b.49.i; A.118.b.49.i; A.119.b.49.i;
A.120.b.49.i;
A.121.b.49.i; A.122.b.49.i; A.123.b.49.i; A.124.b.49.i; A.125.b.49.i;
A.126.b.49.i;
A.127.b.49.i; A.128.b.49.i; A.129.b.49.i; A.130.b.49.i; A.131.b.49.i;
A.132.b.49.i;
A.133.b.49.i; A.134.b.49.i; A.135.b.49.i; A.136.b.49.i; A.137.b.49.i;
A.138.b.49.i;
A.139.b.49.i; A.140.b.49.i; A.141.b.49.i; A.2.b.50.i; A.3.b.50.i; A.4.b.50.i;
A.5.b.50.i;
A.7.b.50.i; A.9.b.50.i; A.100.b.50.i; A.lOl.b.50.i; A.102.b.50.i;
A.103.b.50.i;
A.104.b.50.i; A.105.b.50.i; A.106.b.50.i; A.107.b.50.i; A.lO8.b.50.i;
A.109.b.50.i;
A.110.b.50.i; A.111.b.50.i; A.112.b.50.i; A.113.b.50.i; A.114.b.50.i;
A.115.b.50.i;
A.116.b.50.i; A.117.b.50.i; A.118.b.50.i; A.119.b.50.i; A.120.b.50.i;
A.121.b.50.i;
A.122.b.50.i; A.123.b.50.i; A.124.b.50.i; A.125.b.50.i; A.126.b.50.i;
A.127.b.50.i;
A.128.b.50.i; A.129.b.50.i; A.I30.b.50.i; A.131.b.50.i; A.132.b.50.i;
A.133.b.50.i;
A.134.b.50.i; A.135.b.50.i; A.136.b.50.i; A.137.b.50.i; A.138.b.50.i;
A.139.b.50.i;
A.140.b.50.i; A.141.b.50.i; A.2.b.51.i; A.3.b.51.i; A.4.b.51.i; A.5.b.51.i;
A.7.b.51.i;
A.9.b.51.i; A.100.b.51.i; A.IOl.b.5l.i; A.102.b.51.i; A.103.b.51.i;
A.104.b.51.i;
A.105.b.51.i; A.106.b.51.i; A.107.b.51.i; A.108.b.51.i; A.109.b.51.i;
A.110.b.5Li;
A.111.b.51.i; A.112.b.51.i; A.113.b.51.i; A.114.b.51.i; A.115.b.51.i;
A.116.b.51.i;
A.117.b.51.i; A.118.b.51.i; A.119.b.51.i; A.120.b.51.i; A.121.b.51.i;
A.122.b.51.i;
A.123.b.51.i; A.124.b.51.i; A.125.b.51.i; A.126.b.51.i; A.127.b.51.i;
A.128.b.51.i;
A.129.b.51.i; A.130.b.51.i; A.131.b.51.i; A.132.b.51.i; A.133.b.51.i;
A.134.b.51.i;
A.135.b.51.i; A.136.b.51.i; A.137.b.51.i; A.138.b.51.i; A.139.b.51.i;
A.140.b.51.i;
A.141.b.51.i; A.2.x.46.i; A.3.x.46.i; A.4.x.46.i; A.5.x.46.i; A.7.x.46.i;
A.9.x.46.i;
A.100.x.46.i; A.101.x.46.i; A.102.x.46.i; A.103.x.46.i; A.104.x.46.i;
A.105.x.46.i;
A.106.x.46.i; A.107.x.46.i; A.108.x.46.i; A.109.x.46.i; A.110.x.46.i;
A.lll.x.46.i;
A.112.x.46.i; A.lI3.x.46.i; A.114.x.46.i; A.115.x.46.i; A.llb.x.46.i;
A.117.x.46.i;
A.118.x.46.i; A.119.x.46.i; A.120.x.46.i; A.121.x.46.i; A.122.x.46.i;
A.123.x.46.i;
A.124.x.46.i; A.125.x.46.i; A.126.x.46.i; A.127.x.46.i; A.128.x.46.i;
A.129.x.46.i;
A.130.x.46.i; A.131.x.46.i; A.132.x.46.i; A.133.x.46.i; A.134.x.46.i;
A.135.x.46.i;
A.136.x.46.i; A.137.x.46.i; A.138.x.46.i; A.139.x.46.i; A.140.x.46.i;
A.141.x.46.i;
A.2.x.47.i; A.3.x.47.i; A.4.x.47.i; A.5.x.47.i; A.7.x.47.i; A.9.x.47.i;
A.100.x.47.i;
A.lOl.x.47.i; A.102.x.47.i; A.103.x.47.i; A.104.x.47.i; A.105.x.47.i;
A.106.x.47.i;
A.107.x.47.i; A.108.x.47.i; A.109.x.47.i; A.110.x.47.i; A.111.x.47.i;
A.112.x.47.i;
A.113.x.47.i; A.114.x.47.i; A.115.x.47.i; A.116.x.47.i; A.117.x.47.i;
A.118.x.47.i;
A.119.x.47.i; A.120.x.47.i; A.121.x.47.i; A.122.x.47.i; A.123.x.47.i;
A.124.x.47.i;
A.125.x.47.i; A.126.x.47.i; A.127.x.47.i; A.128.x.47.i; A.129.x.47.i;
A.130.x.47.i;
A.131.x.47.i; A.132.x.47.i; A.133.x.47.i; A.134.x.47.i; A.135.x.47.i;
A.136.x.47.i;
A.137.x.47.i; A.138.x.47.i; A.139.x.47.i; A.140.x.47.i; A.141.x.47.i;
A.2.x.48.i;
A.3.x.48.i; A.4.x.48.i; A.5.x.48.i; A.7.x.48.i; A.9.x.48.i; A.i00.x.48.i;
A.101.x.48.i;
A.102.x.48.i; A.103.x.48.i; A.104.x.48.i; A.105.x.48.i; A.106.x.48.i;
A.107.x.48.i;
A.108.x.48.i; A.109.x.48.i; A.110.x.48.i; A.111.x.48.i; A.112.x.48.i;
A.113.x.48.i;
A.114.x.48.i; A.115.x.48.i; A.116.x.48.i; A.117.x.48.i; A.118.x.48.i;
A.119.x.48.i;
A.120.x.48.i; A.121.x.48.i; A.122.x.48.i; A.123.x.48.i; A.124.x.48.i;
A.125.x.48.i;

A.126.x.48.i; A.127.x.48.i; A.128.x.48.i; A.129.x.48.i; A.130.x.48.i;
A.131.x.48.i;
A.132.x.48.i; A.133.x.48.i; A.134.x.48.i; A.135.x.48.i; A.136.x.48.i;
A.137.x.48.i;
A.138.x.48.i; A.139.x.48.i; A.140.x.48.i; A.141.x.48.i; A.2.x.49.i;
A.3.x.49.i;
A.4.x.49.i; A.5.x.49.i; A.7.x.49.i; A.9.x.49.i; A.100.x.49.i; A.lOl.x.49.i;
A.102.x.49.i;
A.103.x.49.i; A.104.x.49.i; A.105.x.49.i; A.106.x.49.i; A.107.x.49.i;
A.108.x.49.i;
A.109.x.49.i; A.110.x.49.i; A.lll.x.49.i; A.112.x.49.i; A.113.x.49.i;
A.114.x.49.i;
A.115.x.49.i; A.116.x.49.i; A.117.x.49.i; A.118.x.49.i; A.119.x.49.i;
A.I20.x.49.i;
A.121.x.49.i; A.122.x.49.i; A.123.x.49.i; A.124.x.49.i; A.125.x.49.i;
A.126.x.49.i;
A.127.x.49.i; A.128.x.49.i; A.129.x.49.i; A.130.x.49.i; A.131.x.49.i;
A.132.x.49.i;
A.133.x.49.i; A.134.x.49.i; A.135.x.49.i; A.136.x.49.i; A.137.x.49.i;
A.138.x.49.i;
A.139.x.49.i; A.140.x.49.i; A.141.x.49.i; A.2.x.50.i; A.3.x.50.i; A.4.x.50.i;
A.5.x.50.i;
A.7.x.50.i; A.9.x.50.i; A.100.x.50.i; A.101.x.50.i; A.102.x.50.i;
A.103.x.50.i;
A.104.x.50.i; A.105.x.50.i; A.106.x.50.i; A.107.x.50.i; A.108.x.50.i;
A.109.x.50.i;
A.110.x.50.i; A.111.x.50.i; A.112.x.50.i; A.113.x.50.i; A.114.x.50.i;
A.115.x.50.i;
A.116.x.50.i; A.117.x.50.i; A.118.x.50.i; A.119.x.50.i; A.120.x.50.i;
A.121.x.50.i;
A.122.x.50.i; A.123.x.50.i; A.124.x.50.i; A.125.x.50.i; A.126.x.50.i;
A.127.x.50.i;
A.128.x.50.i; A.129.x.50.i; A.130.x.50.i; A.131.x.50.i; A.132.x.50.i;
A.133.x.50.i;
A.134.x.50.i; A.135.x.50.i; A.136.x.50.i; A.137.x.50.i; A.138.x.50.i;
A.139.x.50.i;
A.140.x.50.i; A.141.x.50.i; A.2.x.51.i; A.3.x.51.i; A.4.x.51.i; A.5.x.51.i;
A.7.x.51.i;
A.9.x.51.i; A.100.x.51.i; A.101.x.51.i; A.102.x.51.i; A.103.x.51.i;
A.104.x.51.i;
A.105.x.51.i; A.106.x.51.i; A.107.x.51.i; A.108.x.51.i; A.109.x.51.i;
A.110.x.51.i;
A.111.x.51.i; A.112.x.51.i; A.113.x.51.i; A.114.x.51.i; A.115.x.51.i;
A.116.x.51.i;
A.117.x.51.i; A.118.x.51.i; A.119.x.51.i; A.120.x.51.i; A.121.x.51.i;
A.122.x.51.i;
A.123.x.51.i; A.124.x.51.i; A.125.x.51.i; A.126.x.51.i; A.127.x.51.i;
A.128.x.51.i;
A.129.x.51.i; A.130.x.51.i; A.131.x.51.i; A.132.x.51.i; A.133.x.51.i;
A.134.x.51.i;
A.135.x.51.i; A.136.x.51.i; A.137.x.51.i; A.138.x.51.i; A.139.x.51.i;
A.140.x.51.i;
A.I41.x.51.i; A.2.y.46.i; A.3.y.46.i; A.4.y.46.i; A.5.y.46.i; A.7.y.46.i;
A.9.y.46.i;
A.100.y.46.i; A.lOl.y.46.i; A.102.y.46.i; A.103.y.46.i; A.104.y.46.i;
A.105.y.46.i;
A.106.y.46.i; A.107.y.46.i; A.108.y.46.i; A.109.y.46.i; A.110.y.46.i;
A.lll.y.46.i;
A.112.y.46.i; A.113.y.46.i; A.114.y.46.i; A.115.y.46.i; A.116.y.46.i;
A.117.y.46.i;
A.118.y.46.i; A.119.y.46.i; A.120.y.46.i; A.121.y.46.i; A.122.y.46.i;
A.123.y.46.i;
A.124.y.46.i; A.125.y.46.i; A.126.y.46.i; A.127.y.46.i; A.128.y.46.i;
A.129.y.46.i;
A.130.y.46.i; A.131.y.46.i; A.132.y.46.i; A.133.y.46.i; A.134.y.46.i;
A.135.y.46.i;
A.136.y.46.i; A.137.y.46.i; A.138.y.46.i; A.139.y.46.i; A.140.y.46.i;
A.141.y.46.i;
A.2.y.47.i; A.3.y.47.i; A.4.y.47.i; A.5.y.47.i; A.7.y.47.i; A.9.y.47.i;
A.100.y.47.i;
A.lOl.y.47.i; A.102.y.47.i; A.103.y.47.i; A.104.y.47.i; A.105.y.47.i;
A.106.y.47.i;
A.107.y.47.i; A.108.y.47.i; A.109.y.47.i; A.110.y.47.i; A.111.y.47.i;
A.112.y.47.i;
A.113.y.47.i; A.114.y.47.i; A.115.y.47.i; A.116.y.47.i; A.117.y.47.i;
A.118.y.47.i;
A.119.y.47.i; A.120.y.47.i; A.121.y.47.i; A.122.y.47.i; A.123.y.47.i;
A.124.y.47.i;
A.125.y.47.i; A.126.y.47.i; A.127.y.47.i; A.128.y.47.i; A.129.y.47.i;
A.130.y.47.i;
A.131.y.47.i; A.132.y.47.i; A.133.y.47.i; A.134.y.47.i; A.135.y.47.i;
A.136.y.47.i;
A.137.y.47.i; A.138.y.47.i; A.139.y.47.i; A.140.y.47.i; A.141.y.47.i;
A.2.y.48.i;
A.3.y.48.i; A.4.y.48.i; A.5.y.48.i; A.7.y.48.i; A.9.y.48.i; A.100.y.48.i;
A.lOl.y.48.i;
A.102.y.48.i; A.103.y.48.i; A.104.y.48.i; A.105.y.48.i; A.106.y.48.i;
A.107.y.48.i;
A.108.y.48.i; A.109.y.48.i; A.110.y.48.i; A.111.y.48.i; A.112.y.48.i;
A.113.y.48.i;
A.114.y.48.i; A.115.y.48.i; A.116.y.48.i; A.117.y.48.i; A.118.y.48.i;
A.119.y.48.i;
A.120.y.48.i; A.121.y.48.i; A.122.y.48.i; A.123.y.48.i; A.124.y.48.i;
A.125.y.48.i;

A.126.y.48.i; A.127.y.48.i; A.128.y.48.i; A.129.y.48.i; A.130.y.48.i;
A.131.y.48.i;
A.132.y.48.i; A.133.y.48.i; A.134.y.48.i; A.135.y.48.i; A.136.y.48.i;
A.137.y.48.i;
A.138.y.48.i; A.139.y.48.i; A.140.y.48.i; A.141.y.48.i; A.2.y.49.i;
A.3.y.49.i;
A.4.y.49.i; A.5.y.49.i; A.7.y.49.i; A.9.y.49.i; A.100.y.49.i; A.lOl.y.49.i;
A.102.y.49.i;
A.103.y.49.i; A.104.y.49.i; A.105.y.49.i; A.106.y.49.i; A.107.y.49.i;
A.108.y.49.i;
A.109.y.49.i; A.110.y.49.i; A.111.y.49.i; A.112.y.49.i; A.113.y.49.i;
A.114.y.49.i;
A.115.y.49.i; A.116.y.49.i; A.117.y.49.i; A.118.y.49.i; A.119.y.49.i;
A.120.y.49.i;
A.121.y.49.i; A.122.y.49.i; A.123.y.49.i; A.124.y.49.i; A.125.y.49.i;
A.126.y.49.i;
A.127.y.49.i; A.128.y.49.i; A.129.y.49.i; A.130.y.49.i; A.131.y.49.i;
A.132.y.49.i;
A.133.y.49.i; A.134.y.49.i; A.135.y.49.i; A.136.y.49.i; A.137.y.49.i;
A.138.y.49.i;
A.139.y.49.i; A.140.y.49.i; A.141.y.49.i; A.2.y.50.i; A.3.y.50.i; A.4.y.50.i;
A.5.y.50.i;
A.7.y.50.i; A.9.y.50.i; A.100.y.50.i; A.lOl.y.50.i; A.102.y.50.i;
A.103.y.50.i;
A.104.y.50.i; A.105.y.50.i; A.106.y.50.i; A.107.y.50.i; A.108.y.50.i;
A.109.y.50.i;
A.110.y.50.i; A.111.y.50.i; A.112.y.50.i; A.113.y.50.i; A.114.y.50.i;
A.115.y.50.i;
A.116.y.50.i; A.117.y.50.i; A.118.y.50.i; A.119.y.50.i; A.120.y.50.i;
A.121.y.50.i;
A.122.y.50.i; A.123.y.50.i; A.124.y.50.i; A.125.y.50.i; A.126.y.50.i;
A.127.y.50.i;
A.128.y.50.i; A.129.y.50.i; A.130.y.50.i; A.131.y.50.i; A.132.y.50.i;
A.133.y.50.i;
A.134.y.50.i; A.135.y.50.i; A.136.y.50.i; A.137.y.50.i; A.138.y.50.i;
A.139.y.50.i;
A.140.y.50.i; A.141.y.50.i; A.2.y.51.i; A.3.y.51.i; A.4.y.51.i; A.5.y.51.i;
A.7.y.51.i;
A.9.y.51.i; A.100.y.51.i; A.lOl.y.5l.i; A.102.y.51.i; A.103.y.51.i;
A.104.y.5Li;
A.105.y.51.i; A.106.y.51.i; A.107.y.51.i; A.108.y.51.i; A.109.y.51.i;
A.110.y.51.i;
A.lll.y.5l.i; A.112.y.51.i; A.113.y.51.i; A.114.y.51.i; A.115.y.51.i;
A.116.y.51.i;
A.117.y.51.i; A.118.y.51.i; A.119.y.51.i; A.120.y.51.i; A.121.y.51.i;
A.122.y.51.i;
A.123.y.51.i; A.124.y.51.i; A.125.y.51.i; A.126.y.5I.i; A.127.y.51.i;
A.128.y.51.i;
A.129.y.51.i; A.130.y.51.i; A.131.y.51.i; A.132.y.51.i; A.133.y.51.i;
A.134.y.51.i;
A.135.y.51.i; A.136.y.51.i; A.137.y.51.i; A.138.y.51.i; A.139.y.51.i;
A.140.y.51.i;
A.141.y.5Li; A.2.z.46.i; A.3.z.46.i; A.4.z.46.i; A.5.z.46.i; A.7.z.46.i;
A.9.z.46.i;
A.100.z.46.i; A.101.z.46.i; A.102.z.46.i; A.103.z.46.i; A.104.z.46.i;
A.105.z.46.i;
A.lOd.z.46.i; A.107.z.46.i; A.108.z.46.i; A.109.z.46.i; A.110.z.46.i;
A.lll.z.46.i;
A.112.z.46.i; A.113.z.46.i; A.114.z.46.i; A.115.z.46.i; A.116.z.46.i;
A.117.z.46.i;
A.118.z.46.i; A.119.z.46.i; A.120.z.46.i; A.121.z.46.i; A.122.z.46.i;
A.123.z.46.i;
A.124.z.46.i; A.125.z.46.i; A.126.z.46.i; A.127.z.46.i; A.128.z.46.i;
A.129.z.46.i;
A.130.z.46.i; A.131.z.46.i; A.132.z.46.i; A.133.z.46.i; A.134.z.46.i;
A.135.z.46.i;
A.136.z.46.i; A.137.z.46.i; A.138.z.46.i; A.139.z.46.i; A.140.z.46.i;
A.141.z.46.i;
A.2.z.47.i; A.3.z.47.i; A.4.z.47.i; A.5.z.47.i; A.7.z.47.i; A.9.z.47.i;
A.IOO.z.47.i;
A.lOl.z.47.i; A.102.z.47.i; A.103.z.47.i; A.104.z.47.i; A.105.z.47.i;
A.106.z.47.i;
A.107.z.47.i; A.lO8.z.47.i; A.109.z.47.i; A.110.z.47.i; A.111.z.47.i;
A.112.z.47.i;
A.113.z.47.i; A.114.z.47.i; A.115.z.47.i; A.116.z.47.i; A.117.z.47.i;
A.118.z.47.i;
A.119.z.47.i; A.120.z.47.i; A.121.z.47.i; A.122.z.47.i; A.123.z.47.i;
A.124.z.47.i;
A.125.z.47.i; A.126.z.47.i; A.127.z.47.i; A.128.z.47.i; A.129.z.47.i;
A.130.z.47.i;
A.131.z.47.i; A.132.z.47.i; A.133.z.47.i; A.134.z.47.i; A.135.z.47.i;
A.136.z.47.i;
A.137.z.47.i; A.138.z.47.i; A.139.z.47.i; A.140.z.47.i; A.141.z.47.i;
A.2.z.48.i;
A.3.z.48.i; A.4.z.48.i; A.5.z.48.i; A.7.z.48.i; A.9.z.48.i; A.100.z.48.i;
A.lOl.z.48.i;
A.102.z.48.i; A.103.z.48.i; A.104.z.48.i; A.105.z.48.i; A.106.z.48.i;
A.107.z.48.i;
A.108.z.48.i; A.I09.z.48.i; A.110.z.48.i; A.lll.z.48.i; A.112.z.48.i;
A.113.z.48.i;
A.114.z.48.i; A.115.z.48.i; A.116.z.48.i; A.117.z.48.i; A.118.z.48.i;
A.119.z.48.i;
A.120.z.48.i; A.121.z.48.i; A.122.z.48.i; A.123.z.48.i; A.124.z.48.i;
A.125.z.48.i;

A.126.z.48.i; A.127.z.48.i; A.128.z.48.i; A.129.z.48.i; A.130.z.48.i;
A.131.z.48.i;
A.132.z.48.i; A.133.z.48.i; A.134.z.48.i; A.135.z.48.i; A.136.z.48.i;
A.137.z.48.i;
A.138.z.48.i; A.139.z.48.i; A.140.z.48.i; A.141.z.48.i; A.2.z.49.i;
A.3.z.49.i;
A.4.z.49.i; A.5.z.49.i; A.7.z.49.i; A.9.z.49.i; A.100.z.49.i; A.101.z.49.i;
A.102.z.49.i;
A.103.z.49.i; A.104.z.49.i; A.105.z.49.i; A.106.z.49.i; A.107.z.49.i;
A.108.z.49.i;
A.109.z.49.i; A.Il0.z.49.i; A.111.z.49.i; A.112.z.49.i; A.113.z.49.i;
A.114.z.49.i;
A.115.z.49.i; A.116.z.49.i; A.117.z.49.i; A.118.z.49.i; A.119.z.49.i;
A.120.z.49.i;
A.121.z.49.i; A.122.z.49.i; A.123.z.49.i; A.124.z.49.i; A.125.z.49.i;
A.126.z.49.i;
A.127.z.49.i; A.128.z.49.i; A.129.z.49.i; A.130.z.49.i; A.131.z.49.i;
A.132.z.49.i;
A.133.z.49.i; A.134.z.49.i; A.135.z.49.i; A.136.z.49.i; A.137.z.49.i;
A.138.z.49.i;
A.139.z.49.i; A.140.z.49.i; A.141.z.49.i; A.2.z.50.i; A.3.z.50.i; A.4.z.50.i;
A.5.z.50.i;
A.7.z.50.i; A.9.z.50.i; A.100.z.50.i; A.lOl.z.50.i; A.102.z.50.i;
A.103.z.50.i;
A.104.z.50.i; A.105.z.50.i; A.106.z.50.i; A.107.z.50.i; A.108.z.50.i;
A.109.z.50.i;
A.110.z.50.i; A.111.z.50.i; A.112.z.50.i; A.113.z.50.i; A.114.z.50.i;
A.115.z.50.i;
A.116.z.50.i; A.117.z.50.i; A.118.z.50.i; A.119.z.50.i; A.120.z.50.i;
A.121.z.50.i;
A.122.z.50.i; A.123.z.50.i; A.124.z.50.i; A.125.z.50.i; A.126.z.50.i;
A.127.z.50.i;
A.128.z.50.i; A.129.z.50.i; A.130.z.50.i; A.131.z.50.i; A.132.z.50.i;
A.133.z.50.i;
A.134.z.50.i; A.135.z.50.i; A.136.z.50.i; A.137.z.50.i; A.138.z.50.i;
A.139.z.50.i;
A.140.z.50.i; A.141.z.50.i; A.2.z.51.i; A.3.z.51.i; A.4.z.51.i; A.5.z.51.i;
A.7.z.51.i;
A.9.z.51.i; A.100.z.51.i; A.101.z.51.i; A.102.z.51.i; A.103.z.51.i;
A.104.z.51.i;
A.105.z.51.i; A.106.z.51.i; A.107.z.51.i; A.108.z.51.i; A.109.z.51.i;
A.1l.O.z.5l.i;
A.lll.z.5l.i; A.112.z.51.i; A.113.z.51.i; A.114,z.51.i; A.115.z.51.i;
A.116.z.51.i;
A.117.z.51.i; A.118.z.51.i; A.119.z.51.i; A.120.z.51.i; A.121.z.51.i;
A.122.z.51.i;
A.123.z.51.i; A.124.z.51.i; A.125.z.51.i; A.126.z.51.i; A.127.z.51.i;
A.128.z.51.i;
A.129.z.51.i; A.130.z.51.i; A.131.z.51.i; A.132.z.51.i; A.133.z.51.i;
A.I34.z.51.i;
A.135.z.51.i; A.136.z.51.i; A.137.z.51.i; A.138.z.51.i; A.139.z.51.i;
A.140.z.51.i;
A.141.z.51.i; A.2.A.46.i; A.3.A.46.i; A.4.A.46.i; A.5.A.46.i; A.7.A.46.i;
A.9.A.46.i;
A.100.A.46.i; A.lOl.A.46.i; A.102.A.46.i; A.103.A.46.i; A.104.A.46.i;
A.105.A.46.i; A.106.A.46.i; A.107.A.46.i; A.108.A.46.i; A.109.A.46.i;
A.110.A.46.i; A.111.A.46.i; A.112.A.46.i; A.113.A.46.i; A.114.A.46.i;
A.115.A.46.i; A.116.A.46.i; A.117.A.46.i; A.118.A.46.i; A.119.A.46.i;
A.120.A.46.i; A.121.A.46.i; A.122.A.46.i; A.123.A.46.i; A.124.A.46.i;
A.125.A.46.i; A.126.A.46.i; A.127.A.46.i; A.128.A.46.i; A.129.A.46.i;
A.130.A.46.i; A.131.A.46.i; A.132.A.46.i; A.133.A.46.i; A.134.A.46.i;
A.135.A.46.i; A.136.A.46.i; A.137.A.46.i; A.138.A.46.i; A.139.A.46.i;
A.140.A.46.i; A.141.A.46.i; A.2.A.47.i; A.3.A.47.i; A.4.A.47.i; A.5.A.47.i;
A.7.A.47.i; A.9.A.47.i; A.100.A.47.i; A.101.A.47.i; A.102.A.47.i;
A.103.A.47.i;
A.104.A.47.i; A.105.A.47.i; A.106.A.47.i; A.107.A.47.i; A.108.A.47.i;
A.109.A.47.i; A.110.A.47.i; A.111.A.47.i; A.112.A.47.i; A.113.A.47.i;
A.114.A.47.i; A.115.A.47.i; A.116.A.47.i; A.117.A.47.i; A.118.A.47.i;
A.119.A.47.i; A.120.A.47.i; A.121.A.47.i; A.122.A.47.i; A.123.A.47.i;
A.124.A.47.i; A.125.A.47.i; A.126.A.47.i; A.127.A.47.i; A.128.A.47.i;
A.129.A.47.i; A.130.A.47.i; A.13LA.47.i; A.132.A.47.i; A.133.A.47.i;
A.134.A.47.i; A.135.A.47.i; A.136.A.47.i; A.137.A.47.i; A.138.A.47.i;
A.139.A.47.i; A.140.A.47.i; A.141.A.47.i; A.2.A.48.i; A.3.A.48.i; A.4.A.48.i;
A.5.A.48.i; A.7.A.48.i; A.9.A.48.i; A.100.A.48.i; A.lOl.A.48.i; A.102.A.48.i;
A.103.A.48.i; A.104.A.48.i; A.105.A.48.i; A.106.A.48.i; A.107.A.48.i;

A.108.A.48.i; A.109.A.48.i; A.110.A.48.i; A.111.A.48.i; A.112.A.48.i;
A.113.A.48.i; A.114.A.48.i; A.115.A.48.i; A.116.A.48.i; A.117.A.48.i;
A.118.A.48.i; A.119.A.48.i; A.120.A.48.i; A.121.A.48.i; A.122.A.48.i;
A.123.A.48.i; A.124.A.48.i; A.125.A.48.i; A.126.A.48.i; A.127.A.48.i;
A.128.A.48.i; A.129.A.48.i; A.130.A.48.i; A.131.A.48.i; A.132.A.48.i;
A.133.A.48.i; A.134.A.48.i; A.135.A.48.i; A.136.A.48.i; A.137.A.48.i;
A.138.A.48.i; A.139.A.48.i; A.140.A.48.i; A.141.A.48.i; A.2.A.49.i;
A.3.A.49.i;
A.4.A.49.i; A.S.A.49.i; A.7.A.49.i; A.9.A.49.i; A.100.A.49.i; A.101.A.49.i;
A.102.A.49.i; A.103.A.49.i; A.104.A.49.i; A.105.A.49.i; A.106.A.49.i;
A.107.A.49.i; A.108.A.49.i; A.109.A.49.i; A.110.A.49.i; A.111.A.49.i;
A.112.A.49.i; A.113.A.49.i; A.114.A.49.i; A.115.A.49.i; A.116.A.49.i;
A.117.A.49.i; A.118.A.49.i; A.119.A.49.i; A.120.A.49.i; A.121.A.49.i;
A.122.A.49.i; A.123.A.49.i; A.124.A.49.i; A.125.A.49.i; A.126.A.49.i;
A.127.A.49.i; A.128.A.49.i; A.129.A.49.i; A.130.A.49.i; A.131.A.49.i;
A.132.A.49.i; A.133.A.49.i; A.134.A.49.i; A.135.A.49.i; A.136.A.49.i;
A.137.A.49.i; A.138.A.49.i; A.139.A.49.i; A.140.A.49.i; A.141.A.49.i;
A.2.A.50.i;
A.3.A.50.i; A.4.A.50.i; A.5.A.50.i; A.7.A.50.i; A.9.A.50.i; A.100.A.50.i;
A.lOl.A.50.i; A.102.A.50.i; A.103.A.50.i; A.104.A.50.i; A.105.A.SO.i;
A.106.A.50.i; A.107.A.50.i; A.lO8.A.50.i; A.109.A.50.i; A.110.A.50.i;
A.111.A.50.i; A.112.A.50.i; A.113.A.50.i; A.114.A.50.i; A.115.A.50.i;
A.116.A.50.i; A.117.A.50.i; A.118.A.50.i; A.119.A.50.i; A.120.A.50.i;
A.121.A.50.i; A.122.A.50.i; A.123.A.50.i; A.124.A.50.i; A.125.A.50.i;
A.126.A.50.i; A.127.A.50.i; A.128.A.50.i; A.129.A.50.i; A.130.A.50.i;
A.131.A.SO.i; A.132.A.50.i; A.133.A.50.i; A.134.A.SO.i; A.135.A.50.i;
A.136.A.50.i; A.137.A.50.i; A.138.A.50.i; A.139.A.SO.i; A.140.A.50.i;
A.141.A.50.i; A.2.A.51.i; A.3.A.51.i; A.4.A.51.i; A.5.A.51.i; A.7.A.51.i;
A.9.A.51.i; A.100.A.Sl.i; A.101.A.51.i; A.102.A.Sl.i; A.103.A.51.i;
A.104.A.51.i;
A.105.A.51.i; A.106.A.51.i; A.107.A.51.i; A.108.A.51.i; A.109.A.51.i;
A.110.A.51.i; A.111.A.51.i; A.112.A.51.i; A.113.A.51.i; A.114.A.51.i;
A.115.A.51.i; A.116.A.51.i; A.117.A.51.i; A.118.A.51.i; A.119.A.51.i;
A.120.A.51.i; A.121.A.51.i; A.122.A.51.i; A.123.A.51.i; A.124.A.51.i;
A.125.A.51.i; A.126.A.51.i; A.127.A.51.i; A.128.A.51.i; A.129.A.Sl.i;
A.130.A.51.i; A.131.A.51.i; A.132.A.51.i; A.133.A.51.i; A.134.A.51.i;
A.135.A.51.i; A.136.A.51.i; A.137.A.51.i; A.138.A.51.i; A.139.A.51.i;
A.140.A.51.i; A.141.A.51.i; A.2.B.4b.i; A.3.B.46.i; A.4.B.46.i; A.5.B.46.i;
A.7.B.46.i; A.9.B.46.i; A.100.B.46.i; A.101.B.46.i; A.102.B.46.i;
A.103.B.46.i;
A.104.B.46.i; A.105.B.46.i; A.106.B.46.i; A.107.B.46.i; A.108.B.46.i;
A.109.B.46.i;
A.110.B.46.i; A.111.B.46.i; A.112.B.46.i; A.113.B.46.i; A.114.B.46.i;
A.115.B.46.i;
A.116.B.46.i; A.117.B.46.i; A.118.B.46.i; A.119.B.46.i; A.120.B.46.i;
A.121.B.46.i;
A.122.B.46.i; A.123.B.46.i; A.124.B.46.i; A.125.B.46.i; A.126.B.46.i;
A.127.B.46.i;
A.128.B.46.i; A.129.B.46.i; A.130.B.46.i; A.131.B.46.i; A.132.B.46.i;
A.133.B.46.i;
A.134.B.46.i; A.135.B.46.i; A.136.B.46.i; A.137.B.46.i; A.138.B.46.i;
A.139.B.46.i;
A.140.B.46.i; A.141.B.46.i; A.2.B.47.i; A.3.B.47.i; A.4.B.47.i; A.S.B.47.i;
A.7.B.47.i; A.9.B.47.i; A.100.B.47.i; A.lOl.B.47.i; A.102.B.47.i;
A.103.B.47.i;
A.104.B.47.i; A.105.B.47.i; A.106.B.47.i; A.107.B.47.i; A.108.B.47.i;
A.109.B.47.i;
A.110.B.47.i; A.111.B.47.i; A.112.B.47.i; A.113.B.47.i; A.114.B.47.i;
A.115.B.47.i;
A.116.B.47.i; A.117.B.47.i; A.118.B.47.i; A.119.B.47.i; A.120.B.47.i;
A.121.B.47.i;

A.122.B.47.i; A.123.B.47.i; A.124.B.47.i; A.125.B.47.i; A.126.B.47.i;
A.127.B.47.i;
A.128.B.47.i; A.129.B.47.i; A.130.B.47.i; A.131.B.47.i; A.132.B.47.i;
A.133.B.47.i;
A.134.B.47.i; A.135.8.47.i; A.136.B.47.i; A.137.B.47.i; A.138.B.47.i;
A.139.B.47.i;
A.140.B.47.i; A.141.B.47.i; A.2.B.48.i; A.3.B.48.i; A.4.B.48.i; A.5.B.48.i;
A.7.B.48.i; A.9.B.48.i; A.100.B.48.i; A.101.B.48.i; A.102.B.48.i;
A.103.B.48.i;
A.104.8.48.i; A.105.B.48.i; A.106.B.48.i; A.107.B.48.i; A.lO8.B.48.i;
A.109.B.48.i;
A.110.B.48.i; A.111.B.48.i; A.112.B.48.i; A.113.B.48.i; A.114.B.48.i;
A.115.B.48.i;
A.116.B.48.i; A.117.B.48.i; A.118.B.48.i; A.119.B.48.i; A.120.B.48.i;
A.121.B.48.i;
A.122.B.48.i; A.123.B.48.i; A.124.B.48.i; A.125.B.48.i; A.126.B.48.i;
A.127.B.48.i;
A.128.B.48.i; A.129.B.48.i; A.130.B.48.i; A.131.B.48.i; A.132.B.48.i;
A.133.B.48.i;
A.134.B.48.i; A.135.B.48.i; A.136.B.48.i; A.137.B.48.i; A.138.B.48.i;
A.139.B.48.i;
A.140.B.48.i; A.141.B.48.i; A.2.B.49.i; A.3.B.49.i; A.4.B.49.i; A.5.B.49.i;
A.7.B.49.i; A.9.B.49.i; A.100.B.49.i; A.lOl.Ba49.i; A.102.B.49.i;
A.103.B.49.i;
A.104.B.49.i; A.105.B.49.i; A.106.B.49.i; A.107.B.49.i; A.108.B.49.i;
A.109.B.49.i;
A.110.B.49.i; A.11I.B.49.i; A.112.B.49.i; A.113.B.49.i; A.114.B.49.i;
A.115.B.49.i;
A.116.B.49.i; A.117.B.49.i; A.118.B.49.i; A.119.B.49.i; A.120.B.49.i;
A.121.B.49.i;
A.122.B.49.i; A.123.B.49.i; A.124.B.49.i; A.125.B.49.i; A.126.B.49.i;
A.127.B.49.i;
A.128.B.49.i; A.129.B.49.i; A.130.B.49.i; A.131.B.49.i; A.132.B.49.i;
A.133.B.49.i;
A.134.B.49.i; A.135.B.49.i; A.136.B.49.i; A.137.B.49.i; A.138.B.49.i;
A.139.B.49.i;
A.140.B.49.i; A.141.B.49.i; A.2.B.50.i; A.3.B.50.i; A.4.B.50.i; A.5.B.50.i;
A.7.B.50.i; A.9.B.50.i; A.100.B.50.i; A.lOl.B.50.i; A.102.B.50.i;
A.103.B.50.i;
A.104.B.50.i; A.105.B.50.i; A.106.B.50.i; A.107.B.50.i; A.108.B.50.i;
A.109.B.50.i;
A.110.B.50.i; A.111.B.50.i; A.112.B.50.i; A.113.B.50.i; A.114.B.50.i;
A.115.B.50.i;
A.116.B.50.i; A.117.B.50.i; A.118.B.50.i; A.119.B.50.i; A.120.B.50.i;
A.121.B.50.i;
A.122.B.50.i; A.123.B.50.i; A.124.B.50.i; A.125.B.50.i; A.126.B.50.i;
A.127.B.50.i;
A.128.B.50.i; A.129.B.50.i; A.130.B.50.i; A.131.B.50.i; A.132.8.50.i;
A.133.B.50.i;
A.134.B.50.i; A.135.B.50.i; A.136.B.50.i; A.137.B.50.i; A.138.B.50.i;
A.139.B.50.i;
A.140.B.50.i; A.141.B.50.i; A.2.B.51.i; A.3.B.51.i; A.4.B.51.i; A.5.B.51.i;
A.7.B.51.i; A.9.B.51.i; A.100.B.51.i; A.101.B.51.i; A.102.B.51.i;
A.103.B.51.i;
A.104.B.51.i; A.105.B.51.i; A.106.B.51.i; A.107.B.51.i; A.108.B.51.i;
A.109.B.51.i;
A.110.B.51.i; A.111.8.51.i; A.112.B.51.i; A.113.B.51.i; A.114.B.51.i;
A.115.B.51.i;
A.116.B.51.i; A.117.B.51.i; A.118.B.51.i; A.119.B.51.i; A.120.8.51.i;
A.121.B.51.i;
A.122.B.51.i; A.123.B.51.i; A.124.B.51.i; A.125.B.51.i; A.126.B.51.i;
A.127.B.51.i;
A.128.B.51.i; A.129.B.51.i; A.130.B.51.i; A.131.B.51.i; A.132.B.51.i;
A.133.B.51.i;
A.134.B.51.i; A.135.B.51.i; A.136.B.51.i; A.137.B.51.i; A.138.B.51.i;
A.139.B.51.i;
A.140.B.51.i; A.141.B.51.i; A.2.C.46.i; A.3.C.46.i; A.4.C.46.i; A.5.C.46.i;
A.7.C.46.i; A.9.C.46.i; A.100.C.46.i; A.101.C.46.i; A.102.C.46.i;
A.103.C.46.i;
A.104.C.46.i; A.105.C.46.i; A.106.C.46.i; A.107.C.46.i; A.108.C.46.i;
A.109.C.46.i;
A.110.C.46.i; A.111.C.46.i; A.112.C.46.i; A.113.C.46.i; A.114.C.46.i;
A.115.C.46.i;
A.116.C.46.i; A.117.C.46.i; A.118.C.46.i; A.119.C.46.i; A.120.C.46.i;
A.121.C.46.i;
A.122.C.46.i; A.123.C.46.i; A.124.C.46.i; A.125.C.46.i; A.126.C.46.i;
A.127.C.46.i;
A.128.C.46.i; A.129.C.46.i; A.130.C.46.i; A.131.C.46.i; A.132.C.46.i;
A.133.C.46.i;
A.134.C.46.i; A.135.C.46.i; A.136.C.46.i; A.137.C.46.i; A.138.C.46.i;
A.139.C.46.i;
A.140.C.46.i; A.141.C.46.i; A.2.C.47.i; A.3.C.47.i; A.4.C.47.i; A.5.C.47.i;
A.7.C.47.i; A.9.C.47.i; A.100.C.47.i; A.101.C.47.i; A.102.C.47.i;
A.103.C.47.i;
A.104.C.47.i; A.105.C.47.i; A.106.C.47.i; A.107.C.47.i; A.108.C.47.i;
A.109.C.47.i;
A.110.C.47.i; A.111.C.47.i; A.112.C.47.i; A.113.C.47.i; A.114.C.47.i;
A.115.C.47.i;

A.116.C.47:i; A.117.C.47.i; A.118.C.47.i; A.lI9.C.47.i; A.120.C.47.i;
A.121.C.47.i;
A.122.C.47.i; A.123.C.47.i; A.124.C.47.i; A.125.C.47.i; A.126.C.47.i;
A.127.C.47.i;
A.128.C.47.i; A.129.C.47.i; A.130.C.47.i; A.131.C.47.i; A.132.C.47.i;
A.133.C.47.i;
A.134.C.47.i; A.135.C.47.i; A.136.C.47.i; A.137.C.47.i; A.138.C.47.i;
A.139.C.47.i;
A.140.C.47.i; A.141.C.47.i; A.2.C.48.i; A.3.C.48.i; A.4.C.48.i; A.5.C.48.i;
A.7.C.48.i; A.9.C.48.i; A.100.C.48.i; A.101.C.48.i; A.102.C.48.i;
A.103.C.48.i;
A.104.C.48.i; A.105.C.48.i; A.106.C.48.i; A.107.C.48.i; A.108.C.48.i;
A.109.C.48.i;
A.110.C.48.i; A.111.C.48.i; A.112.C.48.i; A.113.C.48.i; A.114.C.48.i;
A.115.C.48.i;
A.116.C.48.i; A.117.C.48.i; A.118.C.48.i; A.119.C.48.i; A.120.C.48.i;
A.121.C.48.i;
A.122.C.48.i; A.123.C.48.i; A.124.C.48.i; A.125.C.48.i; A.126.C.48.i;
A.127.C.48.i;
A.128.C.48.i; A.129.C.48.i; A.130.C.48.i; A.131.C.48.i; A.132.C.48.i;
A.133.C.48.i;
A.134.C.48.i; A.135.C.48.i; A.136.C.48.i; A.137.C.48.i; A.138.C.48.i;
A.139.C.48.i;
A.140.C.48.i; A.141.C.48.i; A.2.C.49.i; A.3.C.49.i; A.4.C.49.i; A.5.C.49.i;
A.7.C.49.i; A.9.C.49.i; A.100.C.49.i; A.101.C.49.i; A.102.C.49.i;
A.103.C.49.i;
A.104.C.49.i; A.105.C.49.i; A.106.C.49.i; A.107.C.49.i; A.108.C.49.i;
A.109.C.49.i;
A.110.C.49.i; A.111.C.49.i; A.112.C.49.i; A.113.C.49.i; A.114.C.49.i;
A.115.C.49.i;
A.116.C.49.i; A.117.C.49.i; A.118.C.49.i; A.119.C.49.i; A.120.C.49.i;
A.121.C.49.i;
A.122.C.49.i; A.123.C.49.i; A.124.C.49.i; A.125.C.49.i; A.126.C.49.i;
A.127.C.49.i;
A.128.C.49.i; A.129.C.49.i; A.130.C.49.i; A.131.C.49.i; A.132.C.49.i;
A.133.C.49.i;
A.I34.C.49.i; A.135.C.49.i; A.136.C.49.i; A.137.C.49.i; A.138.C.49.i;
A.139.C.49.i;
A.140.C.49.i; A.141.C.49.i; A.2.C.50.i; A.3.C.50.i; A.4.C.50.i; A.5.C.50.i;
A.7.C.50.i; A.9.C.50.i; A.100.C.50.i; A.101.C.50.i; A.102.C.50.i;
A.103.C.50.i;
A.104.C.50.i; A.105.C.50.i; A.106.C.50.i; A.107.C.50.i; A.108.C.50,i;
A.109.C.50.i;
A.110.C.50.i; A.111.C.50.i; A.112.C.50.i; A.113.C.50.i; A.114.C.50.i;
A.115.C.50.i;
A.116.C.50.i; A.117.C.50.i; A.118.C.50.i; A.119.C.50.i; A.120.C.50.i;
A.121.C.50.i;
A.122.C.50.i; A.123.C.50.i; A.124.C.50.i; A.125.C.50.i; A.I26.C.50.i;
A.127.C.50.i;
A.128.C.50.i; A.129.C.50.i; A.130.C.50.i; A.131.C.50.i; A.132.C.50.i;
A.133.C.50.i;
A.134.C.50.i; A.135.C.50.i; A.136.C.50.i; A.137.C.50.i; A.138.C.50.i;
A.139.C.50.i;
A.140.C.50.i; A.141.C.50.i; A.2.C.51.i; A.3.C.51.i; A.4.C.51.i; A.5.C.51.i;
A.7.C.51.i; A.9.C.51.i; A.100.C.51.i; A.101.C.51.i; A.102.C.51.i;
A.103.C.51.i;
A.104.C.51.i; A.105.C.51.i; A.106.C.51.i; A.107.C.51.i; A.108.C.51.i;
A.109.C.51.i;
A.110.C.51.i; A.111.C.51.i; A.112.C.51.i; A.113.C.51.i; A.114.C.51.i;
A.115.C.51.i;
A.116.C.51.i; A.117.C.51.i; A.118.C.51.i; A.119.C.51.i; A.120.C.51.i;
A.121.C.51.i;
A.122.C.51.i; A.123.C.51.i; A.124.C.51.i; A.125.C.51.i; A.126.C.51.i;
A.127.C.51.i;
A.128.C.51.i; A.129.C.51.i; A.130.C.51.i; A.131.C.51.i; A.132.C.51.i;
A.133.C.51.i;
A.134.C.51.i; A.135.C.51.i; A.136.C.51.i; A.137.C.51.i; A.138.C.51.i;
A.139.C.51.i;
A.140.C.51.i; A.141.C.51.i; A.2.D.46.i; A.3.D.46.i; A.4.D.46.i; A.5.D.46.i;
A.7.D.46.i; A.9.D.46.i; A.100.D.46.i; A.lOl.D.46.i; A.102.D.46.i;
A.103.D.46.i;
A.104.D.46.i; A.105.D.46.i; A.106.D.46.i; A.107.D.46.i; A.108.D.46.i;
A.109.D.46.i;
A.110.D.46.i; A.111.D.46.i; A.112.D.46.i; A.1I3.D.46.i; A.114.D.46.i;
A.115.D.46.i;
A.116.D.46.i; A.117.D.46.i; A.118.D.46.i; A.119.D.46.i; A.120.D.46.i;
A.121.D.46.i;
A.122.D.46.i; A.123.D.46.i; A,124.D.46.i; A.125.D.46.i; A.126.D.46.i;
A.127.D.46.i;
A.128.D.46.i; A.129.D.46.i; A.130.D.46.i; A.131.D.46.i; A.132.D.46.i;
A.133.D.46.i;
A.134.D.46.i; A.135.D.46.i; A.136.D.46.i; A.137.D.46.i; A.138.D.46.i;
A.139.D.46.i;
A.140.D.46.i; A.141.D.46.i; A.2.D.47.i; A.3.D.47.i; A.4.D.47.i; A.5.D.47.i;
A.7.D.47.i; A.9.D.47.i; A.100.D.47.i; A.lOl.D.47.i; A.102.D.47.i;
A.103.D.47.i;
A.104.D.47.i; A.105.D.47.i; A.106.D.47.i; A.107.D.47.i; A.108.D.47.i;
A.109.D.47.i;

A.110.D.47.i; A.111.D.47.i; A.112.D.47.i; A.113.D.47.i; A.114.D.47.i;
A.115.D.47.i;
A.116.D.47.i; A.117.D.47.i; A.118.D.47.i; A.119.D.47.i; A.120.D.47.i;
A.121.D.47.i;
A.122.D.47.i; A.123.D.47.i; A.124.D.47.i; A.125.D.47.i; A.126.D.47.i;
A.127.D.47.i;
A.128.D.47.i; A.129.D.47.i; A.130.D.47.i; A.131.D.47.i; A.132.D.47.i;
A.133.D.47.i;
A.134.D.47.i; A.135.D.47.i; A.136.D.47.i; A.137.D.47.i; A.138.D.47.i;
A.139.D.47.i;
A.140.D.47.i; A.141.D.47.i; A.2.D.48.i; A.3.D.48.i; A.4.D.48.i; A.5.D.48.i;
A.7.D.48.i; A.9.D.48.i; A.100.D.48.i; A.101.D.48.i; A.102.D.48.i;
A.103.D.48.i;
A.104.D.48.i; A.105.D.48.i; A.106.D.48.i; A.107.D.48.i; A.108.D.48.i;
A.109.D.48.i;
A.110.D.48.i; A.111.D.48.i; A.112.D.48.i; A,113.D.48.i; A.114.D.48.i;
A.115.D.48.i;
A.116.D.48.i; A.117.D.48.i; A.118.D.48.i; A.119.D.48.i; A.120.D.48.i;
A.121.D.48.i;
A.122.D.48.i; A.123.D.48.i; A.124.D.48.i; A.125.D.48.i; A.126.D.48.i;
A.127.D.48.i;
A.128.D.48.i; A.I29.D.48.i; A.130.D.48.i; A.131.D.48.i; A.132.D.48.i;
A.133.D.48.i;
A.134.D.48.i; A.135.D.48.i; A.136.D.48.i; A.137.D.48.i; A.138.D.48.i;
A.139.D.48.i;
A.140.D.48.i; A.141.D.48.i; A.2.D.49.i; A.3.D.49.i; A.4.D.49.i; A.5.D.49.i;
A.7.D.49.i; A.9.D.49.i; A.100.D.49.i; A.lOI.D.49.i; A.102.D.49.i;
A.103.D.49.i;
A.104.D.49.i; A.105.D.49.i; A.106.D.49.i; A.107.D.49.i; A.108.D.49.i;
A.109.D.49.i;
A.110.D.49.i; A.111.D.49.i; A.112.D.49.i; A.113.D.49.i; A.114.D.49.i;
A.115.D.49.i;
A.116.D.49.i; A.117.D.49.i; A.I18.D.49.i; A.119.D.49.i; A.120.D.49.i;
A.121.D.49.i;
A.122.D.49.i; A.123.D.49.i; A.124.D.49.i; A.125.D.49.i; A.126.D.49.i;
A.127.D.49.i;
A.128.D.49.i; A.129.D.49.i; A.130.D.49.i; A.131.D.49.i; A.132.D.49.i;
A.133.D.49.i;
A.134.D.49.i; A.135.D.49.i; A.136.D.49.i; A.137.D.49.i; A.138.D.49.i;
A.139.D.49.i;
A.140.D.49.i; A.141.D.49.i; A.2.D.50.i; A.3.D.50.i; A.4.D.50.i; A.5.D.50.i;
A.7.D.50.i; A.9.D.50.i; A.100.D.50.i; A.lOl.D.50.i; A.102.D.50.i;
A.103.D.50.i;
A.104.D.50.i; A.105.D.50.i; A.106.D.50.i; A.107.D.50.i; A.108.D.50.i;
A.109.D.50.i;
A.110.D.50.i; A.111.D.50.i; A.112.D.50.i; A.113.D.50.i; A.114.D.50.i;
A.115.D.50.i;
A.116.D.50.i; A.117.D.50.i; A.118.D.50.i; A.119.D.50.i; A.120.D.50.i;
A.121.D.50.i;
A.122.D.50.i; A.123.D.50.i; A.124.D.50.i; A.125.D.50.i; A.126.D.50.i;
A.127.D.50.i;
A.128.D.50.i; A.129.D.50.i; A.130.D.50.i; A.131.D.50.i; A.132.D.50.i;
A.133.D.50.i;
A.134.D.50.i; A.135.D.50.i; A.136.D.50.i; A.137.D.50.i; A.138.D.50.i;
A.139.D.50.i;
A.140.D.50.i; A.141.D.50.i; A.2.D.51.i; A.3.D.51.i; A.4.D.51.i; A.5.D.51.i;
A.7.D.51.i; A.9.D.51.i; A.100.D.51.i; A.lOl.D.5l.i; A.102.D.51.i;
A.103.D.51.i;
A.104.D.51.i; A.105.D.51.i; A.106.D.51.i; A.107.D.51.i; A.108.D.51.i;
A.109.D.51.i;
A.110.D.51.i; A.111.D.51.i; A.112.D.51.i; A.113.D.51.i; A.114.D.51.i;
A.115.D.51.i;
A.116.D.51.i; A.117.D.51.i; A.118.D.51.i; A.119.D.51.i; A.120.D.51.i;
A.121.D.51.i;
A.122.D.51.i; A.123.D.51.i; A.124.D.51.i; A.125.D.5Li; A.126.D.51.i;
A.127.D.51.i;
A.128.D.51.i; A.129.D.51.i; A.130.D.51.i; A.131.D.51.i; A.132.D.51.i;
A.133.D.51.i;
A.134.D.51.i; A.135.D.51.i; A.I36.D.51.i; A.137.D.5Li; A.138.D.51.i;
A.139.D.51.i;
A.140.D.51.i; A.141.D.51.i; A.2.E.46.i; A.3.E.46.i; A.4.E.46.i; A.5.E.46.i;
A.7.E.46.i;
A.9.E.46.i; A.100.E.46.i; A.101.E.46.i; A.102.E.46.i; A.103.E.46.i;
A.104.E.46.i;
A.105.E.46.i; A.I06.E.46.i; A.107.E.46.i; A.108.E.46.i; A.109.E.46.i;
A.110.E.46.i;
A.111.E.46.i; A.112.E.46.i; A.113.E.46.i; A.114.E.46.i; A.115.E.46.i;
A.116.E.46.i;
A.117.E.46.i; A.118.E.46.i; A.119.E.46.i; A.120.E.46.i; A.121.E.46.i;
A.122.E.4b.i;
A.123.E.46.i; A.124.E.46.i; A.125.E.46.i; A.126.E.46.i; A.127.E.46.i;
A.128.E.46.i;
A.129.E.46.i; A.130.E.46.i; A.131.E.46.i; A.132.E.46.i; A.133.E.46.i;
A.134.E.46.i;
A.135.E.46.i; A.136.E.46.i; A.137.E.46.i; A.138.E.46.i; A.139.E.46.i;
A.140.E.46.i;
A.141.E.46.i; A.2.E.47.i; A.3.E.47.i; A.4.E.47.i; A.5.E.47.i; A.7.E.47.i;
A.9.E.47.i;
A.100.E,47.i; A.101.E.47.i; A.102.E.47.i; A.103.E.47.i; A.104.E.47.i;
A.105.E.47.i;

A.106.E.47.i; A.107.E.47.i; A.108.E.47.i; A.109.E.47.i; A.110.E.47.i;
A.111.E.47.i;
A.112.E.47.i; A.113.E.47.i; A.lI4.E.47.i; A.115.E.47.i; A.116.E.47.i;
A.117.E.47.i;
A.118.E.47.i; A.119.E.47.i; A.120.E.47.i; A.12I.E.47.i; A.122.E.47.i;
A.123.E.47.i;
A.124.E.47.i; A.125.E.47.i; A.126.E.47.i; A.127.E.47.i; A.128.E.47.i;
A.129.E.47.i;
A.130.E.47.i; A.131.E.47.i; A.132.E.47.i; A.133.E.47.i; A.134.E.47.i;
A.135.E.47.i;
A.136.E.47.i; A.137.E.47.i; A.138.E.47.i; A.139.E.47.i; A.140.E.47.i;
A.141.E.47.i;
A.2.E.48.i; A.3.E.48.i; A.4.E.48.i; A.5.E.48.i; A.7.E.48.i; A.9.E.48.i;
A.100.E.48.i;
A.lOl.E.48.i; A.102.E.48.i; A.103.E.48.i; A.104.E.48.i; A.105.E.48.i;
A.106.E.48.i;
A.107.E.48.i; A.108.E.48.i; A.109.E.48.i; A.110.E.48.i; A.111.E.48.i;
A.112.E.48.i;
A.113.E.48.i; A.114.E.48.i; A.115.E.48.i; A.116.E.48.i; A.117.E.48.i;
A.118.E.48.i;
A.119.E.48.i; A.120.E.48.i; A.121.E.48.i; A.122.E.48.i; A.123.E.48.i;
A.124.E.48.i;
A.125.E.48.i; A.126.E.48.i; A.127.E.48.i; A.128.E.48.i; A.129.E.48.i;
A.130.E.48.i;
A.131.E.48.i; A.132.E.48.i; A.133.E.48.i; A.134.E.48.i; A.135.E.48.i;
A.136.E.48.i;
A.137.E.48.i; A.138.E.48.i; A.139.E.48.i; A.140.E.48.i; A.141.E.48.i;
A.2.E.49.i;
A.3.E.49.i; A.4.E.49.i; A.5.E.49.i; A.7.E.49.i; A.9.E.49.i; A.100.E.49.i;
A.lOl.E.49.i;
A.102.E.49.i; A.103.E.49.i; A.104.E.49.i; A.105.E.49.i; A.106.E.49.i;
A.107.E.49.i;
A.108.E.49.i; A.109.E.49.i; A.110.E.49.i; A.111.E.49.i; A.112.E.49.i;
A.113.E.49.i;
A.114.E.49.i; A.115.E.49.i; A.116.E.49.i; A.117.E.49.i; A.118.E.49.i;
A.119.E.49.i;
A.120.E.49.i; A.121.E.49.i; A.122.E.49.i; A.123.E.49.i; A.124.E.49.i;
A.125.E.49.i;
A.126.E.49.i; A.127.E.49.i; A.128.E.49.i; A.129.E.49.i; A.130.E.49.i;
A.131.E.49.i;
A.132.E.49.i; A.133.E.49.i; A.134.E.49.i; A.135.E.49.i; A.136.E.49.i;
A.137.E.49.i;
A.138.E.49.i; A.139.E.49.i; A.140.E.49.i; A.141.E.49.i; A.2.E.50.i;
A.3.E.50.i;
A.4.E.50.i; A.5.E.50.i; A.7.E.50.i; A.9.E.50.i; A.100.E.50.i; A.lOl.E.50.i;
A.102.E.50.i; A.103.E.50.i; A.104.E.50.i; A.105.E.50.i; A.106.E.50.i;
A.107.E.50.i;
A.108.E.50.i; A.109.E.50.i; A.110.E.50.i; A.111.E.50.i; A.112.E.50.i;
A.113.E.50.i;
A.114.E.50.i; A.115.E.50.i; A.116.E.50.i; A.117.E.50.i; A.118.E.50.i;
A.119.E.50.i;
A.120.E.50.i; A.121.E.50.i; A.122.E.50.i; A.123.E.50.i; A.124.E.50.i;
A.125.E.50.i;
A.126.E.50.i; A.127.E.50.i; A.128.E.50.i; A.129.E.50.i; A.130.E.50.i;
A.131.E.50.i;
A.132.E.50.i; A.133.E.50.i; A.134.E.50.i; A.135.E.50.i; A.136.E.50.i;
A.137.E.50.i;
A.138.E.50.i; A.139.E.50.i; A.140.E.50.i; A.141.E.50.i; A.2.E.51.i;
A.3.E.51.i;
A.4.E.51.i; A.5.E.51.i; A.7.E.51.i; A.9.E.51.i; A.100.E.51.i; A.lOl.E.5l.i;
A.102.E.51.i; A.103.E.51.i; A.104.E.51.i; A.105.E.51.i; A.106.E.51.i;
A.107.E.51.i;
A.108.E.51.i; A.109.E.51.i; A.110.E.51.i; A.111.E.51.i; A.112.E.51.i;
A.113.E.51.i;
A.114.E.51.i; A.115.E.51.i; A.lI6.E.51.i; A.117.E.51.i; A.118.E.51.i;
A.119.E.51.i;
A.120.E.51.i; A.121.E.51.i; A.122.E.51.i; A.123.E.51.i; A.124.E.51.i;
A.125.E.51.i;
A.126.E.51.i; A.127.E.51.i; A.128.E.51.i; A.129.E.51.i; A.130.E.51.i;
A.131.E.51.i;
A.132.E.51.i; A.133.E.51.i; A.134.E.51.i; A.135.E.51.i; A.136.E.51.i;
A.137.E.51.i;
A.138.E.51.i; A.139.E.51.i; A.140.E.51.i; A.141.E.51.i; A.2.F.46.i;
A.3.F.46.i;
A.4.F.46.i; A.S.F.46.i; A.7.F.46.i; A.9.F.46.i; A.100.F.46.i; A.101.F.46.i;
A.102.F.46.i; A.103.F.46.i; A.104.F.46.i; A.105.F.46.i; A.106.F.46.i;
A.107.F.46.i;
A.108.F.46.i; A.109.F.46.i; A.110.F.46.i; A.111.F.46.i; A.112.F.46.i;
A.113.F.46.i;
A.114.F.46.i; A.115.F.46.i; A.116.F.46.i; A.117.F.46.i; A.118.F.46.i;
A.119.F.46.i;
A.120.F.46.i; A.121.F.46.i; A.122.F.46.i; A.123.F.46.i; A.124.F.46.i;
A.125.F.46.i;
A.126.F.46.i; A.127.F.46.i; A.128.F.46.i; A.129.F.46.i; A.130.F.46.i;
A.131.F.46.i;
A.132.F.46.i; A.133.F.46.i; A.134.F.46.i; A.135.F.46.i; A.136.F.46.i;
A.137.F.46.i;
A.138.F.46.i; A.139.F.46.i; A.140.F.46.i; A.141.F.46.i; A.2.F.47.i;
A.3.F.47.i;
A.4.F.47.i; A.5.F.47.i; A.7.F.47.i; A.9.F.47.i; A.100.F.47.i; A.101.F.47.i;

A.102.F.47.i; A.103.F.47.i; A.104.F.47.i; A.105.F.47.i; A.106.F.47.i;
A.107.F.47.i;
A.108.F.47.i; A.109.F.47.i; A.110.F.47.i; A.111.F.47.i; A.112.F.47.i;
A.113.F.47.i;
A.114.F.47.i; A.115.F.47.i; A.116.F.47.i; A.117.F.47.i; A.118.F.47.i;
A.119.F.47.i;
A.120.F.47.i; A.121.F.47.i; A.122.F.47.i; A.123.F.47.i; A.124.F.47.i;
A.125.F.47.i;
A.126.F.47.i; A.127.F.47.i; A.128.F.47.i; A.129.F.47.i; A.130.F.47.i;
A.131.F.47.i;
A.132.F.47.i; A.133.F.47.i; A.134.F.47.i; A.135.F.47.i; A.136.F.47.i;
A.137.F.47.i;
A.138.F.47.i; A.139.F.47.i; A.140.F.47.i; A.141.F.47.i; A.2.F.48.i;
A.3.F.48.i;
A.4,F.48.i; A.5.F.48.i; A.7.F.48.i; A.9.F.48.i; A.100.F.48.i; A.101.F.48.i;
A.102.F.48.i; A.103.F.48.i; A.104.F.48.i; A.105.F.48.i; A.106.F.48.i;
A.107.F.48.i;
A.108.F.48.i; A.109.F.48.i; A.110.F.48.i; A.111.F.48.i; A.112.F.48.i;
A.113.F.48.i;
A.114.F.48.i; A.115.F.48.i; A.116.F.48.i; A.117.F.48.i; A.118.F.48.i;
A.119.F.48.i;
A.120.F.48.i; A.121.F.48.i; A.122.F.48.i; A.123.F.48.i; A.124.F.48.i;
A.125.F.48.i;
A.126.F.48.i; A.127.F.48.i; A.128.F.48.i; A.129.F.48.i; A.130.F.48.i;
A.131.F.48.i;
A.132.F.48.i; A.133.F.48.i; A.134.F.48.i; A.135.F.48.i; A.136.F.48.i;
A.137.F.48.i;
A.138.F.48.i; A.139.F.48.i; A.140.F.48.i; A.141.F.48.i; A.2.F.49.i;
A.3.F.49.i;
A.4.F.49.i; A.5.F.49.i; A.7.F.49.i; A.9.F.49.i; A.100.F.49.i; A.lOl.F.49.i;
A.102.F.49.i; A.103.F.49.i; A.104.F.49.i; A.105.F.49.i; A.106.F.49.i;
A.107.F.49.i;
A.108.F.49.i; A.109.F.49.i; A.110.F.49.i; A.111.F.49.i; A.112.F.49.i;
A.113.F.49.i;
A.114.F.49.i; A.115.F.49.i; A.116.F.49.i; A.117.F.49.i; A.118.F.49.i;
A.119.F.49.i;
A.120.F.49.i; A.121.F.49.i; A.122.F.49.i; A.123.F.49.i; A.I24.F.49.i;
A.125.F.49.i;
A.126.F.49.i; A.127.F.49.i; A.128.F.49.i; A.129.F.49.i; A.130.F.49.i;
A.131.F.49.i;
A.132.F.49.i; A.133.F.49.i; A.134.F.49.i; A.135.F.49.i; A.136.F.49.i;
A.137.F.49.i;
A.138.F.49.i; A.139.F.49.i; A.140.F.49.i; A.141.F.49.i; A.2.F.50.i;
A.3.F.50.i;
A.4.F.50.i; A.5.F.50.i; A.7.F.50.i; A.9.F.50.i; A.100.F.50.i; A.lOl.F.50,i;
A.102.F.50.i; A.103.F.50.i; A.104.F.50.i; A.105.F.50.i; A.106.F.50.i;
A.107.F.50.i;
A.108.F.50.i; A.109.F.50.i; A.110.F.50.i; A.111.F.50.i; A.112.F.50.i;
A.113.F.50.i;
A.114.F.50.i; A.115.F.50.i; A.116.F.50.i; A.117.F.50.i; A.118.F.50.i;
A.119.F.50.i;
A.120.F.50.i; A.121.F.50.i; A.122.F.50.i; A.123.F.50.i; A.124.F.50.i;
A.125.F.50.i;
A.126.F.50.i; A.127.F.50.i; A.128.F.50.i; A.129.F.50.i; A.130.F.50.i;
A.131.F.50.i;
A.132.F.50.i; A.133.F.50.i; A.134.F.50.i; A.135.F.50.i; A.136.F.50.i;
A.137.F.50.i;
A.138.F.50.i; A.139.F.50.i; A.140.F.50.i; A.141.F.50.i; A.2.F.51.i;
A.3.F.51.i;
A.4.F.51.i; A.5.F.51.i; A.7.F.51.i; A.9.F.51.i; A.100.F.51.i; A.101.F.51.i;
A.102.F.51.i; A.103.F.51.i; A.104.F.51.i; A.105.F.51.i; A.106.F.51.i;
A.107.F.51.i;
A.108.F.51.i; A.109.F.51.i; A.110.F.51.i; A.111.F.51.i; A.112.F.51.i;
A.113.F.51.i;
A.114.F.51.i; A.115.F.51.i; A.116.F.51.i; A.117.F.51.i; A.118.F.51.i;
A.119.F.51.i;
A.120.F.51.i; A.121.F.51.i; A.122.F.51.i; A.123.F.51.i; A.124.F.51.i;
A.125.F.51.i;
A.126.F.51.i; A.127.F.51.i; A.128.F.51.i; A.129.F.51.i; A.130.F.51.i;
A.131.F.51.i;
A.132.F.51.i; A.133.F.51.i; A.134.F.51.i; A.135.F.51.i; A.136.F.51.i;
A.137.F.51.i;
A.138.F.51.i; A.139.F.51.i; A.140.F.51.i; A.141.F.51.i;
The compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+~ Ca++ and Mg++. Such salts may include those derived by combination of appropriate cations such as alkali WO 99!14185 PCT/US98/19355 and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically the W 1 group carboxylic acid.
Monovalent salts are preferred if a water soluble salt is desired.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCI, HBr, H2S04, H3P04, or organic sulfonic acids, to basic centers, typically amines of group G1, or to acidic groups such as E1.
Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoiochimetric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the amino acids described above are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
Methods of Inhibition of Neuraminidase.
Another aspect of the invention relates to methods of inhibiting the activity of neuraminidase comprising the step of treating a sample suspected of containing neuraminidase with a compound of the invention.
Compositions of the invention act as inhibitors of neuraminidase, as intermediates for such inhibitors or have other utilities as described below.
The inhibitors will bind to locations on the surface or in a cavity of neuraminidase having a geometry unique to neuraminidase. Compositions binding neuraminidase may bind with varying degrees of reversibility.
Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. In a typical embodiment the compositions bind neuraminidase with a binding coefficient of less than 10' 4M, more typically less than 10'6M, still more typically 10'8M. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of neuraminidase. Accordingly, the invention relates to methods of detecting neuraminidase in a sample suspected of containing neuraminidase comprising the steps of: treating a sample suspected of containing neuraminidase with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino.
Within the context of the invention samples suspected of containing neuraminidase include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
Typically the sample will be suspected of containing an organism which produces neuraminidase, frequently a pathogenic organism such as a virus.
Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
The treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample. The addition step comprises any method of administration as described above.
If desired, the activity of neuraminidase after application of the composition can be observed by any method including direct and indirect methods of detecting neuraminidase activity. Quantitative, qualitative, and semiquantitative methods of determining neuraminidase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
Organisms that contain neuraminidase include bacteria (Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, and Arthrobacter sialophilus) and viruses (especially orthomyxoviruses or paramyxoviruses such as influenza virus A and B, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and sendai virus).
Inhibition of neuraminidase activity obtained from or found within any of these organisms is within the objects of this invention. The virology of influenza viruses is described in "Fundamental ~lirology" (Raven Press, New York, 1986), Chapter 24. The compounds of this invention are useful in the treatment or prophylaxis of such infections in animals, e.g. duck, rodents, or swine, or in man.
However, in screening compounds capable of inhibiting influenza viruses it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays, as shown Table 1 of Chandler et al., i~upra.
Thus, a plaque reduction assay should be the primary screening tool.
Screens for Neuraminidase Inhibitors.
Compositions of the invention are screened for inhibitory activity against neuraminidase by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of neuraminidase in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10-6 M, typically less than about 1 X 10-7 M and preferably less than about 5 X 10-8 M are preferred for in vivo use.
Useful in vitro screens have been described in detail and will not be elaborated here. However, von Itzstein, M. et al.; "Nature", 363(6428):418-423 {1993), in particular page 420, column 2, full paragraph 3, to page 421, column 2, first partial paragraph, describes a suitable in vitro assay of Potier, M.; et al.; "Analyt. Biochem.", 94:287-296 (1979), as modified by Chong, A.K.J.;
et al.; "Biochern. Biophys. Acta", 1077:65-71 (1991); and Colman, P. M.; et al.;
International Publication No. WO 92/06691 (Int. App. No. PCT/AU90/00501, publication date April 30, 1992) page 34, line 13, to page 35, line 16, describes another useful in vitro screen.
In vivo screens have also been described in detail, see von Itzstein, M.
et al.; op. cit., in particular page 421, column 2, first full paragraph, to page 423, column 2, first partial paragraph, and Colman, P. M.; et al.; op. cit.
page 36, lines 1-38, describe suitable in vivo screens.

Pharmaceutical F~;Zmulations and Routes of Administration.
The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like.
Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally; it is not necessary to administer them by intrapulmonary or intranasal routes. Surprisingly, (in view of, inter ~jj~, Bamford, M. J., "J.
Enzyme Inhibition" 10:1-6 (1995), and especially p. 15, first full paragraph), the anti-influenza compounds of WO 91 / 16320, WO 92 / 06691 and U.S.
Patent 5,360,817 are successfully administered by the oral or intraperitoneal routes. See Example 161 infra.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing -17$-administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).
Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration are prepared as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules;
as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
In one embodiment acid hydrolysis of the medicament is obviated by use of an enteric coating.
For infections of the eye or other external tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredients) in an amount of, for example, 0.075 to 20% w/w (including active ingredients) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinuc or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol {including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers) with or without stabilizers) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween~ 60, Span~ 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc. ), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of influenza A or B
infections as described below.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations are presented in unit-dose or mufti-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient axe controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active influenza infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .Ol to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, for inhalation the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
Typical doses include 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100,110,115,120,125,130,135,140,145,150,157, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, and 1000 mg of GS 4104, phosphate salt, once or twice a day; more typically, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100,110,115, 120, 125,130, 135,140, 145,150,157, 200 mg of GS 4104, phosphate salt, once or twice a day; more typically still 20, 50, 75,100, 150 and 200 mg of GS 4104, phosphate salt, once or twice a day; more typically yet 75 or 150 mg of GS
4104, phosphate salt, once or twice a day.
Active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating viral infections of the respiratory system, in particular influenza infection, the compositions of the invention are combined with antivirals (such as amantidine, rimantadine and ribavirin), mucolytics, expectorants, bronchialdilators, antibiotics, antipyretics, or analgesics. Ordinarily, antibiotics, antipyretics, and analgesics are administered together with the compounds of this invention.
~etahnl;tPs of the Com~unds of the Invention Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. C14 or H3) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no neuraminidase inhibitory activity of their own.
Additional, Uses fob the Compounds of This Invention.
The compounds of this invention, or the biologically active substances produced from these compounds by hydrolysis or metabolism in vivo, are used as immunogens or for conjugation to proteins, whereby they serve as components of immunogenic compositions to prepare antibodies capable of binding specifically to the protein, to the compounds or to their metabolic products which retain immunologically recognized epitopes (sites of antibody binding). The immunogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostic, quality control, or the like, methods or in assays for the compounds or their novel metabolic products. The compounds are useful for raising antibodies against otherwise non-immunogenic polypeptides, in that the compounds serve as haptenic sites stimulating an immune response that cross-reacts with the unmodified conjugated protein.
The hydrolysis products of interest include products of the hydrolysis of the protected acidic and basic groups discussed above. As noted above, the acidic or basic amides comprising immunogenic polypeptides such as albumin or keyhole limpet hemocyanin generally are useful as immunogens. The metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention. Thus, the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds; alternatively the metabolic products, will be capable of binding to the protected compounds and/or the metabolitic products without binding to the protected compounds of the invention, or will, be capable of binding specifically to any one or all three. The antibodies desirably will not substantially cross-react with naturally-occurring materials. Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results.
The immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance. Within the context of the invention such association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above. Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharides. Typically, the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent. Methods for the manufacture of hapten immunogens are conventional per se. and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance.
Typically the polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized.
The conjugates are prepared in conventional fashion. For example, the cross-linking agents N-hydroxysuccinimide, succinic anhydride or alkN=C=Nalk are useful in preparing the conjugates of this invention. The conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance. The conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
The compounds of this invention are cross-linked for example through any one or more of the following groups: a hydroxyl group of Ul; a carboxyl group of El; a carbon atom of Ul, E1, Gl, or Tl, in substitution of H;
and an amine group of G1. Included within such compounds are amides of polypeptides where the polypeptide serves as an above-described R~,c or It6b groups.
Animals are typically immunized against the immunogenic conjugates or derivatives and antisera or monoclonal antibodies prepared in conventional fashion.
The compounds of the invention are useful for maintaining the structural integrity of glycoproteins in recombinant cell culture, i.e., they are added to fermentations in which glycoproteins are being produced for recovery so as to inhibit neuraminidase-catalyzed cleavage of the desired glycoproteins. This is of particular value in the recombinant synthesis of proteins in heterologous host cells that may disadvantageously degrade the carbohydrate portion of the protein being synthesized.
The compounds of the invention are polyfunctional. As such they represent a unique class of monomers for the synthesis of polymers. By way of example and not limitation, the polymers prepared from the compounds of this invention include polyamides and polyesters.
The present compounds are used as monomers to provide access to polymers having unique pendent functionalities. The compounds of this invention are useful in homopolymers, or as comonomers with monomers which do not fall within the scope of the invention. Homopolymers of the compounds of this invention will have utility as cation exchange agents (polyesters or polyamides) in the preparation of molecular sieves {polyamides), textiles, fibers, films, formed articles and the like where the acid functionality El is esterified to a hydroxyl group in Ul, for example, whereby the pendant basic group Gl is capable of binding acidic functionalities such as are found in polypeptides whose purification is desired. Polyamides are prepared by cross-linking E1 and Gl, with Ul and the adjacent portion of the ring remaining free to function as a hydrophilic or hydrophobic affinity group, depending up the selection of the Ul group.
The preparation of these polymers from the compounds of the invention is conventional per se.
The compounds of the invention are also useful as a unique class of polyfunctional surfactants. Particularly when Ul does not contain a hydrophilic substituent and is, for example, alkyl or alkoxy, the compounds have the properties of bi-functional surfactants. As such they have useful surfactant, surface coating, emulsion modifying, rheology modifying and surface wetting properties.
As polyfunctional compounds with defined geometry and carrying simultaneously polar and non-polar moieties, the compounds of the invention are useful as a unique class of phase transfer agents. By way of example and not limitation, the compounds of the invention are useful in phase transfer catalysis and liquid/liquid ion extraction (LIX).
The compounds of the invention optionally contain asymmetric carbon atoms in groups U1, E1, G1, and T1. As such, they are a unique class of chiral auxiliaries for use in the synthesis or resolution of other optically active materials. For example, a racemic mixture of carboxylic acids can be resolved into its component enantiomers by: 1 ) forming a mixture of diastereomeric esters or amides with a compound of the invention wherein U1 is an asymmetric hydroxyalkane or amino alkane group; 2) separating the diastereomers; and 3) hydrolyzing the ester skructure. Racemic alcohols are separated by ester formation with an acid group of E1. Further, such a method can be used to resolve the compounds of the invention themselves if optically active acids or alcohols are used instead of racemic starting materials.
The compounds of this invention are useful as linkers or spacers in preparing affinity absorption matrices, immobilized enzymes for process control, or immunoassay reagents. The compounds herein contain a multiplicity of functional groups that are suitable as sites for cross-linking desired substances. For example, it is conventional to link affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates. These insolublized reagents are employed in known fashion to absorb binding partners for the affinity reagents from manufactured preparations, diagnostic samples and other impure mixtures. Similarly, immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme. Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
Many functional groups in the compounds of this invention are suitable for use in cross-linking. For example, the carboxylic or phosphoric acid of group El is used to form esters with alcohols or amides with amines of the reagent to be cross-linked. The Gl sites substituted with OH, NHRl, SH, azido (which is reduced to amino if desired before cross-linking), CN, N02, amino, guarvidino, halo and the like are suitable sites. Suitable protection of reactive groups will be used where necessary while assembling the cross-linked reagent to prevent polymerization of the bifunctional compound of this invention. In general, the compounds here are used by linking them through carboxylic or phosphonic acid to the hydroxyl or amino groups of the first linked partner, then covalently bonded to the other binding partner through a Tl or Gl group. For example a first binding partner such as a steroid hormone is esterified to the carboxylic acid of a compound of this invention and then this conjugate is cross-linked through a Gl hydroxyl to cyanogen bromide activated Sepaharose, whereby immobilized steroid is obtained. Other chemistries for conjugation are well known. See for example Maggio, "Enzyme-Immunoassay" (CRC, 1988, pp 71-135) and references cited therein.
As noted above, the therapeutically useful compounds of this invention in which the Wl, or Gl carboxyl, hydroxyl or amino groups are protected are useful as oral or sustained release forms. In these uses the protecting group is removed in vivo, e.g., hydrolyzed or oxidized, so as to yield the free carboxyl, amino or hydroxyl. Suitable esters or amides for this utility are selected based on the substrate specificity of esterases and/or carboxypeptidases expected to be found within cells where precursor hydrolysis is desired. To the extent that the specificity of these enzymes is unknown, one will screen a plurality of the compounds of this invention until the desired substrate specificity is found. This will be apparent from the appearance of free compound or of antiviral activity. One generally selects amides or esters of the invention compound that are (i) not hydrolyzed or hydrolyzed comparatively slowly in the upper gut, (ii) gut and cell permeable and (iii) hydrolyzed in the cell cytoplasm and/or systemic circulation. Screening assays preferably use cells from particular tissues that are susceptible to influenza infection, e.g. the mucous membranes of the bronchopulmonary tract. Assays known in the art are suitable for determining in vivo bioavailability including intestinal lumen stability, cell permeation, liver homogenate stability and plasma stability assays.
However, even if the ester, amide or other protected derivatives are not converted in vivo to the free carboxyl, amino or hydroxyl groups, they remain useful as chemical intermediates.
Exemplarlt Methods of Making the So~pouBds of the Icy ntion.
The invention also relates to methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in "Compendium of Organic Synthetic Methods" {John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.
Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984;
and Vol. 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes", Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).
A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
Generally, the reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days.
Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20°C), although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common.
Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
One exemplary method of preparing the compounds of the invention is shown in Scheme 1 below. A detailed description of the methods is found in the Experimental section below.

Scheme 1 HO~, C02H HO.a, C02CH3 HO~
OH

Shikimic Acid 0,,. C02CH3 0,,, CO2CH3 HO~~~ --O' 0,,, CO2CH3 0,,. CO2CH3 NY ---~ N~' i Om( H CHs a 5 OH
~oH
0,,. CO2CH3 O 0.,. C02CH3 H Ns OH
~OH
O 0... C02H

Modifications of Scheme 1 to form additional embodiments is shown in Schemes 2..4.
Scheme 2 ~0~.. ~ C02Me /~0~.. ~ C02Me Ny AcHN
Ac CN

C 02Me /~0... ~ C 02Me AcHN
AcHN
H2N~ NH ~ NH2 ~ 11 C 02Me AcHN
NBoc BocHN~ NH

Scheme 2 Aziridine 5 is converted to the amino nitrite 9 by Yb(CN)3 catalyzed addition of TMSCN according to the procedure of Utimoto and co-workers, "Tetrahedron Lett.", 31:6379 {1990).

10 Conversion of nitrite 9 to the corresponding amidine 10 is accomplished using a standard three step sequence: i) H2S; ii) CH3I; iii) NH40Ac. A typical conversion is found in "J. Med. Chem.", 36:1811 (1993).
Nitrite 9 is converted to the amino methyl compound 11 by reduction using any of the available methods found in "Modern Synthetic Reactions"
2nd ed. H.O. House, Benjamin/Cummings Publishing Co., 1972.
Amino methyl compound 11 is converted to the bis-Boc protected guarvidino compound 12 by treating 11 with N,N'-bis-Boc-1H-pyrazole-1-carboxamidine according to the method found in "Tetrahedron Lett.", 36:299 (1995).

Scheme. 3 /~0~,, ~ C 02M a /~0~... ~ C 02Me N AcH N
Ac N CSC p2tBu /~O~~. ~ COZMe 13 AcHN
~C N

C02Me ~O~,. ~ C02Me AcHN AcHN
~NH

/~p~-. ~ C 02Me AcHN

BocN.~NH
16 NHBoc Scheme 3 The aziridine 5 is opened with a-cyano acetic acid t-butyl ester to give 13. Aziridine openings of this type are found in "Tetrahedron Lett.", 23:5021 (1982). Selective hydrolysis of the t-butyl ester moiety under acidic condtions followed by decarboxylation gives nitrile 14.
Reduction of 14 to the amino ethyl derivative 15 is accomplished in the same fashion as the conversion of 9 to 11. The amine 15 is then converted into the guanidino derivative 16 with N,N'-bis-Boc-1H-pyrazole 1-carboxamidine according to the method found in "Tetrahedron Lett.", 36:299 (1995).
The nitrite 14 is converted to the corresponding amidine 17 using the same sequence described above for the conversion of 9 to 10.

Scheme 4 HO.,, ~ C02Me PGO.,, ~ C02Me PGO.,, ~ Cp2Me .v --i- : -- H O', O,~

PGO.,. ~ C02Me PGO.,, ~ CO Me N AcHN
Ac 21 N3 22 TsO.,, ~ Cp2Me ~ C02Me ----- ~ AcN
AcHN

RO.,, .~ C02Me RS.,. ~ C02Me AcHN
N3 AcHN

RHN.,, ~ C02Me R~-. ~ C02M a AcHN
N3 26 AcHN
N3 27.1 5 The epoxy alcohol 1 is protected (PG=protecting group), for example with MOMCI. Typical conditions are found in "Protective Groups in Organic Synthesis" 2nd ed.,T.W. Greene and P.G.M. Wuts, John Wiley &
Sons, New York, NY, 1991.
The epoxide 19 is opened with NaN3/NH4Cl to the amino alcohol 20 10 according to the procedure of Sharpless and co-workers, "J. Org. Chem.", 50:1557 {1985).
Reduction of 20 to the N-acetyl aziridine 21 is accomplished in a three step sequence: 1) MsCI/triethyl amine; 2) HZ/Pd; 3) AcCI/pyridine. Such WO 99/14185 PC"T/US98/19355 transformations can be found in "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Aziridine 21 is converted to the azido amide 22 by opening with NaN3/NH4Cl in DMF at 65°C as described in "J. Chem. Soc. Perkin Trans I", 801 (1976).
Removal of the MOM protecting group of 22 is accomplished using the methods described in "Protective Groups in Organic Synthesis" 2nd ed.,T.W. Greene and P.G.M. Wuts, john Wiley & Sons, New York, NY, 1991.
The resulting alcohol is converted directly to aziridine 24 with TsCI in pyridine. Such transformations are found in "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Aziridine 24 is then reacted with ROH, RNH2, RSH or an organometallic (metal-R) to give the corresponding ring opened derivatives 25, 26, 27 and 27.1 respectively. Aziridine openings of this type are found in "Tetrahedron Lett.", 23:5021 (19$2) and "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Another class of compounds of the invention are prepared by the method of Schemes 5a and 5b. Quinic acid is converted to 28 by the method of Shing, T.K.M.; et al.; "Tetrahedron", 47{26):4571 {1991). Mesylation with MsCI in TEA/CH2Cl2 will give 29 which is reacted with NaN3 in DMF to give 30. Reaction of 30 with TFA in CH2Cl2 will give 31 which is mesylated with MsCI in TEA/CH2C12 to give 32. Reaction with triphenyiphosphine in water will give 33 which is converted to 35 by sequential application of: 1) CH3C(O)Cl in pyridine, 2) NaN3 in DMF, and 3) NaH in THF. Alkylation of with a wide variety of nucleophiles common in the art will provide a number of compounds such as 36. Methods for elaboration of the compounds such as 36 to other embodiments of the invention will be 30 similar to those described above.

Scheme 5a HO.~. 0~... C02CH3 ..,~~OH
,,. ,,..
HO O
OH OH
Gluinic Acid 28 O",. I C02CH3 0.... C02CH3 ,,.. -.-.
O ,,..
O
OMs N

HO~... C02CH3 HO''~

MsO~... I C02CH3 MsO~... I C02CH3 Ms0''. -'-"' H

Scheme 5b H-N ~ ~ ~N I

Ns Ns 0.,,. C02CH3 H, I
N
H3C~0 N3 OH OH
~OH ~OH
O 0.,,, I C02CH3 0.,.. I C02H
H3C N _ H3C N

37 3$

Scheme 6 PGO~,,,, C02CH3 HO~,~, ~ C02CH3 ACHN ~ ~ ACHN
Na N3 ACO~,. CO2CH3 O ~ C02CH3 ACH N ~N

__ RO~~, C02CH3 R'RN,~,,. C02CH3 RS.,,,, C02CH3 ACHN v ACHN v AcHN
i Another class of compounds of the invention are prepared by the method of Scheme 6. Protected alcohol 22 (PG=methoxymethyl ether) is deprotected under standard conditions described in "Protective Groups in Organic Synthesis" 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley &
Sons, New York, NY, 1991. Alcohol 51 is converted to acetate 52 with acetic anhydride and pyridine under standard conditions. Acetate 52 is treated with TMSOTf or BF3~OEt to afford oxazoline 53. Such transformations are described in "Liebigs Ann. Chem.", 129 (1991) and "Carbohydrate Research", 181 (1993), respectively. Alternatively, alcohol 51 is transformed to oxazoline 53 by conversion to the corresponding mesylate or tosylate 23 and subsequently cyclized to the oxazoline under standard conditions, as described in "J. Org. Chem.", 50:1126 (1985) and "J. Chem. Soc.", 1385 (1970).
Oxazoline 53 is reacted with ROH, RR'NH, or RSH (wherein R and R' are selected to be consistent with the definition of W6 above) provide the corresponding ring opened derivatives 54, 55, and 56 respectively. Such transformations are described in "J. Org. Chem.", 49:4889 (1984) and "Chem.

Rev.", 71:483 (1971).
Schemes 7-6~
Other exemplary methods of preparing the compounds of the invention are shown in Schemes 7-63 below. A detailed description of the methods is found in the Experimental section below.
Scheme 7a HO,.~ ~ C02H OH
0~~... .r' --- O
HO"' O O
OH
(~uinic Acid ON,~. C02Me OH
Ow", ~ C02Me a~,.. .~-O
R~ R2 O"'.
OH
64 R ~ = R2 = O 63 28 Ri = OH, R2 = H
RO~.. C02Me CO Me PivO~...
O O R ~ O,.~.f 66R=H 68 R~=R2=H
67 R = Piv 69 R~ + R2 = -S(O)-Scheme 7b PivO~,.. I COzMe PivO.. C02Me O ~ RO
S'~O ~ N
i, 3 gg 70 R = H
71 R=Ms PivO... I C02Me CO Me PivO.. I 2 AcHN ~ '-73 A~ 72 HO..,. C02H
AcHN
R
74 R=N3 75 R=NH2 Scheme 7c HO~.. I C02H AcO~... C02H
AcHN ~ AcHN

74 78 R = N3 79 R = NH2 HO.,".. C02CHPh2 C02CHPh2 I AcO~,,~.
AcHN I
AcHN

BocHN O'~.. C02CHPh2 H N O~~~ COZH
I 2~ I
AcOH N ----.. AcOH N =
s 80 81 R = N3 82 R = NH2 Scheme 8 H3C0'-0~.. CO2CH3 H3C0~0~~, CO2CH3 AcHN AcHN

BocHN NBoc 91 g2 H3C0~0~. ~ C02H HO.,. ~ C02H
AcHN AcHN
NH NH .TFA
BocHN ~ NBoc H2N~ NH

Scheme 9 ~'0~,, ~ C02H
~0.,, ~ C02CH3 AcH N

AcHN

6 +
0.,. C02H
AcHN

Scheme 10 CH30~p,,. ~ C02H CH30~0.,. ~ C02Na AcHN
AcHN -..

H ~~ N H

Scheme 11 OH OH
0~... = C02Me 0,,~.. = C02Me p~-OH OTs 0~,~.. ~ C02Me O""..
OTs Scheme 12 0~~.. ~ C02CH3 HO~,,,. ~ C02CH3 ~ _-..
'O.r ,w, HO
OMs OMs HO,,~ ~ CO2CH3 O'"', Scheme 13 PGO.,,,, ~ C02CH3 HO.,,.. ~ C02CH3 AcHN AcHN

H3C0~..... ~ CO2CH3 H3C0.,,,, ~ C02H
AcHN a AcHN
N3 NH2 ~HCI
150 15i Scheme 14 -0~~,.. \ C02CH3 //\.0~~,.. \ CO CH

AcHN AcHN

fi 1S2 //\-0..,.. \ C02H
AcHN

Scheme 15a CO Me O
~0,, ~~ C02Me Ms0"' Ms0' Ns N3 OH
HO~O,I "~ C02Me Ol~p~ ~ C02Me Ms0''~ -'-' Ms0' Na N3 OH
p,, ~ C02Me MSO"' OAc ~0,, ~" C02Me OAc ~0,, ~ C02Me N
Boc Scheme 15b OAc ~0,, ~ C02Me AcHN

OH
~O. ~ C02H
AcHN

Scheme 16 HO,,. ~ C02Me PGO,,, ~ C02Me O"... O ",..
PG=MOM

CH30,,r0~~ ~ C02Me N
H

PGO.,,, ~ C02Me -.
AcHN

PG=MOM

CH30~0~, ~ C02H HO,.. ~ C02H
AcHN ------~ AcHN

Scheme 17 HO~,,, COzH O",~. .,~ C02CH3 HO''~~~ O'"'. --OH OH
Shikimic Acid 180 CO2CH3 HO~.,. \ CO2CH3 HO'p._ OMs OMs HO~,~. C02CH3 PGO,,,, \ C02CH3 N',. N,.
PG=MOM

H3CO~O.a.. COzCH3 H3C0~0~,,, \ C02CH3.
HO''~~~ --~ Ms0' H3C:O~O.,.. \ C02CH3 H3CO~0~,, .~ C02CH3 N~- ~ HzN ~ -.
H Ns Ph3CN

Scheme 18 CO2CH3 ON~, ~ C02CH3 Ph3CN
AcN
N3 H Ns 0.,,,. ~ C02H
AcN

Scheme 19 /~O~-... ~ C02CH3 /~,~0'",.. ~ C02CH3 AcHN AcHN
NH2 HN~NBoc NHBoc '~~.. ~ CO H
2 ~0,,... ~., C02H
AcHN ~" AcHN
HN~NBoc HN~NH
NHBoc NH2 ~TFA

Scheme 20 O~.. ~ C02H ~0,,,, ~~ C02Na AcHN ~ AcHN
NH2 HN ~H
NH

Scheme 21 C02CH3 ~0,,,.

H2N ~! ~ H2N
Ns N3 O,, w co2H o °r -.~ co2H
- ~ F3C ~ H _ Ns NH2 Scheme 22 ~ C02CH3 ~.0~,.. ~. 02CH

O
N
H2N Ns HsC_S~ H Ns O

~ C02CH3 ~0.,.. ~ CO H

-"~,~ O
H3C S H NH2 H3C S' H NH

Scheme 23 n.0 ~.. ~ C02CH3 ~O~~ w C02CH3 O O
n~N ~ "~N .
H3Clp H NH2 H3C ~ H HN~NBoc NHBoc o.,. ~ co2H ~.o... ., co H

o _~ o ~~~N .
H3C ~ H HN~NBoc H3C O H HN NH
NHBoc NH2 Scheme 24 ~Om, CO2CH3 ~"O''. \ C02CH3 O
H2N = ~ ~N
N3 H Ns C02CH3 ~0,, \ C02H
--N
H = N t 21 fi 217 Scheme 25 ~0~... \ C02CH3 ~0~.~. \ CO2CH3 AcHN ~ -~- AcHN
NH2 HN~NBoc N Boc i \ C02H ~0~,..
\ C02H
AcHN -" AcHN
HN~NBoc HN~NH
NBoc NH

WO 99/141$5 PCT/US98/19355 Scheme 26 ~ CO2CH3 /'~0,.~,. ~ C02CH3 TrN~ -'~/
AcHN
Ns Na CO2CH3 /'~0~.,,. ~ C02H
- -AcHN AcHN

Scheme 27 /~O'~ ~ CO2CH3 ~O~' \ C02CH3 AcHN
AcHN - HN NBoc NHBoc C02H /~0,,, ~ C02H
- .--r _ AcHN AcHN
HN~NBoc HN NH
NHBoc H2 Scheme 28 \ C02CH3 TrN~ \ C02CH3 _--N3 AcHN

O~. \ C02CH3 p,,, \ C02H
AcHN = ~ AcHN
NHz NHZ

Scheme 29 CO2CH3 ~~!~~0,,, \ C02CH3 TrN
AcHN

O~.. \ C02CH3 ~%~~O~, .~ C02H
AcHN AcHN

Scheme 30 CO2CH3 ~5.,,. CO2CH3 TrN
_--~ H2N

/'~S'~ CO2CH3 /~S'~ \ CO2CH3 AcHN AcHN

Scheme 31 HO,,,,_ 0~02H 0~... ~aOH
O
HON
OH O

Gluinic Acid 0,.,~. ~~02Me OH
Oa,,.. = C02Me W ". , O
w~".
OTS O

HO~.. ~ C02Me HO~,... ~ C02Me HO'"'°
OTs O

Scheme 32 C02CH3 ~0~.. \ CO2CH3 N N
H H

/\i0~. C02CH3 ~0,,,. CO CH
\ 2 3 HZN AcHN
Ns Ns ~\,0~, \ C02CH3 ~0,,, \ C02H
AcHN AcHN

Scheme 33 0~.. CO2CH3 O~. C02CH3 AcHN '~ AcHN
NH2 NH2 ~HCI

0~~. \ CO2CH3 'O''~ \ CO2CH3 AcHN , ~ AcHN
NH2 HN\ /NHBoc ~NHBoc AcHN

NH ~CF3C02H

Scheme 34 0,,, .~ Cp2CH3 0~,. C02H
AcHN s ~ AcHN

0~.. \ CO2CH2CH3 0,,, CO CH CH

AcHN AcHN a Scheme 35 C02CH2CH3 0,,. ~ C02CH2CH3 AcHN v ~ AcHN v NH2 HN~NHBoc NBoc 0,,. ~ C02CH2CH3 AcHN
HN~NH2 ~ CF3C02H
NH

Scheme 36 ~0~~,.. ~ C02R5~
HO,,,. 5 1 C02H Rs HO~

Shikimic Acid 270 O.".. ~ C02R51 i 270 B -- R5~0~"..
~R52 HO.,,,. ~ CO2R51 HO~"

HO.~,, ~ C02R5~

Scheme 37 HO~,,.S 1-'' C02H /p~... ~ O

HO's. 2 E R5°~0~~..

OH O
Gluinic Acid 274 OH
274 F R,ON.. ~ C02R5~
.,.. s~0',..
OH

OH
275 G .. ,0~.. = CO2R51 ~0,,..
OR~2 27fi H H0~4. \ CO2R51 HO~

Scheme 38 HOw,.. \ C~2R51 ' RSgOi.... \ C~2R51 O~a,.. Ow:

R5s0'~-.. \ C02R51 277 -~-HO~

R53Oa... \ C~2R51 N
H

R53O~.... \ C02R51 280 ~ R54-N \ C02R51 Scheme 39 CO2R51 RSS,..,. C02R51 Rs4_N N Rss -._ N
Ns H Na R56''~. C~2R51 R55~N

RSS,,,,. C02H

Rss~N

Scheme 40 R5s..,,. C02R5i Rss''~.. C02R5~
y=_ ~._.~. ~
R55~N ~ R55~N
H NHZ H H~N~NRs~
283 NHR5~

RSS.,,,. C02H
285 ~ -- R55~N
I
H H~N~NH

Scheme 40.1 Rs2 J~ JW E~ Rs2 J' J E~
Rs~ Ji ~ J2 Ji J2 Rso l ,J~ NUJ ~Ji J2 i 2 Rss J~
Rs2 J' E~
T
288 ~'~'' J2 ~Rsa)2N J

Rss J
E~
289 ~ Rss N
J~
J2 J Ji Rss J~ J~
Rs~ Ei i 290 ~ J2 J
{Rse)2N J ~J~

Rss Ji J~
W ~~ Ei T~ J G ;J~

Additional embodiments of methods of making and using compositions of the invention are depicted in Schemes 36-40.1. One aspect of the invention is directed to methods of making compounds of the invention comprising processes A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V or W of Schemes 36-40.1, alone or in combination with each other. Table 27 describes exemplary method embodiments of processes A-W. Each embodiment is an individual method using the unit processes A-W alone or in combination. Each method embodiment of Table 27 is separated by a ";". If the embodiment is a single letter than it corresponds to one of the processes A-W. If it is more than one letter than it corresponds to each of the processes performed sequentially in the order indicated.
Other aspects of the invention are directed to methods of using shikimic acid to prepare compound 270 shown as A in Scheme 36, methods of using compound 270 to prepare compound 271 shown as B in Scheme 36, methods of using compound 271 to prepare compound 272 shown as C in Scheme 36, methods of using compound 272 to prepare compound 273 shown as D in Scheme 36, methods of using quinic acid to prepare compound 274 shown as E in Scheme 37, methods of using compound 274 to prepare compound 275 shown as F in Scheme 37, methods of using compound 275 to prepare compound 276 shown as G in Scheme 37, methods of using compound 276 to prepare compound 272 shown as H in Scheme 37, methods of using compound 273 to prepare compound 277 shown as I in Scheme 38, methods of using compound 277 to prepare compound 278 shown as J in Scheme 38, methods of using compound 278 to prepare compound 279 shown as K in Scheme 38, methods of using compound 279 to prepare compound 280 shown as L in Scheme 38, methods of using compound 280 to prepare compound 281 shown as M in Scheme 38, methods of using compound 281 to prepare compound 282 shown as N in Scheme 39, methods of using compound 282 to prepare compound 283 shown as O in Scheme 39, methods of using compound 283 to prepare compound 284 shown as P in Scheme 39, methods of using compound 283 to prepare compound 285 shown as Q in Scheme 40, methods of using compound 285 to prepare compound 286 shown as R in Scheme 40, methods of using compound 287 to prepare compound 288 shown as S in Scheme 40.1, methods of using compound 288 to prepare compound 289 shown as T
in Scheme 40.1, methods of using compound 289 to prepare compound 290 shown as U in Scheme 40.1, methods of using compound 290 to prepare compound 291 shown as V in Scheme 40.1, and methods of using compound 291 to prepare compound 292 shown as W in Scheme 40.1.
General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsecquent processes.
The terms "treated", "treating", "treatment", and the like, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions common in the art of organic synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two.
"Treating" indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100°C to 250°C, typically -78°C to 150°C, more typically -78°C to 100°C, still more typically 0°C to 100°C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for "treating" in a given process. In particular, one of ordinary skill in the art of organic sysnthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Process A, Scheme 3b Shikimic acid is used to prepare compound 270 by the following process.
The cis-4,5-diol function of shikimic acid is differentiated from the carboxylic acid at carbon l .by selective protection of these two functionalities.
Typically the cis-4,5-diol function is protected as a cyclic ketal and the carboxylic acid function is protected as an ester.
150 is an acid labile 1,2-diol protecting group such as those described in the above cited work of Greene, typically a cyclic ketal or acetal, more typically, a ketal of cyclohexanone or acetone. I~51 is an and stable carboxylic acid protecting group such as those described in the above cited work of Greene, typically a linear, branched or cyclic alkyl, alkenyl, or alkynyl of 1 to 12 carbon atoms such as those shown as groups 2-7, 9-10, 15, or 100-660 of Table 2, more typically a linear or branched alkyl of 1 to 8 carbon atoms such as those shown as groups 2-5, 9, or 100-358 of Table 2, still more typically a linear or branched alkyl of 1 to 6 carbon atoms such as those shown as groups 2-5, 9, or 100-141 of Table 2, more typically yet, R,51 is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl.
Shikimic acid is reacted to protect the carboxylic acid with group I~51 and the cis-4,5-diol with group R,50. Typically shikimic acid is treated with an alcohol, such as methanol, ethanol, n-propanol, or i-propanol, and an acid catalyst, such as a mineral acid or a sulfonic acid such as methane, benzene or toluene sulfonic acid, followed by a dialkyl ketal or acetal of a ketone or aldehyde, such as 2,2-dimethoxy-propane, or 1,1-dimethoxy-cyclohexane, in the presence of the corresponding ketone or aldehyde, such as acetone or cyclohexanone. Optionally, the product of the alcohol and acid catalyst treatment is separated, isolated and/or purified prior to treatment with dialkyl ketal or acetal. Alternatively shikimic acid is treated with CH2N2.
Typically, the process comprises treating shikimic acid with an alkanol and a sulfonic acid followed by treating with a geminal-dialkoxyalkane or geminal dialkoxycycloalkane and an alkanone or cycloalkanone to form compound 270. More typically, the process comprises treating shikimic acid with an alkanol and a sulfonic acid; evaporating excess alkanol to form a residue; treating the residue with a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane and an alkanone or cycloalkanone to form compound 270. Still more typically, the process comprises treating shikimic acid with methanol and para-toiuenesulfonic acid; evaporating excess methanol to form a residue; treating the residue with 2,2-dimethoxypropane and acetone to form compound 270.

An exemplary embodiment of this process is given as Example 55 below.
Compound 270 is used to prepare compound 271 by the following process.
The hydroxy group at position 3 is activated, typically, activated toward displacement reactions, more typically, activated toward epoxide ring forming displacement with an alcohol at position 4.
R52 is an alcohol activating group, typically, an activating group toward displacement reactions, more typically, an activating group toward epoxide ring forming displacement with an alcohol at position 4. Such groups include those typical in the art such as sulfonic acid esters, more typically, methane, benzene or toluene sulfonic acid esters. In one embodiment, R,52, taken together with O (i.e. -OR,52), is a leaving group such as those common in the art.
Typically the process comprises treating compound 270 with an acid halide to form compound 271. More typically, the process comprises treating compound 270 with a sulfonic acid halide in a suitable solvent to form compound 271. Still more typically, the process comprises treating compound 270 with a sulforuc acid halide in a suitable solvent such as an amine, optionally, in the presence of a cosolvent, such as a haloalkane, to form compound 271. More typically yet; the process comprises treating compound 270 with methane sulfonyl chloride in triethylamine/dichloromethane to form compound 271.
An exemplary embodiment of this process is given as Example 56 below.
Process C. Scheme 36 Compound 271 is used to prepare compound 272 by the following process.
The acid labile protecting group (R,5p) for the hydroxy groups at positions 4 and 5 is removed. Typically, I~50 is removed without substaintially removing base labile carboxylic acid protecting groups (e.g.
I~51) or hydroxy activating groups (e.g. R,52). Still more typically, R,Sp is cleaved under acidic conditions.

Typically the process comprises treating compound 271 with a erotic solvent, more typically, in the presence of an acid catalyst as described above.
Still more typically, the process comprises treating compound 271 with an alkanol as described above and an acid catalyst as described above. More typically yet, the process comprises treating compound 271 with methanol and para-toluene sulfonic acid to produce compound 272.
An exemplary embodiment of this process is given as Example 57 below.
Process D. Scheme 36 Compound 272 is used to prepare compound 273 by the following process.
The activated hydroxy group at position 3 of compound 272 is displaced by the hydroxy at position 4 of compound 272 to produce epoxide compound 273. Typically the displacement is catalyzed by a suitable base, more typically, an amine base such as DBU or DBN.
Typically the process comprises treating compound 272 with a basic catalyst, optionally in the presecnce of a suitable solvent. Still more typically, the process comprises treating compound 272 with an amine base in a polar, non-erotic solvent such as diethyl ether or THF. More typically yet, the process comprises treating compound 272 with DBU in THF to produce compound 273.
An exemplary embodiment of this process is given as Example 58 below.
Process E. Scheme 37 Quinic acid is used to prepare compound 274 by the following process.
The cis-4,5-diol function of quiruc acid is differentiated from the carboxylic acid at carbon 1 by selective protection of these two functionalities.
Typically the cis-4,5-diol function is protected as a cyclic ketal and the carboxylic acid function is protected as a lactone with the hydroxy group at position 3.
I~50 is as described above.
Typically, the process comprises treating quinic acid with a geminal-dialkoxyalkane or geminal dialkoxycycioalkane, as described above, and an alkanone or cycloalkanone, as described above, optionally, in the presence of an acid catalyst, as described above, to form compound 274. More typically, the process comprises treating quinic acid with a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane, an alkanone or cycloalkanone, and an acid catalyst to form compound 270. Still more typically, the process comprises treating quinic acid with 2,2-dimethoxypropane, acetone, and para-toluenesulfonic acid to form compound 274.
An exemplary embodiment of this process is given as Example 101 below.
Process F. Scheme 37 Compound 274 is used to prepare compound 275 by the following process.
The lactone is opened to form compound 275. Typically, the lactone is opened to produce a protected carboxylic acid at position 1 and a free hydroxy at position 3. More typically, the lactone is opened under basic conditions to produce an I~51 protected carboxylic acid at position 1 and a free hydroxy group at position 3.
I~51 is as described above.
Typically compound 274 is treated with a suitable base in a suitable protic solvent. More typically compound 275 is treated with a metal alkoxide base, such as sodium, potassium or lithium alkoxide, in an alkanol, as described above. Still more typically, compound 274 is treated with NaOMe in MeOH to produce compound 275.
An exemplary embodiment of this process is given as Example 102 below.
Compound 275 is used to prepare compound 276 by the following process.
The hydroxy group at position 3 is activated, typically, activated toward displacement reactions, more typically, activated toward epoxide ring forming displacement with an alcohol at position 4.
I~,52 is an alcohol activating group, typically, an activating group toward displacement reactions, more typically, an activating group toward epoxide ring forming displacement with an alcohol at position 4. Such groups include those typical in the art such as sulfonic acid esters, more typically, methane, benzene or toluene sulfonic acid esters. In one embodiment, 152, taken together with O (i.e. -OI~52), is a leaving group such as those common in the art.
Typically the process comprises treating compound 275 with an acid halide to form compound 276. More typically, the process comprises treating compound 275 with a sulfonic acid halide in a suitable solvent to form compound 276. Still more typically, the process comprises treating compound 275 with a sulfonic acid halide in a suitable solvent such as an amine, optionally, in the presence of a cosolvent, such as a haloalkane, to form compound 276. More typically yet, the process comprises treating compound 275 with p-toluene sulfonyl chloride in pyridine dichloromethane to form compound 276.
An exemplary embodiment of this process is given as Example 103 below.
Compound 276 is used to prepare compound 272 by the following process.
The hydroxy group at position 1 is eliminated and the cis-4,5-diol protecting group is removed. The hydroxy group at position 1 is eliminated to form an olefinic bond between positions 1 and 6 and the cis-4,5-diol protecting group is removed to regenerate the cis-4,5-diol.
Typically the process comprises treating compound 276 with a suitable dehydrating agent, such as a mineral acid (HCI, H2S04) or S02C12. More typically, compound 276 is treated with S02C12, followed by an alkanol, optionally in the presence of an acid catalyst. Still more typically, compound 276 is treated with S02C12 in a suitable polar, aprotic solvent, such as an amine to form an olefin; the olefin is treated with an alkanol, as described above, and an acid catalyst, as described above, to form compound 272. More typically yet, compound 276 is treated with S02C12 in pyridine/CH2Cl2 at a temperature between -100°C and 0°C, typically -100°C and -10°C, more typically -78°C, to form an olefin; the olefin is treated with methanol and para-toluene sulfonic acid to form compound 272.
An exemplary embodiment of this process is given as Example 104 below.

Process I. Scheme 38 Compound 273 is used to prepare compound 277 by the following process.
The hydroxy group at position 5 is protected. Typically the protecting group is an acid labile hydroxy protecting. More typically, the protecting group resists transfer to adjacent hydroxy groups.
I~53 is an acid labile hydroxy protecting group such as those described in the above cited work of Greene. More typically, I~53 is as acid cleavable ether, still more typically, I~53 is methoxymethyl (MOM, CH3-0-CH2-).
Typically the process comprises treating compound 273 with a hydroxy protecting group reagent as described in Greene. More typically the process comprises treating compound 273 with a substituted or unsubstituted haloalkane or alkene, such as methoxymethyl chloride (MOM
chloride, CH3-O-CH2-CI), in a suitable solvent, such as a polar, aprotic solvent. Still more typically, the process comprises treating compound 273 with MOM chloride in an amine solvent. More typically yet, the process comprises treating compound 273 with MOM chloride in diisoproply ethyl amine.
An exemplary embodiment of this process is given as Example 59 below.
Process j4 Sc~~me 38 Compound 277 is used to prepare compound 278 by the following process.
The epoxide at positions 3 and 4 is opened to form an azide. More typically, the epoxide at positions 3 and 4 is opened to form a 3-azido-4-hydroxy compound 278.
Typically the process comprises treating compound 277 with an azide salt in a suitable solvent. More typically, the process comprises treating compound 277 with sodium azide and a mild base, such as an ammonium halide, in a polar, protic solvent, such as an alkanol or water. Still more typically, the process comprises treating compound 277 with sodium azide and ammonium chloride in water/methanol solution to produce compound 278.
An exemplary embodiment of this process is given as Example 60 below.

Proces~jC. Scheme 38 Compound 278 is used to prepare compound 279 by the following process.
The hydroxy group at position 4 of compound 278 is displaced by the 3-azido group to form the aziridine compound 279.
Typically the process comprises treating compound 278 with a hydroxy activating group as described above, an organophosphine and a base. More typically the process comprises treating compound 278 with a sulfonic acid halide, such as those described above, to form an activated hydroxy compound, treating the activated hydroxy compound with trialkyl or tri arylphosphine, such as triphenylphosphine, to form a phosphonium salt, and treating the phosphonium salt with a base, such as an amine, to form compound 279. Still more typically, the process comprises treating compound 278 with mesyl chloride, to form an activated hydroxy compound, treating the activated hydroxy compound with triphenylphosphine, to form a phosphonium salt, and treating the phosphonium salt with triethylamine and H20, to form compound 279.
An exemplary embodiment of this process is given as Examples 61 and 62 below.
Compound 279 is used to prepare compound 280 by the following process.
The aziridine compound 279 is opened with azide to form azido amine 280.
Typically the process comprises treating compound 279 with with an azide salt in a suitable solvent. More typically, the process comprises treating compound 279 with sodium azide and a mild base, such as an ammonium halide, in a polar, aprotic solvent, such as an ether, amine, or amide. Still more typically, the process comprises treating compound 279 with sodium azide and ammonium chloride in DMF solution to produce compound 280.
An exemplary embodiment of this process is given as Example 63 below.

Compound 280 is used to prepare compound 281 by the following process.
The protected hydroxy group at position 5 is displaced by the amine at position 4 to form aziridine 281. Typically the aziridine 281 is substituted with an acid labile group, more typically an aziridine activating group.
I~54 is an acid labile group, typically an acid labile amine protecting group such as those described in the above cited work of Greene. More typically, R,54 is an aziridine activating group, still more typically, a group capable of activating an aziridine toward acid catalyzed ring opening.
Typical I~54 groups include by way of example and not Limitation, a linear or branched 1-oxo-alk-1-yl group of 1 to 12 carbons wherein the alkyl portion is a 1 to 11 carbon linear or branched chain alkyl group (such as CH3(CH2)zC(O)-, z is an integer from 0 to 10, i.e. acetyl CH,3C(O)-, etc.), substituted methyl (e.g. triphenylmethyl; Ph3C-, trityl, Tr), or a carbamate such as BOC or Cbz or a sulfonate (e.g. alkyl sulphonates such as methyl sulphonate). More typical R,54 groups include triphenylmethyl and 1-oxo-alk-1-yl groups having 1 to 8, still more typically, 1, 2, 3, 4, 5, or 6, more typically yet, 2 or 3 carbon atoms.
Typically the process comprises treating compound 280 with a deprotecting agent to remove group I~53, an I~54 producing reagent such as those described in Greene (R54-halide, such as acetylchloride, or Tr-Cl, or I~54-O-I~54, such as acetic anhydride), and a hydroxy activating group such as those described in process B, Scheme 3b. More typically the process comprises treating compound 280 with a polar, protic solvent, optionally in the presence of an acid catalyst as described above, to form a first intermediate; treating the first intermediate with Tr-Cl in a polar, aprotic solvent, such as an amine, to form a second intermediate; and treating the second intermediate with a sulfonic acid halide, such as mesyl chloride or para toluene sulfonyl chloride, in a polar aprotic solvent, such as an amine, to produce compound 281. Still more typically, the process comprises treating compound 280 with methanol and HCI, to form a first intermediate;
treating the first intermediate with Tr-CI and triethylamine, to form a second intermediate; and treating the second intermediate with mesyl chloride and triethylamine, to produce compound 281.
An exemplary embodiment of this process is given as Example 64 below.

Compound 281 is used to prepare compound 282 by the following process.
Aziridine 281 is opened and the resulting amine is substituted with an R55 group to form compound 282. Typically, aziridine 281 is opened by acid catalyzed ring opening and the resulting amine is acylated.
R55 is W3 as defined above. Typically R55 is -C(O)R5. More typically, R55 is -C(O)Rl. Still more typically, I~55 is -C(O)CH3.
R56 is Ul as described above. Typically R56 is W6-0-, W6-S-, or W6-N(H)-. More typically, R56 is I~5-0-, R5-S-, or R5-N(H)-, still more tyically, R56 is R5-O-, still more typically yet, R56 is Rl-O-.
Typically the process comprises treating compound 281 with an acid catalyst and a compound of the formula W6-Xl-H, wherein Xl is as defined above to form an amine intermediate; and treating the amine intermediate with a compound of the formula W3-X1-W3, W3-X10, wherein X10 is a leaving group, to form compound 282. The acid catalyst is typically a Lewis acid catalyst common in the art, such as BF3~Et20, TiCl3, TMSOTf, SmI2(THF)2, LiC104, Mg(C104)2, Ln(OTf)3 (where Ln=Yb, Gd, Nd), Ti(Oi-Pr)4, A1C13, AlBr3, BeClz, CdCl2, ZnCl2, BF3, BC13, BBr3, GaCl3, GaBr3, TiCl.4, TiBr4, ZrCl4, SnCl,4, SnBr4, SbClS, SbCl3, BiCl3, FeCl3, UCl,4, ScCl3, YC13, LaCl3, CeCl3, PrCl3, NdCl3, SmCl3, EuCl3, GdCl3, TbCl3, LuCl3, DyCl3, HoCl3, ErCl3, TmCl3, YbCl3, ZnI2, Al(OPri)3, Al(acac)3, ZnBr2, for SnCl4. Xl is typically -0-, -S-, or -N(H)-. X10 is typically a halide such as Cl, Br, or I.
More typically, the process comprises treating compound 281 with a compound of the formula R5-OH, R5-SH, or R5-NH2, and BF3 ~ Et20 to form an intermediate; and treating the intermediate with an alkanoic acid anhydride to form compound 282. Still more typically, the process comprises treating compound 281 with a compound of the formula R5-OH
and BF3~Et20 to form an intermediate; and treating the intermediate with a substituted or unsubstituted acetic anhydride to form compound 282.
Exemplary compounds of the formula R5-0H include those described by Table 2, groups 2-7, 9-10, 15, and 100-660 wherein Ql is -OH. Further exemplary compounds of the formula R5-OH include those shown in Table 25 below (together with their Chemical Abstracts Service Registry Numbers) and those shown in Table 26 below (together with their Chemical Abstracts Service Registry Numbers, and Aldrich Chemical Company Product Numbers). More typical exemplary compounds of the formula R5-0H are those described by Table 2, groups 2-5, 9, and 100-141 wherein Ql is -0H.
In another embodiment of Process N, Scheme 39, R55 is H.
Typically this process embodiment comprises treating compound 281 with an acid catalyst and a compound of the formula R56-Xl-H, wherein Xl is as defined above to form an amine intermediate to form compound 282.
The acid catalyst and Xl are as described above. More typically, the process comprises treating compound 281 with a compound of the formula RS-OH, R5-SH, or R5-NH2, and BF3 ~ EtzO to form compound 282. Still more typically, the process comprises treating compound 281 with a compound of the formula R5-OH and BF3 ~ Et20 to form compound 282. Exemplary compounds of the formula R5-OH are described above.
Exemplary embodiments of this process are given as Examples 65, 86, 92, and 95 below.
Process O. Scheme 39 Compound 282 is used to prepare compound 283 by the following process.
The azide of compound 282 is reduced to form amino compound 283.
Typically the process comprises treating compound 282 with a reducing agent to form compound 283. More typically the process comprises treating compound 282 with hydrogen gas and a catalyst {such as platinum on carbon or Lindlar's catalyst), or reducing reagents (such as a trialkyl or triaryl phosphine as described above). More typically still, the process comprises treating compound 282 with triphenylphosphine in water/THF to form compound 283.
Exemplary embodiments of this process are given as Examples 87, 93, and 96 below.
Process P. S~,heme 39 Compound 283 is used to prepare compound 284 by the following process.
The carboxylic acid protecting group is removed.
Typically the process comprises treating compound 283 with a base.
More typically, the process comprises treating compound 283 with a metal hydroxide in a suitable solvent such as an aprotic, polar solvent. More typically still, the process comprises treating compound 283 with aqueous potassium hydroxide in THF to produce compound 284.
Exemplary embodiments of this process are given as Examples 88, 94, and 97 below.
Compound 283 is used to prepare compound 285 by the following process.
The amine is converted to a protected guanidine.
R57 is a guanidine protecting group common in the art, such as BOC
or Me.
Typically the process comprises treating compound 283 with a guanidylating reagent such as those common in the art. Exemplary reagents include Bis-BOC Thio-Urea aminoiminomethanesulfonic acid (Kim; et al.;
"Tet. Lett." 29(26):3183-3186 (1988) and 1-guanylpyrazoles (Bernatowicz; et al.;
"Tet. Lett." 34(21):3389-3392 (1993). More typically, the process comprises treating compound 283 with Bis-BOC Thio-Urea acid. Still more typically, the process comprises treating compound 283 with Bis-BOC Thio-Urea and and HgCl2 to form compound 285.
An exemplary embodiment of this process is given as Example b7 below.
Compound 285 is used to prepare compound 286 by the following process.
The carboxylic acid and guanidine protecting groups are removed.
Typically the process comprises treating compound 285 with a base;
followed by treating with an acid, as described above. More typically the process comprises treating compound 285 with a metal hydroxide base, described above, to form an intermediate; and treating the intermediate with acid to form compound 286. Still more typically the process comprises treating compound 285 with aqueous potassium hydroxide and THF, to form an intermediate; and treating the intermediate with TFA to form compound 286.

Compound 287 is used to prepare compound 288 by the following process.
El, Jl and J2 of compounds 287 and 288 are as described above.
Typically, El is -C02I~51 as described above. Typically, J1 is H, F, or methyl, more typically, H. Typically, J2 is H or a linear or branched alkyl of 1 to 6 carbon atoms, more typically, H, methyl, ethyl, n-propyl, or i-propyl, still more typically, H.
R6p and R61 are groups capable of reacting to form the R63 (defined below) substituted aziridine ring of compound 288. Typically, one of R6p or R61 is a primary or secondary amine, or a group capable of being converted to a primary or secondary amine. Such groups for R6p and R61 include by way of example and not limitation, -NH2, -N{H)(R6b), -N(R6b)2, -N(H)(Rl), -N(Rl)(It6b), and -N3. The other of R6p and R61 is typically a group capable of being displaced by a primary or secondary amine to form an aziridine.
Such groups include by way of example and not limitation, -OH, -OR(,a, Br, Cl, and I. Typically, R6p and R61 are in a trans configuration. More typically, R6p is a primary or secondary amine, or a group capable of being converted to a primary or secondary amine and R61 is a group capable of being displaced by a primary or secondary amine to form an aziridine. Still more typically, R6p is p-azido or ~i-NH2, and R61 is a-OH, a-OMesyl, or a-OTosyl.
R62 is described below in Process U, Scheme 40.1.
The process comprises treating compound 287 to form compound 288.
This is typically accomplished by treating compound 287 to displace R61 by R6p. More typically, compound 287 is treated to activate R61 toward displacement by R6p. Still more typically, compound 287 is treated to activate R( 1 toward displacement by R6p, and R6p is activated toward displacement of R61. If both R6p and R61 are activated, the activations can be performed simultaneously or sequentially. If the activations are performed sequentially, they can be performed in any order, typically the activation of 1261 precedes the activation of R6p.
Activation of R61 toward displacement by R6p is typically accomplished by treating compound 287 with a hydroxy activating reagent such as mesyl or tosyl chloride. Activation of R6p toward displacement of R61 is typically accomplished by treating compound 287 to form a primary or secondary amine and treating the amine with a base. By way of example and not limitation, compound 287 is treated with a reducing agent capable of reducing an azide to an amine and a base.
In one embodiment of this process, compound 287 is treated with an R61 activating reagent, and an Rfp activating reagent to produce compound 288. In another embodiment, compound 287 is treated in a suitable solvent with an It61 activating reagent, and an Itbp activating reagent to produce compound 288. In another embodiment, compound 287 is treated with an Rb1 activating reagent, an R~,O activating reagent, and a base to produce compound 288. In another embodiment, compound 287 is treated in a suitable solvent with an R(1 activating reagent, an R(0 activating reagent, and a base to produce compound 288. In another embodiment, compound 287 wherein R6p is an azide is treated with an R61 activating reagent, and an azide reducing reagent to produce compound 288. In another embodiment, compound 287 wherein RE,p is an azide is treated in a suitable solvent with an Rb1 activating reagent, and an azide reducing reagent to produce compound 288. In another embodiment, compound 287 wherein It6p is an azide is treated with an It61 activating reagent, an azide reducing reagent, and a base to produce compound 288. In another embodiment, compound 287 wherein R60 is an azide is treated in a suitable solvent with an R61 activating reagent, an azide reducing reagent, and a base to produce compound 288. In another embodiment, compound 287 wherein Itbp is an azide and R61 is a hydroxy, is treated with a hydroxy activating reagent, and an azide reducing reagent to produce compound 288. In another embodiment, compound 287 wherein It6p is an azide and R61 is a hydroxy, is treated in a suitable solvent with an hydroxy activating reagent, and an azide reducing reagent to produce compound 288. In another embodiment, compound 287 wherein It60 is an azide and RE,1 is a hydroxy, is treated with a hydroxy activating reagent, an azide reducing reagent, and a base to produce compound 288. In another embodiment, compound 287 wherein R60 is an azide and Rb1 is a hydroxy, is treated in a suitable solvent with a hydroxy activating reagent, an azide reducing reagent, and a base to produce compound 288.
An exemplary embodiments of this process are given as Process K, Scheme 38, above.
Process T, Schyne 40.1 Compound 288 is used to prepare compound 289 by the following WO 99/14185 PC'f/IJS98/19355 process.
R~ is typically H, R6b or a group capable of being converted to H or R6b.. More typically, R~ is H. It65 is typically G1 or a group capable of being converted to Gl. More typically, Rb5 is -N3, -CN, or -(CR1R1)mlW2~ More typically IZ65 is -N3, -NH2, -N(H)(R(b), -N(R6b)2, -CH2N3, or -CH2CN.
Typically, compound 288 is treated to form amine 289. More typically, compound 288 is treated with a nucleophile, typically a nitrogen nucleophile such as RbS, a cationic salt of R65, or a protonated analog of RbS, such as by way of example and not limitation, NH3, an azide salt (such as NaN3, KN3, or the like), HCN, a cyanide salt (such as NaCN, KCN, or the like), or a salt of a cyanoalkyl (e.g. (CH2CN)-) (such as NaCH2CN, KCH2CN, or the like). Still more typically, compound 288 is treated with an azide salt. Optionally a base, typically a mild base such as an ammonium halide and a solvent, typically a polar, aprotic solvent, such as an ether, amine, or amide are used.
In one embodiment, compound 288 is treated with a nucleophile. In another embodiment, compound 288 is treated with a nucleophile in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base to produce compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base to produce compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with an azide salt to produce compound 289. In another embodiment, compound 288 is treated with an azide salt in a suitable solvent to produce compound 289. In another embodiment, compound 288 is treated with an azide salt and a base to produce compound 289. In another embodiment, compound 288 is treated with an azide salt and a base in a suitable solvent to produce compound 289.
An exemplary embodiment of this process is given as Process L, Scheme 38, above.

Compound 289 is used to prepare compound 290 by the following process.
R62 is a group capable of reacting with an amine to form the R66 (defined below) substituted aziridine ring of compound 290. Typically, R(2 is a group capable of being displaced by a primary or secondary amine to form an aziridine. Such groups include by way of example and not limitation, -OR53, -OH, -OR fa, Br, Cl, and I. Typically, R f,2 is in a traps configuration relative to the nitrogen in position 4. More typically, R(2 is -0R53.
Itb4 is H or R6b, typically an acid labile protecting group such as Rte.
R66 is H, It6b or R54.
The process comprises treating compound 289 to form compound 290.
This is typically accomplished by treating compound 289 to displace R62 by the amine at position 4. More typically, compound 289 is treated to activate the amine at position 4 toward displacement of R62. Still more typically, compound 289 is treated to activate the amine at position 4 toward displacement of It62, and Rf,2 is activated toward displacement by the amine at position 4. If both R62 and the amine at position 4 are activated, the activations can be performed simultaneously or sequentially. If the activations are performed sequentially, they can be performed in any order, typically the activation of R(2 precedes the activation of the amine at position 4.
Activation of R62 toward displacement by the amine at position 4 is typically accomplished by treating compound 289 with a hydroxy activating agent such as those described in process B, Scheme 36. Optionally, R62 is deprotected prior to activation. Activation of the amine at position 4 toward R(2 displacement is typically accomplished by treating compound 289 to form a primary or secondary amine and treating the amine with an acid catalyst such as those described in Process N, Scheme 39, above.
Typically when R62 is -OR53 and RE,6 is R56, the process comprises treating compound 289 with a deprotecting agent to remove group R53, an R54 producing reagent such as those described in Greene (R54-halide, such as acetylchloride, or Tr-Cl, or R54-O-R54, such as acetic anhydride), and a hydroxy activating group such as those described in Process B, Scheme 36.
More typically the process comprises treating compound 289 with a polar, protic solvent, optionally in the presence of an acid catalyst as described above, to form a first intermediate; treating the first intermediate with Tr-Cl in a polar, aprotic solvent, such as an amine, to form a second intermediate;
and treating the second intermediate with a suifonic acid halide, such as mesyl chloride or para toluene sulfonyl chloride, in a polar aprotic solvent, such as an amine, to produce compound 290. Still more typically, the process comprises treating compound 289 with methanol and HCI, to form a first intermediate; treating the first intermediate with Tr-Cl and triethylamine, to form a second intermediate; and treating the second intermediate with mesyl chloride and triethylamine, to produce compound 290.
In one embodiment compound 289 is treated with an acid catalyst to produce compound 290. In another embodiment compound 289 is treated with an acid catalyst in a suitable solvent to produce compound 290. In another embodiment compound 289 is treated with a hydroxy activating reagent and an acid catalyst to produce compound 290. In another embodiment compound 289 is treated with a hydroxy activating reagent and an acid catalyst in a suitable solvent to produce compound 290. In another embodiment compound 289 is treated with a hydroxy deprotecting reagent, a hydroxy activating reagent and an acid catalyst to produce compound 290. In another embodiment compound 289 is treated with a hydroxy activating reagent and an acid catalyst in a suitable solvent to produce compound 290.
An exemplary embodiment of this process is given as Process M, Scheme 38, above.
Process V. Scheme 40.1 Compound 290 is used to prepare compound 291 by the following process.
Aziridine 290 is treated to form compound 291. Typically, aziridine 290 is opened by acid catalyzed ring opening and the resulting amine is acylated.
R6g is independently H, It~b, Rl or R55 as defined above. Typically R55 is -C(O)R5. Typically one IZ6g is H or It6b and the other is W3.
It6~ is U1 as described above. Typically R6~ is W6-O-, W6-S-, or W6-N(H)-. More typically, R6~ is I~5-O-, R,5-S-, or R5-N(H)-.
Typically the process comprises treating compound 290 with an acid catalyst and a compound of the formula W6-Xl-H, wherein Xl is as defined above to form an amine intermediate; and treating the amine intermediate with a compound of the formula W3-Xl-W3, or W3-X10, wherein X10 is a leaving group, to form compound 291. The treatment with a compound of the formula W6-X1-H and an acid catalyst may be prior to or simultaneous with the treatment with a compound of the formula W3-Xl-W3, or W3-X10.
The acid catalyst is typically one of those described in Process N, Scheme 39, above. More typically, the process comprises treating compound 290 with a compound of the formula R5-OH, R5-SH, or R5-NH2 and an acid catalyst;
and treating the intermediate with an alkanoic acid anhydride to form compound 291.
One embodiment comprises treating compound 290 with a compound of the formula W6-Xl-H and an acid catalyst to produce compound 291. Another embodiment comprises treating compound 290 with a compound of the formula W6-Xl-H and an acid catalyst in a suitable solvent to produce compound 291. Another embodiment comprises treating compound 290 with a compound of the formula W6-X1-H, an acid catalyst and a compound of the formula W3-Xl-W3 or W3-X10 to produce compound 291. Another embodiment comprises treating compound 290 with a compound of the formula W6-Xl-H, an acid catalyst and a compound of the formula W3-X1-W3 or W3-X10 in a suitable solvent to produce compound 291.
Exemplary embodiments of this process are given as Process N, Scheme 39, above.
Process W. Scheme 40.1 Compound 291 is used to prepare compound 292 by the following process.
Compound 291 is treated to form compound 292. Typically R(5 is converted to form G1. Ul is an embodiment of R6~ and Tl is an embodiment of -N(Rgg)2 prepared in Process V, Scheme 40.1, above.
In one embodiment, It~,S is deprotected, alkylated, guanidinylated, oxidized or reduced to form G1. Any number of such treatments can be performed in any order or simultaneously. By way of example and not limitation, when R65 is azido, embodiments of this process include Processes O, OQ, OQR, and OP. Typical alkylating agents are those common in the art including, by way of example and not limitation, an alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, n-propyl iodide, n-propyl bromide, i-propyl iodide, i-propyl bromide; and an olefin oxide such as ethylene oxide or propylene oxide. A base catalyst as described herein maybe optionally employed in the alkylation step.
One embodiment comprises treating compound 291 wherein R65 is azido with a reducing agent to produce compound 292. Another embodiment comprises treating compound 291 wherein RF,S is azido with a reducing agent to produce compound 292 in a suitable solvent. Another embodiment comprises treating compound 291 wherein It65 is amino with an alkylating agent to produce compound 292. Another embodiment comprises treating compound 291 wherein RE,S is amino with an alkylating agent to produce compound 292 in a suitable solvent. Another embodiment comprises treating compound 291 wherein R65 is azido with a reducing agent and an alkylating agent to produce compound 292. Another embodiment comprises treating compound 291 wherein R f,5 is azido with a reducing agent and an alkylating agent to produce compound 292 in a suitable solvent. Another embodiment comprises treating compound 291 wherein Rf,S is amino with an alkylating agent and a base catalyst to produce compound 292. Another embodiment comprises treating compound 291 wherein It65 is amino with an alkylating agent and a base catalyst to produce compound 292 in a suitable solvent. Another embodiment comprises treating compound 291 wherein R65 is azido with a reducing agent, an alkylating agent and a base catalyst to produce compound 292. Another embodiment comprises treating compound 291 wherein R65 is azido with a reducing agent, an alkylating agent and a base catalyst to produce compound 292 in a suitable solvent.
Exemplary embodiments of this process are given as Process O, Scheme 39, above.
Exemplary embodiments of this process are given as Examples 68 and 69 below.

Table 25 - Exemplary Compounds of Formula R5-OH (CAS No.) C4 Fluoro Alcohols (R*,R*)-(t)-3-fluoro-2-Butanol (139755-61-6) 1-fluoro-2-Butanol (124536-12-5) (R)-3-fluoro-l-Butanol (120406-57-7) 3-fluoro-1-Butanol (19808-95-8) 4-fluoro-2-Butanol (18804-31-4) (R*,S*)-3-fluoro-2-Butanol (6228-94-0) (R*,R*)-3-fluoro-2-Butanol (6133-82-0) 2-fluoro-l-Butanol (4459-24-9) 2-fluoro-2-methyl-1-Propanol (3109-99-7) 3-fluoro-2-Butanol {1813-13-4) 4-fluoro-1-Butanol (372-93-0) 1-fluoro-2-methyl-2-Propanol (353-80-0) C5 Fluoro Alcohols 2-fluoro-1-Pentanol (123650-81-7) (R)-2-fluoro-3-methyl-1-Butanol (113943-11-6) (S)-2-fluoro-3-methyl-1-Butanol (113942-98-6) 4-fluoro-3-methyl-1-Butanol (104715-25-5) 1-fluoro-3-Pentanol (30390-84-2) 4-fluoro-2-Pentanol (19808-94-7) 5-fluoro-2-Pentanol (18804-35-8) 3-fluoro-2-methyl-2-Butanol (7284-96-0) 2-fluoro-2-methyl-1-Butanol (4456-02-4) 3-fluoro-3-methyl-2-Butanol (1998-77-2) 5-fluoro-1-Pentanol (592-80-3) C6 Fluoro Alcohols (R-(R*,S*))-2-fluoro-3-methyl-1-Pentanol (168749-88-0) 1-fluoro-2,3-dimethyl-2-Butanol (161082-90-2) 2-fluoro-2,3-dimethyl-1-Butanol (161082-89-9) (R)-2-fluoro-4-methyl-1-Pentanol (157988-30-2) {S-(R*,R*))-2-fluoro-3-methyl-1-Pentanol (151717-18-9) (R*,S*)-2-fluoro-3-methyl-1-Pentanol (151657-14-6) (S)-2-fluoro-3,3-dimethyl-1-Butanol (141022-94-8) (M)-2-fluoro-2-methyl-1-Pentanol (137505-57-8) {S)-2-fluoro-l-Hexanol (127608-47-3) 3-fluoro-3-methyl-1-Pentanol (112754-22-0) 3-fluoro-2-methyl-2-Pentanol (69429-54-5) 2-fluoro-2-methyl-3-Pentanol (69429-53-4) 1-fluoro-3-Hexanol (30390-85-3) 5-fluoro-2-methyl-2-Pentanol (21871-78-3) 5-fluoro-3-Hexanol (19808-92-5) 4-fluoro-3-methyl-2-Pentanol (19808-90-3) 4-fluoro-4-methyl-2-Pentanol (19031-69-7) 1-fluoro-3,3-dimethyl-2-Butanol (4604-66-4) 2-fluoro-2-methyl-1-Pentanol (4456-03-5) 2-fluoro-4-methyl-1-Pentanol (4455-95-2) 2-fluoro-1-Hexanol (1786-48-7) 3-fluoro-2,3-dimethyl-2-Butanol (661-63-2) 6-fluoro-l-Hexanol (373-32-0) C7 Fluoro Alcohols 5-fluoro-5-methyl-1-Hexanol (168268-63-1) (R)-1-fluoro-2-methyl-2-Hexanol (153683-63-7) (S)-3-fluoro-l-Heptanol (141716-56-5) (S)-2-fluoro-2-methyl-1-Hexanol {132354-09-7) (R)-3-fluoro-1-Heptanol (120406-54-4) (S)-2-fluoro-l-Heptanol (110500-31-7) I-fluoro-3-Heptanol (30390-86-4) 7-fluoro-2-Heptanol (18804-38-I) 2-ethyl-2-(fluoromethyl}-1-Butanol (14800-35-2) 2-(fluoromethyl)-2-methyl-1-Pentanol (13674-80-1) 2-fluoro-5-methyl-I-Hexanol (4455-97-4) 2-fluoro-1-Heptanol (1786-49-8) 7-fluoro-l-Heptanol (408-16-2) C8 Fluoro Alcohols (M)-2-fluoro-2-methyl-1-Heptanol (137505-55-6) 6-fluoro-6-methyl-1-Heptanol (135124-57-1) 1-fluoro-2-0ctanol (127296-11-1) (R)-2-fluoro-1-Octanol (118205-91-7) (~)-2-fluoro-2-methyl-1-Heptanol (117169-40-1) (S)-2-fluoro-I-Octanol (110500-32-8) (S)-1-fluoro-2-Octanol {110270-44-5) (R)-1-fluoro-2-Octanol (110270-42-3) (t)-1-fluoro-2-Octanol (110229-70-4) 2-fluoro-4-methyl-3-Heptanol (8T777-41-1) 2-fluoro-6-methyl-1-Heptanol (4455-99-6) 2-fluoro-1-Octanol (4455-93-0) 8-fluoro-l-0ctanol (408-27-5) C9 Fluoro Alcobols 6-fluoro-2,6-dimethyl-2-Heptanol {160981-64-6) (S)-3-fluoro-1-Nonanol (160706-24-1) (R-(R*,R*))-3-fluoro-2-Nonanol (137909-46-7) (R-(R*,S*))-3-fluoro-2-Nonanol (137909-45-6) 3-fluoro-2-Nonanol (137639-20-4) (S-{R*,R*))-3-fluoro-2-Nonanol (137639-19-1) (S-{R*,S*))-3-fluoro-2-Nonanol (137639-18-0) (~)-3-fluoro-1-Nonanol (134056-76-1) 2-fluoro-1-Nonanol (123650-79-3) 2-fluoro-2-methyl-1-Octanol (120400-89-7) (R)-2-fluoro-1-Nonanol (118243-18-8) (S)-1-fluoro-2-Nonanol {111423-41-7) (S)-2-fluoro-1-Nonanol (110500-33-9) 1-fluoro-3-Nonanol (30390-87-5) 2-fluoro-2,6-dimethyl-3-Heptanol (684-74-2) 9-fluoro-l-Nonanol (463-24-1) Clf~ Fluoro Alcohols 4-fluoro-1-Decanol (167686-45-5) {P)-10-fluoro-3-Decanol (145438-91-1) {R-(R*,R*))-3-fluoro-5-methyl-1-Nonanol (144088-79-9) (P)-10-fluoro-2-Decanol (139750-57-5) 1-fluoro-2-Decanol (130876-22-1) (S)-2-fluoro-1-Decanol (127608-48-4) (R)-1-fluoro-2-Decanol (119105-16-7) (S)-1-fluoro-2-Decanol (119105-15-6) 2-fluoro-1-Decanol (110500-35-1) 1-fluoro-5-Decanol (106533-31-7) 4-fluoro-2,2,5,5-tetramethyl-3-Hexanol (24212-87-1) 10-fluoro-l-Decanol (334-64-5) 1 i Fl fro Alcohols 10-fluoro-2-methyl-1-Decanol (139750-53-1) 2-fluoro-1-Undecanol (110500-34-0) 8-fluoro-5,8-dimethyl-5-Nonanol (110318-90-6) 11-fluoro-2-Undecanol (101803-63-8) 11-fluoro-1-Undecanol (463-36-5) X12 Fluoro Alcohols 11-fluoro-2-methyl-1-Undecanol (139750-52-0) 1-fluoro-2-Dodecanol (132547-33-2) (R*,S*)-7-fluoro-6-Dodecanol (130888-52-7) (R*,R*)-7-fluoro-6-Dodecanol (130876-18-5) (S)-2-fluoro-1-Dodecanol (127608-49-5) 12-fluoro-2-pentyl--Heptanol (120400-91-1) (R*,S*)-(t)-7-fluoro-6-Dodecanol {119174-39-9) (R*,R*)-(t)-7-fluoro-6-Dodecanol (119174-38-8) 2-fluoro-1-Dodecanol (110500-36-2) 11-fluoro-2-methyl-2-Undecanol (101803-67-2) 1-fluoro-1-Dodecanol (100278-87-3) 12-fluoro-1-Dodecanol (353-31-1) C4 Nitro Alcohols (R)-4-vitro-2-Butanol (129520-34-9) (S)-4-vitro-2-Butanol (120293-74-5) 4-nitro-l-Butanol radical ion(1-) (83051-13-2) (R*,S*)-3-vitro-2-Butanol (82978-02-7) (R*,R*)-3-vitro-2-Butanol (82978-Ol-6) 4-vitro-1-Butanol (75694-90-5) (~)-4-vitro-2-Butanol (72959-86-5) 4-vitro-2-Butanol (55265-82-2), 1-aci-vitro-2-Butanol (22916-75-2) 3-aci-nitro2-Butanol (22916-74-1}
2-methyl-3-vitro-1-Propanol (21527-52-6) 3-vitro-2-Butanol (6270-16-2) 2-methyl-1-vitro-2-Propanol (5447-98-3) 2-aci-vitro-1-Butanol (4167-97-9) 1-rutro-2-Butanol {3156-74-9) 2-vitro-1-Butanol (609-31-4) 2-methyl-2-vitro-1-Propanol (76-39-1) C5 Nitro AIcQ~QIs (R)-3-methyl-3-vitro-2-Butanol (154278-27-0) 3-methyl-1-vitro-1-Butanol (153977-20-9) (t)-1-rutro-3-Pentanol (144179-64-6) (S)-1-vitro-3-Pentanol (144139-35-5) (R)-1-vitro-3-Pentanol (144139-34-4) (R)-3-methyl-1-vitro-2-Butanol (141434-98-2) (t)-3-methyl-1-vitro-2-Butanol (141377-55-1) {R*,R*)-3-vitro-2-Pentanol (138751-72-1) (R*,S*)-3-vitro-2-Pentanol (138751-71-0) (R*,R*)-2-vitro-3-Pentanol (138668-26-5) (R*,S*)-2-vitro-3-Pentanol (138668-19-6) 3-vitro-1-Pentanol (135462-98-5) (R)-5-vitro-2-Pentanol (129520-35-0) (S)-5-vitro-2-Pentanol (120293-75-6) 4-vitro-1-Pentanol (116435-64-4) (~)-3-methyl-3-vitro-2-Butanol (114613-30-8) (S)-3-methyl-3-vitro-2-Butanol (109849-50-5) 3-methyl-4-vitro-2-Butanol (96597-30-7) (t)-5-vitro-2-Pentanol (78174-81-9) 2-methyl-2-vitro-1-Butanol (77392-55-3) 3-methyl-2-vitro-1-Butanol (77392-54-2) 3-methyl-4-vitro-1-Butanol (75694-89-2) 2-methyl-4-vitro-2-Butanol (72183-50-7) 3-methyl-3-vitro-1-Butanol (65102-50-3}
5-vitro-2-Pentanol (54045-33-9) 2-methyl-3-aci-vitro-2-Butanol (22916-79-6) 2-methyl-1-aci-vitro-2-Butanol (22916-78-5) 2-methyl-3-vitro-2-Butanol (22916-77-4) 2-methyl-1-vitro-2-Butanol (22916-76-3) 5-vitro-1-Pentanol (21823-27-8) 2-methyl-3-vitro-1-Butanol (21527-53-7) 2-vitro-3-Pentanol (20575-40-0}
3-methyl-3-vitro-2-Butanol (20575-38-6) 3-vitro-2-Pentanol (5447-99-4}
2-vitro-1-Pentanol (2899-90-3) 3-methyl-1-vitro-2-Butanol (2224-38-6) 1-vitro-2-Pentanol (2224-37-5) C6 Nitro Alcohols (-)-4-methyl-1-vitro-2-Pentanol (158072-33-4) 3-(nitromethyl}-3-Pentanol {156544-56-8) (R*,R*}-3-methyl-2-vitro-3-Pentanol (148319-17-9}
(R*,S*)-3-methyl-2-vitro-3-Pentanol (148319-16-8) 6-vitro-2-Hexanol (146353-95-9) (~)-6-vitro-3-Hexanol (144179-63-5) (S)-6-vitro-3-Hexanol (144139-33-3) (R)-6-vitro-3-Hexanol (144139-32-2) 3-vitro-2-Hexanol (127143-52-6) 5-vitro-2-Hexanol (110364-37-9) 4-methyl-1-vitro-2-Pentanol (102014-44-8) (R*,S*)-2-methyl-4-rutro-3-Pentanol (82945-29-7) (R*,R*)-2-methyl-4-vitro-3-Pentanol (82945-20-8) 2-methyl-5-vitro-2-Pentanol (79928-61-3) 2,3-dimethyl-1-vitro-2-Butanol (68454-59-1) 2-methyl-3-vitro-2-Pentanol (59906-62-6) 3,3-dimethyl-1-vitro-2-Butanol (58054-88-9) 2,3-dimethyl-3-vitro-2-Butanol (51483-61-5) 2-methyl-1-vitro-2-Pentanol (49746-26-1}
3,3-dimethyl-2-vitro-1-Butanol (37477-66-0) 6-vitro-1-Hexanol (31968-54-4) 2-methyl-3-vitro-1-Pentanol (21527-55-9) 2,3-dimethyl-3-vitro-1-Butanol (21527-54-8) 2-methyl-4-vitro-3-Pentanol (20570-70-1 ) 2-methyl-2-vitro-3-Pentanol (20570-67-6}
2-vitro-3-Hexanol (5448-00-0) 4-vitro-3-Hexanol (5342-71-2) 4-methyl-4-vitro-1-Pentanol (5215-92-9) 1-vitro-2-Hexanol (2224-40-0) C~~itro Alcohols 1-vitro-4-Heptanol (167696-66-4) (R)-1-vitro-2-Heptanol (146608-19-7) 7-vitro-1-Heptanol (133088-94-5) (R*,S*}-3-vitro-2-Heptanol (127143-73-1) (R*,R*)-3-vitro-2-Heptanol {127143-72-0) (R*,S*)-2-vitro-3-Heptanol (127143-71-9) (R*,R*)-2-vitro-3-Heptanol (127143-70-8) (R*,S*)-2-methyl-5-vitro-3-Hexanol (103077-95-8) (R*,R*)2-methyl-5-vitro-3-Hexanol (103077-87-8) 3-ethyl-4-vitro-1-Pentanol (92454-38-1 ) 3-ethyl-2-nitro-3-Pentanol (77922-54-4) 2-vitro-3-Heptanol (61097-77-b) 2-methyl-1-vitro-3-Hexanol (35469-17-1) 2-methyl-4-vitro-3-Hexanol (20570-71-2) 2-methyl-2-vitro-3-Hexanol (20570-69-8) 5-methyl-5-rutro-2-Hexanol (7251-87-8) 1-nitro-2-Heptanol (6302-74-5) 3-rutro-4-Heptanol (5462-04-4) 4-vitro-3-Heptanol (5342-70-1) C8 Nitro Alcohols (t)-1-rutro-3-0ctanol (141956-93-6) 1-vitro-4-0ctanol (167642-45-7) (S)-1-rutro-4-Octanol (167642-18-4) 6-methyl-6-vitro-2-Heptanol (142991-77-3) (R*,S*)-2-vitro-3-Octanol (135764-74-8) (R*,R*)-2-vitro-3-Octanol (135764-73-7) 5-nitro-4-Octanol (132272-46-9) (R*,R*)-3-vitro-4-Octanol (130711-79-4) (R*,S*)-3-vitro-4-Octanol (130711-78-3) 4-ethyl-2-vitro-3-Hexanol (126939-74-0) 2-nitro-3-Octanol (126939-73-9) 1-nitro-3-Octanol (126495-48-5) (R*,R*)-(t)-3-vitro-4-Octanol (118869-22-0) (R*,S*)-(~)-3-vitro-4-Octanol (118869-21-9) 3-nitro-2-Octanol (127143-53-7) (R*,S*)-2-methyl-5-vitro-3-Heptanol {103078-03-1) (R*,R*)-2-methyl-5-vitro-3-Heptanol (103077-90-3) 8-nitro-l-Octanol (101972-90-1) (~)-2-vitro-1-Octanol (96039-95-1 ) 3,4-dimethyl-1-vitro-2-Hexanol (64592-02-5) 3-(nitromethyl)-4-Heptanol (35469-20-6) 2,5-dimethyl-1-vitro-3-Hexanol (35469-19-3) 2-methyl-1-vitro-3-Heptanol (35469-18-2) 2,4,4-trimethyl-1-vitro-2-Pentanol (35223-67-7) 2,5-dimethyl-4-vitro-3-Hexanol (22482-65-1) 2-nitro-l-0ctanol (2882-67-9) 1-nitro-2-0ctanol (2224-39-7) C9 Nitro Alcohols 4-vitro-3-Nonanol (160487-89-8) (R*,R*)-3-ethyl-2-vitro-3-Heptanol (148319-18-0) 2,6-dimethyl-6-vitro-2-Heptanol (117030-50-9}
(R*,S*}-2-vitro-4-Nonanol (103077-93-6) (R*,R*)-2-vitro-4-Nonanol (103077-85-6) 2-vitro-3-Nonanol (99706-65-7) 9-vitro-1-Nonanol (81541-84-6) 2-methyl-1-vitro-3-0ctanol (53711-06-1 ) 4-vitro-5-Nonanol (34566-13-7) 2-methyl-3-(nitromethyl)-3-Heptenol (5582-88-7}
1-vitro-2-Nonanol (4013-87-0) C10 Nitro Alcohols 2-vitro-4-Decanol (141956-94-7) (R*,S*)-3-vitro-4-Decanol (135764-76-0) (R*,R*)-3-rutro-4-Decanol (135764-75-9) 5,5-dimethyl-4-(2-nitroethyl)-1-Hexanol (133088-96-7) (R*,R*)-(t)-3-vitro-4-Decanol (118869-20-8) (R*,S*)-(t)-3-vitro-4-Decanol (118869-19-5) 5-vitro-2-Decanol (112882-29-8}
3-vitro-4-Decanol (93297-82-6) 4,6,6-trimethyl-1-vitro-2-Heptanol (85996-72-1) 2-methyl-2-vitro-3-Nonanol (80379-17-5) 1-vitro-2-Decanol (65299-35-6) 2,2,4,4-tetramethyl-3-(nitromethyl)-3-Pentanol (58293-26-8) C1i Njno~l_s,~hols 11-vitro-5-Undecanol (167696-69-7) (R*,R*)-2-vitro-3-Undecanol (144434-56-0) (R*,S*)-2-vitro-3-Undecanol (144434-55-9) 2-vitro-3-Undecanol (143464-92-0) 2,2-dimethyl-4-rutro-3-Nonanol (126939-76-2) 4,8-dimethyi-2-vitro-1-Nonanol (118304-30-6) 11-vitro-1-Undecanol (81541-83-5) C12 Nitro Alcohols 2-methyl-2-rutro-3-Undecanol (126939-75-1) 2-vitro-1-Dodecanol (62322-32-1) 1-vitro-2-Dodecanol (62322-31-0) 2-vitro-3-Dodecanol (82981-40-6) 12-vitro-1-Dodecanol (81541-78-8) Table 26 - Exemplary Compounds of Formula R5-OH (CAS No./Aldrich No. ) 1,3-DICHLORO-2-PROPANOL 96231 184489 3-CHLORO-2,2-DIMETHYL-1-PROPANOL 13401564 189316 2,2-BIS(CHLOROMETHYL)-1-PROPANOL 5355544 207691 1,3-DIFLUORO-2-PROPANOL 453134 176923 2-(METHYLTHIO)ET'I-iANOL 5271385 226424 2-(DIBUTYLAMINO)ETHANOL 102818 168491 2-(DIISOPROPYLAMINO)ETHANOL 96800 168726 4-HEXEN-1-0L 928927 23?604 (+/-)-6-METHYL-5-HEPTEN-2-0L 4630062 195871 TRANS,TRANS-2,4-HEXADIEN-1-OL 17102646 183059 2,4-DIMETHYL-2,6-HEPTADIEN-1-OL 80192569 238767 ISETHIONIC ACID, SODIUM SALT 1562001 220078 (4-(2-HYDROXYETHYL)-1-PIPERAZINE-PROPANESULFONIC ACID) 16052065 163740 HEPES, SODIUM SALT 75277393 233889 (+/-)-CHRYSANTHEMYL ALCOHOL 18383590 194654 3-CYCLOPEN'IyL-1-PROPANOL 767055 187275 3-METTiYLCYCLOHEXANOL 591231 139734 3,3,5,5-TETRAMETHYLCYCLOHEXANOL 2650400 190624 (1S,2R,5S)-{+)-MENTHOL 15356704 224464 (1S,2S,5R)-{+)-NEOMENTHOL 2216526 235180 (1S,2R,5R)-(+)-ISOMENTHOL 23283978 242195 (+/-)-3-CYCLOHEXENE-1-METHANOL 72581329 162167 (+)-P-MENTH-1-EN-9-OL 13835308 183741 (S)-(-)-PERILLYL ALCOHOL 536594 218391 (+/-)-TRANS-P-MENTH-6-ENE-2,$-DIOL 32226543 247774 TETItAHYDROFURFURYL ALCOHOL 97994 185396 (S)-(+)-2-PYRROLIDINEMETHANOL 23356969 186511 (+/-)-2-PIPERIDINEMETHANOL 3433372 155225 1-MET'FiYL-2-PIPERIDINEMETHANOL 20845345 155241 (+/-)-3-METHYL-2-NORBORNANEMETHANOL 6968758 130575 ((1S)-ENDO)-(-)-BORNEOL 464459 139114 (1R)-ENDO-(+)-FENCHYL ALCOHOL 2217029 196444 9-ETTiYLBICYCLO(3.3.1 )NONAN-9-OL 21951333 193895 (+/-)-ISOPINOCAMPHEOL 51152115 183229 (S)-CIS-VERBENOL 18881044 247065 (1R,2R,3R,5S)-(-)-ISOPINOCAMPHEOL 25465650 221902 (1R)-(-)-MYRTENOL 515004 188417 3,5-DIMETHYL-1-ADAMANTANOL 707379 231290 2-(3-THIENYL)ETHANOL 13781674 228796 4-(HYDROXYMETHYL)IMIDAZOLE

2-(2-HYDROXYETHYL)PYRIDINE 103742 128643 1-(4-CHLOROPHENYL)-1-(4S,5S)-(-)-2-MET'IiYL-5-PHENYL-2-0XAZOLINE-6-(4-CHLOROPHENYL)-4,5-DIHYDRO-2-(2-HYDROXYBUTYL)-3(2H)-PYRIDAZINONE 38958826 243728 N-(2-HYDROXYETHYL)PI4T'HALIMIDE 3891074 138339 4-CHLORO-ALPHA,ALPHA-3-(4-METHOXYPHENYL)-1-PROPANOL 5406188 142328 4-METFiOXYPHENETHYL ALCOHOL 702238 154180 ALPHA-(CHLOROMETHYL)-2,4-2-METHYLI'HENETHYL ALCOHOL 19819988 188123 3-METHYLI'HENETHYL ALCOHOL 1875894 188131 4-(4-METHOXYPHENYL)-1-BUTANOL 22135508 188239 4-(4-NTTROPHENYL)-1-BUTANOL 79524202 188751 3,3-DIPHENYL-1-PROPANOL 20017678 188972 (+/-)-ALPHA-ETHYLPHENETHYL ALCOHOL 701702 190136 1,1-DIPHENYL-2-PROPANOL 29338496 190756 (+/-)-1-PHENYL-2-PENTANOL 705737 195286 2,2-DIPHENYLETHANOL 1883325 196568 3,4-DIMETHOXYPHENETHYL ALCOHOL 7417212 197653 3-(3,4-DIMETHOXYPHENYL)-1-PROPANOL 3929473 197688 2-(4-BROMOPHENOXY)ETHANOL 34743889 198765 3-(TRIFLUOROMETHYL)PHENET'HYL ALCOHOL 455016 230359 2-(PHENYLTHIO)ETHANOL 699127 232777 1-(2-METHOXYPHENYL)-2-PROPANOL 15541261 233773 Table 27 - Exemplary Method Embodiments of Processes A-R
A;B;C;D;I;J;K;L;M;N;O;P;Q;R;E;F;G;H;AB;BC;CD;DI;IJ;JK;KL;LM;
MN; NO; OP; OQ; QR; EF; FG; GH; HI; ABC; BCD; CDI; DIj; IJK; ]KL; KLM;
LMN; MNO; NOP; NOQ; OQR; EFG; FGH; GHI; HIJ; ABDC; BCDI; CDIJ; DIJK;
IJKL; JKLM; KLMN; LMNO; MNOP; MNOQ; NOQR; EFHG; FGHI; GHIJ;
HIJK; ABCDI; BCDIJ; CDIJK; DIJKL; IJKLM; JKLMN; KLMNO; LMNOP;
LMNOQ; MNOQR; EFGHI; FGHIJ; GHIJK; HIJKL; ABCDIJ; BCDTJK; CDIJKL;
DIJKLM; IJKLMN; JKLMNO; KLMNOP; KLMNOQ; LMNOQR; EFGHIJ;
FGHIJK; GHIJKL; HIJKLM; ABCDIJK; BCDIJKL; CDIJICLM; DIJKLMN;
IJKLMNO; JKLMNOP; JKLMNOQ; KLMNOQR; EFGHIJK; FGHIJKL;
GHIJKLM; HIJKLMN; ABCDIJKL; BCDIJKLM; CDIJKLMN; DIJKLMNO;
IJKLMNOP; IJKLMNOQ; JKLMNOQR; EFGHIJKL; FGHIJKLM; GHIJICLMN;
HIJKLMNO; ABCDIJKLM; BCDIJKLMN; CDIJKLMNO; DIJKLMNOP;
DIJKLMNOQ; IJKLMNOQR; EFGHIJKLM; FGHIJICLMN; GHIJKLMNO;
HIJKtMNOP; HIJKLMNOQ; ABCDIJKLMN; BCDIJKLMNO; CDIJKLMNOP;
CDIJKLMNOQ; DIJKLMNOQR; EFGHIJKLMN; FGHIJKLMNO;
GHIJKLMNOP; GHIJKLMNOQ; HIJKLMNOQR; ABCDIjKLMNO;
BCDIJKLMNOP; BCDTJKLMNOQ; CDIJKLMNOQR; EFGHIJKLMNO;
FGHIJKLMNOP; FGHIJKLMNOQ; GHIjKLMNOQR; ABCDIJKLMNOP;
ABCDIJKLMNOQ; BCDIJKLMNOQR; EFGHIJKLMNOP; EFGHIJKLMNOQ;
FGHIJKLMNOQR; ABCDIJKLMNOQR; EFGHIJKLMNOQR; S; T; U; V; W;
ST; TU; UV; VW; STU; TUV; UVW; STUV; TUVW; STUVW.

Scheme 41 H3CO.~.O~,. .,~ C02CH3 H3C0~0~,, ~ CO2CH3 H2N v -'-'~ BocHN

OH OPMB
H3CO.~O~.. ~ H3C0~0~,.
BocH N BocH N

OPMB OPMB OPMB
HO,~,, --~ TrN~ -~ HN~ --Na Ns Ns OPMB
OPMB Nun......
OPMB Nun,...,, BocN
BocHN AcHN
N3 Ns N3 OH \ Nun,,,,, Nuu,,". ~ Nun,,,,.. C02CH3 ~ COZH
AcHN _ AcHN ~ AcHN a 3i0 311 312 The amine 300 (an intermediate in Example 52, optionally purified prior to use) is treated with Boc anhydride to give the mono Boc protected amine 301. Such a transformation is found in Greene, T.W. "Protective Groups in Organic Synthesis" 2nd Ed. (John Wiley & Sons, New York, 1991) pages 327-328.
Methyl ester 301 is reduced to the corresponding primary allylic alcohol 302 with DIBAL at low temperature. Such a conversion is described by Garner, P. and Park, J. M., "j. Org. Chem.", 52:2361 (1987).
The primary alcohol 302 is protected as its p-methoxy benzyl ether derivative 303 by treatment with 4-methoxybenzyl chloride under basic conditions. Such a conversion is described in Horita, K. et. al., "Tetrahedron", 42:3021 (1986).
The MOM and Boc protecting groups of 303 are removed by treatment with TFA/CH2Cl2 to give the amino alcohol 304. Such transformations are found in Greene, T.W. "Protective Groups in Organic Synthesis", 2nd. Ed.
(John Wiley & Sons, New York, 1991).
Conversion of 304 into the corresponding trityl protected aziridine 305 is accomplished in a one pot reaction two step sequence: 1) TrCI/TEA, 2) MsCI/TEA. Such a transformation has been previously described.
Aziridine 305 is then converted the corresponding Boc protected derivative 307 by first removal of the trityl group with HCl/acetone to give 306. Such a transformation is described in Hanson, R. W. and Law, H. D. "J.
Chem. Soc.", 7285 (1965). Aziridine 306 is then converted into the corresponding Boc derivative 307 by treatment with Boc anhydride. Such a conversion is described in Fitremann, J., et. al. "Tetrahedron Lett.", 35:1201 (1994).
The allylic aziridine 307 is opened selectively at the allylic position with a higher order organocuprate in the presence of BF3-Et20 at low temperature to give the opened adduct 308. Such an opening is described in Hudlicky, T., et. al. "Synlett." 1125 (1995).
The Boc protected amine 308 is converted into the N-acetyl derivative 309 in a two step sequence: 1) TFA/CH2C12; 2) Ac20/pyridine. Such transformations can be found in Greene, T.W., "Protective Groups in Organic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991) pages 327-328 and pages 351-352.

WO 99/14185 PC'T/US98/19355 Benzyl ether 309 is deprotected with DDQ at room temperature to give the primary allylic alcohol 310. Such a transformation is found in Horita, K., et. al. "Tetrahedron" 42:3021 (1986).
Alcohol 310 is oxidized and converted in a one pot reaction into the methyl ester 311 via a Corey oxidation using Mn02/AcOH/MeOH/NaCN.
Such a transformation can be found in Corey, E. J., et. al. "j. Am. Chem.
Soc.", 90:5616 (1968).
Azido ester 311 is converted into amino acid 312 in a two step sequence 1) Ph3P/H20/THF; 2) KOH/THF. Such a conversion has been described previously.

Scheme 42 Or~.. \ C02CH3 Qrw.. \ C02CH3 W ~"' 'o O ''~.F O ~~ F
OAc OMs HOa,. ~ C02CH3 HON. \ COzCH3 HO"" ~~~F ~ -0~,,.. ..,,. F
OMs \ C02CH3 RO~u, \ C02CH3 TrN' I
v.~F ~ AcHN s ~~~~' F
N3 Ns AcHN = F

RO~,,, \ C02H
'''v Scheme 42 The known fluoro acetate 320 (Sutherland, J. K., et.al. "J. Chem. Soc.
Chem. Commun." 464 (1993) is deprotected to the free alcohol and then converted into the corresponding mesylate 321 in two steps: 1) NaOMe; 2) MsCI/TEA. Such transformations are described in Greene, T.W., "Protective Groups in Organic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991).
Deprotection of 321 under acidic conditions gives diol 322 which is cyclized to the epoxy alcohol 323 under basic conditions. Such a conversion has been previously described.
Conversion of 323 to the N-trityl protected aziridine 324 is accomplished with the following sequence: 1) MOMCI/TEA; 2) NaN3/NH4C1; 3) MsCI/TEA; 4) PPh3/TEA/H20; 5) NaN3/NH4Cl; 6) HCl/MeOH; 7) i)TrCI, ii) MsCI/TEA. Such a sequence has been previously described.
The aziridine 324 is then opened with the appropriate alcohol under Lewis acid conditions and then treated with Ac20/pyridine to give the acetylated product 325. Such a transformation has been previously described.
The ester 325 is converted to the corresponding amino acid 326 in a two step sequence: 1) PPh3/H20/THF; 2) KOH/THF. Such a transformation has been previously described.
United States Patent No. 5,214,165, and in particular, the "Descriptions and Examples" at column 9, line 61 to column 18, line 26, describes the preparation of 6a and 6~i fluoro Shikimic acid (numbering is as described therein). These fluoro compounds are suitable starting materials for methods of making compounds of the invention that use Shikimic acid.

Scheme 43 R' O"", ~~ C02CH3 SePh Om.. C02CH3 I~~ O NN ~~ MI.
OAc OAc R, R, Ou,.. \ C02CH3 ~ CO2CH3 1v. _ O
OAc OMs R~ R, ~ C02CH3 HO~,,,. ~ C02CH3 ,. TrN'I

R' R' RO.,,.. ~ C02CH3 RO~,... ~ C02H
AcHN AcHN

Unsaturated ester 330 (obtainable by standard actetylation methods from.the acetonide alcohol described in Campbell, M. M., et. al., "Synthesis", 179 (1993)) is reacted with the appropriate organocuprate where R' is the ligand to be transferred from the organocuprate (R' is J1a). The resultant intermediate is then trapped with PhSeCl to give 331 which is then treated with 30% H202 to give the a,(3-unsaturated ester 332. Such a transformation can be found in Hayashi, Y., et. al, "J. Org. Chem." 47:3428 (1982).
Acetate 332 is then converted into the corresponding mesylate 333 in a two step sequence: 1) NaOMe/MeOH; 2) MsCl/TEA. Such a transformation has been previously described and can also be found in Greene, T.W., "Protective Groups in Organic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991).
The acetonide 333 is then converted into the epoxy alcohol 334 in a two step sequence: 1) p-TsOH/MeOH/~; 2) DBU/THF. Such a transformation has been previously described.
Conversion of epoxide 334 into N-trityl aziridine 335 is accomplished by the following sequence: 1) MOMCI/TEA; 2} NaNg/NH4C1; 3) MsCI/TEA;
4) PPh3/TEA/H20; 5) NaN3/NH4C1; 6) HCl/MeOH; 7) i)TrCI, ii) MsCI/TEA.
Such a sequence has been previously described.
The aziridine 335 is then opened with the appropriate alcohol under Lewis acid conditions and then treated with Ac20/pyridine to give the acetylated product 336. Such a transformation has been previously described.
The azido ester 336 is converted to the corresponding amino acid 337 in a two step sequence: 1) PPh3/H20/THF; 2) KOH/THF. Such a transformation has been previously described.
Schemes 44 and 45 are referred to in the examples.

Scheme 44 \, C02CH3 O~~. \, CO2CH3 AcN _ AcN , O

\ C02CH3 O~~.. \ C02H
AcN _ "'" AcN _:
H /N CF3 H / NH ~CF3C02H
H3C ~ H3C
O

Scheme 45 H3C0~O,, \ C02CH2CH3 H3C0~O,.
~ C02CH2CH3 0 ~ -~ HO~, OH
H3C0~0,,, \
HO~

Scheme 46 OH OH
HO,~ C02CH3 O ss C02CH3 ---~. --H3C(J~O H3C0 O

OH OSiEt3 , i O O

OSiEt3 OH
CO2CH3 ~ h~' C02CH3 0~.,. Ov,.
-.. -/~/~~~,,. ~~,~ C02CH3 ~ CO2CH3 O HO~~,.
H3C0 ~ OH

Scheme 47 ~,, C02CH3 ~~.,,. C02CH3 ~,,,,. ~ C02CH3 HO'~~ ~ HO'~ + Ms0' OH OMs OH

4... C02CH3 ~ Cp2CH3 p',. + ~ i ~ C02CH3 ~4,.. ~ CO2CH3 ~~~~,, ~ C02CH3 O~ ~ HO'~. + N

Ns OH

%,.. ~ CO2CH3 ~,,,_ ~ CO2CH3 Ms0'~ + N3 N3 OMs Scheme 48 /~%.,~, CO2CH3 ~~~,~ ~ CO2CHa ~~,,~ C02CH3 MsO~~~~ + N3 --r N3 OMs N
H

/~/~'~~.. \ CO2CH3 ~%.... \ CO2CH3 O
--,~ H2N --~- ~ N -..
N3 H Ns /~/~~~~.. C02CH3 ~,~,~ C02H
~-N _ _ Scheme 49 0~~~. ~,~ C02H 0,,,,. ~ C02CH2CH2CH3 AcHN AcHN
Ns N3 O,~ ,,~ C02CH2CH2CH3 H.
AcHN
NH2~HCI

Scheme 50 C rSAr C S-Ar AcO., C02CH3 AcO,, '~ C02CH3 Ac0'~ -----.,~ Ac0"
OAc OAc Ar = p-CH30-CsH4 Ar = p-CH30-CsH4 CI CI
HO,~,~ ~,,~ C02CH3 AcO,,, ~ C02CH3 HO"r Ac0"r OH OAc CL CI
j ,~ ~ C02CH3 ,,,k ~",~ C02CH3 O'~ O~
OH OMs Scheme 51 C) CI
/0,,, ~ CO2CH3 O~, ~ CO2CH3 ~, ~ /
-~ o~' OMs ' OMs 0,,,, ~ CO2CH3 ~--0,,~ ~ C02CH3 s DI HO"~
OMs CI
HO,' ~ C02CH3 ~O~
OMs CI

0.,, ~ CO2CH3 HO's Ms0'"

Scheme 52 ~0,,, ~ C02H 0~~. \ C02CH2CH2Ph AcHN -~ --AcHN _ 0,,,, ~ C02CH2CH2Ph AcHN _ NH2~HC!

Scheme 53 p~~,, .~,~ C02H 0~~, ~ C02CH2CH2CH2CH3 AcHN __ --~- AcHN _ Ns Ns On_ ~ C02CH2CH2CH2CH3 AcHN _ NH2~HCI

Scheme 54 OH OH

Ph Ph Ph Ph Scheme 55 Ph 0~.,, ~ Cp2CH3 Ph 0~... ~ C02CH3 ---~ AcH -807a, 807b 808a, 808b Ph 0~,,, ~ ~ C02H
AcN

809a, 809b Scheme 56 Ph 0~~,. ~ C02CH3 Ph ~~., \ C02CH3 PhAcH - ~ PhAcH = --Ph 0~,~ \ C02H
AcN _ Ph H NH2 Scheme 57 Ph ~~'~ \ C02CH3 Ph ~'''~ \ C02CH3 Ph AcN --.~. Ph AcN _ ~ C02H
Ph Ph AcN _ Scheme 58 MOMO~u, ~ Cp2CH2CH3 MOMO~,, ~ C02CH2CH3 --.
N N
H Boc MOMO,,. ~ C02CH2CH3 MOMO,,,, ~ C02CH2CH3 BocH ~ BocH
OH OAc C02CH2CH3 0~~. ~ C02CH2CH3 TrN
_ ----~ AcN _ OAc H OAc ~. ~ C02H
AcN
H OH

Scheme 59 MOMO~,~ ~ C02CH2CH3 MOMO,,,, ~ C02CH2CH3 AcN _ HO,,,. ~ C02H
AcN

Scheme 60 C02CH2CH3 H3C0~,, ~ C02CH2CH3 TrN
AcN _ OAc H OAc H3C0~,~, ~ C02H
AcN
H OH

Scheme 61 MOMO,~~ ~ Cp2CH2CH3 MOMO,,,. ~ C02CH2CH3 N __'~' BocH = --.' ~, C02CH2CH3 H3C0~~... .~ C02CH2CH3 TrN
- .-OCH3 AcH OCH3 H3C0~.,,. ~ C02H
AcN _ Scheme 62 OH OH OH
HO,,,,, C02H 0,,,, O,, C02Et O
HO''~~~ -'' p '''' ~ -'"
OH O OH
Quinic Acid OH OMs C02Et --.~. O
O '',~ + O '',.
OMs O

o,,,,. ~ co2Et ,H,. co2Et ,,,~ c~ co2Et '',. + '',. ~ + '.,. -...
O O O
OMs OMs OMs 0,,,,,, Oi,,,,, ~ C02Et ~ C02Et HO,,,,,.
~ C02Et O ~ HO''~~~ O ''..
OMs OMs OMs 0~,,,, C02Et Oi~,,, C02Et ~ C02Et oi..,, ~.. +
~''~' Ho'',. Ns Scheme 63 ~ C02Et Gl..,,,, ~ C02Et ...

H Ns C02Et ~~.,.. ~ C02Et _-AcHN AcHN

Scheme 64 CI CI
-O., .~ C02CH3 ~-o~ ,,\ C02CH3 MSO'~
N3 i 711 ~ H 712 CI
~-O,~ ~ C02CH3 AcHN

Modification of the exemplary starting materials to form different El groups has been described in detail and will not be elaborated here. See Fleet, G.W.J. et al.; "J. Chem. Soc. Perkin Trans. I", 905-908 (1984), Fleet, G.W.J. et al.; "J. Chem. Soc., Chem. Commun.", 849-850 (1983), Yee, Ying K.
et al.; "J. Med. Chem.", 33:2437-2451 (1990); Olson, R.E. et al.; "Bioorganic &
Medicinal Chemistry Letters", 4(18):2229-2234 (1994); Santella, J.B. III et al.;
"Bioorganic & Medicinal Chemistry Letters", 4(18);2235-2240 (1994); Judd, D.B. et al.; "j. Med. Chem.", 37:3108-3120 (1994) and Lombaert, S. De et al.;
"Bioorganic & Medicinal Chemistry Letters", 5(2):151-154 (1994).
The El sulfur analogs of the carboxylic acid compounds of the invention are prepared by any of the standard techniques. By way of example and not limitation, the carboxylic acids are reduced to the alcohols by standard methods. The alcohols are converted to halides or sulfonic acid esters by standard methods and the resulting compounds are reacted with NaSH to produce the sulfide product. Such reactions are described in Patai, "The Chemistry of the Thiol Group" (John Wiley, New York, 1974), pt. 2, and in particular pages 721-735.
Modifications of each of the above schemes leads to various analogs of the specific exemplary materials produced above. The above cited citations describing suitable methods of organic synthesis are applicable to such modifications.
In each of the above exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials.
The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
All literature and patent citations above are hereby expressly incorporated by reference at the locations of their citation. Specifically cited sections or pages of the above cited works are incorporated by reference with specificity. The invention has been described in detail sufficient to allow one of ordinary skill in the art to make and use the subject matter of the following claims. It is apparent that certain modifications of the methods and compositions of the following claims can be made within the scope and spirit of the invention.
enteric Protection Another embodiment of the present invention is directed toward enteric protected forms of the compounds of the invention. As used herein the term "enteric protection" means protecting a compound of the invention in order to avoid exposing a portion of the gastrointestinal tract, typically the upper gastrointestinal tract, in particular the stomach and esophagus, to the compound of this invention. In this way gastric mucosal tissue is protected against rates of exposure to a compound of the invention which produce adverse effects such as nausea; and, alternatively, a compound of the invention is protected from conditions present in one or more portions of the gastrointestinal tract, typically the upper gastrointestinal tract.
By way of example and not limitation, such enterically protected forms include enteric coated vehicles, such as enteric coated tablets, enteric coated granules, enteric coated beads, enteric coated particles, enteric coated microparticles, and enteric coated capsules. In preferred embodiments, a compound of the invention is placed in a suitable vehicle such as a tablet, granule or capsule, and the vehicle is coated with a pharmaceutically acceptable enteric coating. In alternative preferred embodiments, a compound of the invention is prepared as enterically protected granules, particles, microparHcles, spheres, microspheres, or colloids, and the enteric protected granules, particles, microparticles, spheres, microspheres, or colloids, are prepared as pharmaceutically acceptable dosage forms such as tablets, granules, capsules, or suspensions.
One aspect of the invention is directed to enteric-coated dosage forms of the compounds of the invention to effect delivery to the intestine of a human or other mammal, preferably to the small intestine, of a pharmaceutical composition comprised of a therapeutically effective amount of about 0.1-1000 mg of an active ingredient and optional pharmaceutically acceptable excipients.
The term "vehicle" as used herein includes pharmaceutically acceptable dose vehicles. Many vehicles are well known in the art cited herein such as tablet, coated tablet, capsule, hard capsule, soft gelatin capsule, particle, microparticle, sphere, microsphere, colloid, microencapsulationed, sustained release, semisolid, suppository or granule vehicles.
The term "pharmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular compound of the invention selected for use. These excipients are described elsewhere herein. The excipients may, but need not, provide enteric protection.
The term "unit dose" is used herein in the conventional sense to mean a single application or administration of the compound of this invention to the subject being treated in an amount as stated below. It should be understood that a therapeutic or prophylactic dosage can be given in one unit dose, or alternatively, in multiples of two or more of such dose units with the total adding up to the desired amount of compound for a given time period.
In general, the oral unit dosage form compositions of this invention, preferably employ from about 1 to about 1000 milligrams (mg), typically, about 10 to 500 mg, more typically from about 50 to about 300 mg, more typically yet, 75 mg of the compound for each unit dose. The actual amount will vary depending upon the active compound selected.
In typical embodiments, an enteric protectant is applied to the vehicle containing the compound, or to the compound without vehicle, the protectant prevents nausea inducing exposure, contact or rates of exposure of the mouth, esophagus or stomach with the compound, but which releases the compound for absorption when the dosage form passes into the proximal portion of the lower gastrointestinal tract, or in some embodiments, substantially only in the colon.
The relative proportions of the protectant and compound of the invention are varied to achieve optimum absorption depending on the compound selected. The minimum or maximum amount of enteric protectant by weight percent is not critical. Typically, enteric protected embodiments contain less than about 50% enteric coating by weight. More typically about 1% to about 25%, still more typically, about 1% to about 15%, more typically yet, about 1°/~ to about 10°/« (all by weight).
A number of monographs describe enteric protection and related technology which are useful in preparing the enterically protected compositions of the invention. Such monographs include: "Theory and Practice of Industrial Pharmacy," 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5); Lehmann, K.; "Practical Course in Laquer Coating,", Eudragit, 1989; Lieberman; Lachman, L.; Schwartz, "Pharmaceutical Dosage Forms: Tablets", 1990, Dekker (ISBN: 0-8247-8289-5); Lee, Ping I. Editor Good, William R. Editor, "Controlled-Release Technology: Pharmaceutical Applications", ACS Symposium Ser. Vol. 348 (ISBN: 0-608-03871-7); Wilson, Billie E.; Shannon, Margret T., "Dosage Calculation: A Simplified Approach", 1996, Appleton & Lange (ISBN: 0-8385-9297-X); Lieberman, Herbert A. Editor Rieger, Martin M., "Pharmaceutical Dosage Forms -Disperse Systems", 1996, Dekker (ISBN: 0-8247-9387-0); "Basic Tests for Pharmaceutical Dosage Forms", 1995, World Health (ISBN: 92-4-154418-X);
Karsa, D. R., Editor; Stephenson, R. A., Editor, "Excipients & Delivery Systems for Pharmaceutical Formulations: Proceedings of the "Formulate '94" British Association for Chemical Specialties Symposium", 1995, CRC Pr (ISBN: 0-85404-715-8); Ansel, Howard C.; Popovich, Nicholas G.; Allen, Lloyd V., "Pharmaceutical Dosage Forms & Drug Delivery Systems, 6th ed.", 1994, Williams & Wilkins (ISBN: 0-683-01930-9); "The Sourcebook for Innovative - zsl-Drug Delivery: Manufacturers of Devices & Pharmaceuticals, Suppliers of Products & Services, Sources of Information", 1987, Canon Comns (ISBN: 0-9618649-0-7); Chiellini, E., Editor; Giusti, G., Editor; Migliaresi, C., Editor;
Nicolais, L., Editor, "Polymers in Medicine II: Biomedical & Pharmaceutical Applications", 1986, Plenum (ISBN: 0-306-42390-1); "Pharmaceutical Aerosol:
A Drug Delivery System in Transition", 1994, Technomic (ISBN: 0-87762-971-4); Avis; Lieberman, L.; Lachman, "Pharmaceutical Dosage Forms:
Parenteral Medication, 2nd Expanded; Revised ed.", 1992, Dekker (ISBN: 0-8247-9020-0); Laffer, U., Editor; Bachmann, L, Editor; Metzger, U., Editor, "Implantable Drug Delivery Systems", 1991, S Karger (ISBN: 3-8055-5434-6);
Borchardt, Ronald T., Editor; Repta, Arnold J., Editor; Stella, Valentino J., Editor, "Directed Drug Delivery: A Multidisciplinary Approach", 1985, Humana (ISBN: 0-89603-089-X); Anderson, James M., Editor, "Advances in Drug Delivery Systems 5: Proceedings of the Fifth International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, U. S. A., February 25-28, 1991", Elsevier (ISBN: 0-444-88664-8); Turco, Salvatore J.;
King, Robert E., "Sterile Dosage Forms: Their Preparation & Clinical Application", 1987, Williams & Wilkins (ISBN: 0-8121-1067-6); Tomlinson, E., Editor; Davis, S. S., Editor, "Site-Specific Drug Delivery: Cell Biology, Medical & Pharmaceutical Aspects", 1986, Wiley (ISBN: 0-471-91236-0); Hess, H., Editor, "Pharmaceutical Dosage Forms & Their Use", 1986, Hogrefe &
Huber Pubs (ISBN: 3-456-81422-4); Avis; Lieberman; Lachman, "Pharmaceutical Dosage Forms, Vol. 2", 1986, Dekker (ISBN: 0-8247-7085-4);
Carstensen, Jens T., "Pharmaceutics of Solids & Solid Dosage Forms", 1977, Wiley (ISBN: 0-471-13726-X); Robinson, Joseph R., Editor, "Ophthalmic Drug Delivery Systems", 1980, Am Pharm Assn (ISBN: 0-917330-32-3); Ansel, Howard C., "Introduction to Pharmaceutical Dosage Forms, 4th ed.", 1985, Williams & Wilkins (ISBN: 0-8121-0956-2); "High Tech Drug Delivery Systems", 1984, Intl Res Dev (ISBN: 0-88694-622-0); Swarbrick, James, "Current Concepts in Pharmaceutical Sciences: Dosage Form Design &
Bioavailability", 1985, Lea & Febiger (ISBN: 0-318-79917-0); Sprowls, Joseph B., Editor, "Prescription Pharmacy: Dosage Formulation & Pharmaceutical Adjuncts, 2nd ed.", 1970, Lippincott (ISBN: 0-397-52050-6); and Polderman, J., Editor, "Formulation & Preparation of Dosage Forms: Proceedings of the 37th International Congress of Pharmaceutical Sciences of F.LP., The Hague, Netherlands, September, 1977", Elsevier (ISBN: 0-444-80033-6).

Specific Embodiments:
In another embodiment, the inventive composition is in the form of an enteric coated tablet dosage form. In this embodiment, the formulation is formed into a hard tablet by conventional means and the tablet is coated with the enteric coating in accordance with conventional techniques.
In a preferred embodiment, the inventive compound is in the form of an enteric coated powder dosage form. In this embodiment, the formulation is filled into a hard or soft-shell capsule or their equivalent and the capsule is coated with the enteric coating in accordance with conventional techniques.
In one embodiment the inventive composition is in the form of a liquid suspension of enteric coated particles of a compound of the invention. In this embodiment, a suspension of the inhibitor in a liquid is filled into a hard or soft-shell capsule or their equivalent and the capsule is coated with the enteric coating in accordance with conventional techniques.
As alternatives to the foregoing embodiments the capsule or other dosage container is itself constructed of an enteric protection reagent or component, or otherwise is integral to the container.
In another embodiment enteric protectants are used to administer a compound of the invention to the colon. The delivery system is a tablet comprised of three layers: 1) a core containing the active compound of the invention; 2) a non-swelling, erodible polymer layer surrounding the core (with the combination of core and erodible polymer layer being referred to as the "dual matrix tablet"); and 3) an enteric coating applied to the dual matrix tablet. The composition and function of the components of such a colon targeted delivery system are further described in U.S. Patent 5,482,718, which is incorporated herein by reference in its entirety at this location, in particular column 2, line 29, to column 4, line 12, are incorporated herein with specificity.
Another embodiment of the invention is directed toward enteric protected emulsion, suspension, tablet, coated tablet, hard capsule, soft gelatin capsule, microencapsulation, sustained release, liquid, semisolid, suppositorie, and aerosol dosage forms of the compounds of the invention.
"Theory and Practice of Industrial Pharmacy," 3rd ed. Lea & Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5), describes each of these standard dosage forms in detail at the following locations: emulsion and suspension dosage forms (pp. 100-122), tablets (pp. 293-345), coated tablet (pp. 346-373), hard capsules (pp. 374-397), soft gelatin capsules (pp. 398-411), microencapsulation (pp. 412-430), sustained release dosage forms (pp. 430-456), liquids (pp. 457-478), pharmaceutical suspensions (pp. 479-501), emulsions {pp. 502-533), semisolids (pp. 534-563), suppositories (pp. 564-587), and pharmaceutical aerosols (pp. 589-618).
Alternative embodiments include enteric protected sustained release, controlled release, particulate, microencapsulated, multiparticulate, microparticulate, colloidal, nasal, inhalation, oral mucosal, colonic, dermal, transdermal, ocular, topical, and veterinary dosage forms of the compounds of the invention. Each of these dosage form technologies is described in detail in "Drugs and the Pharmaceutical Sciences", Edited by James Swarbrick, Marcel Dekker, New York.
Materials:
Conventional enteric protectant polymers or mixtures of polymers for use herein include insoluble at a pH below about 5.5, i.e., that which is generally found in the stomach, but are soluble at pH about 5.5 or above, i.e., that present in the small intestine and the large intestine. The effectiveness of particular enteric protectant materials can be measured using known USP
procedures.
Exemplary enteric protectant polymers employable in this embodiment include cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and methyl methacrylate-methacrylic acid copolymers. Another example is an anionic carboxylic copolymers based on methacrylic acid and methacrylate, commercially available as Eudragit(r). Typical examples include cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate, hydroxypropyl methylceilulose phthalate ("HPMCP"), hydroxypropyl methylcellulose phthalate succinate, polyvinyl acetate phthalate ("PVAP"), methacryiic acid, and methacrylic acid esters.
More typically the protectant is selected from, PVAP and / or HPMCP, particularly PVAP. PVAP is known under the trademark Sureteric(r), manufactured by Colorcon, Inc.
The enteric protectant materials may be applied to the vehicle with or without conventional plasticizers, such as acetylated mono glycerides, propylene glycol, glycerol, glyceryl triacetate, polyethylene glycol, triethyl citrate, tributyl citrate, diethyl phthalate, or dibutyi phthalate using methods known to those skilled in the art.
Exemplary Embodiments of Enteric Protection:
Embodiment 1: Enteric Protected ' 4104 ~~sLles In this exemplary embodiment, GS 4104 (compound 262, Example 116, phosphate salt form, 131.4 mg/capsule, 100 mg free base equivalent)) is mixed with Croscarmellose Sodium (2.6 mg/capsule) in a size 4 white opaque hard gelatin capsule shells (capsule composition: gelatin NF, titanium dioxide USP) and the capsule is enterically coated.
The following enteric coating formulations are applied to the capsule by procedures known to those in the art.
Ingredients Preparation A:
Hydroxypropyl methylcellulose phthalate ("HPMCP") 5.0 Triacetin 0.5 Aicohol USP 7.9 Water 15.5 Preparation B:
HPMCP 10.0 Titanium dioxide 0.2 Dimethyl polysiloxane 0.05 Triethyl citrate 1.0 Alcohol USP 72.75 Water 16.00 Preparation C:
Cellulose acetate phthalate ("CAP") g.5 Diethyl phthalate 1.5 Titanium dioxide 0.2 Acetone 44.9 Denatured alcohol 44.9 Polyvinyl acetate phthalate ("PVAP") 5.0 Acetylated glycerides 0.8 Methylene chloride 47.1 Denatured alcohol 47.1 preparation E:
Methacrylic acid or methacrylic 8.0 acid ester (Eudragit (r) S or L, manufactured by Rohm Pharma, GMBH, Wetterstadt, West Germany) Acetone 46.0 Anhydrous alcohol 46.0 Plasticizer q.s.
Typically the enteric polymer (with or without plasticizer) is dissolved in the solvents described under each formulation to form a suspension/solution. Optionally, an opacifer such as titanium dioxide is added. The vehicle is sprayed with the coating suspension/solution in a suitable vessel under conditions such that an enterically-protected coating is laid down on the vehicle without dissolving or disrupting the vehicle.
Approximately 1-50%, typically 1-15°/,, more typically, 5-10% by weight of the finished coated vehicle of the enteric polymer coating will be useful for adequate enteric protection.
In another exemplary embodiment a core tablet is encased within an enteric coating. Optionally, a subcoating is used.
Core Tablets:
Core tablets of the present invention may be formed by combining (a) the active ingredient with pharmaceutically-acceptable excipients in a mixture including for example: a diluent, a binder, a disintegrant, and optionally one or more ingredients selected from a group consisting of:
compression aids, flavors, flavor enhancers, sweeteners, dyes, pigments, buffer systems, and preservatives; (b) lubricating the mixture with a lubricant; and (c) compressing the resultant lubricated mixture into a desired tablet form using various tableting techniques available to those skilled in the art. The term "tablet" as used herein is intended to encompass compressed or formed pharmaceutical dosage formulations of all shapes and sizes.
Typical diluents employable in this embodiment include lactose or microcrystalline cellulose.
Typical binders employable in this embodiment include, but are not limited to, povidone. Povidone is available under the trade name "Avicel"
from ISP Corporation.
The disintegrant may be one of several modified starches, or modified cellulose polymers. Typically, croscarmellose sodium is used.
Croscarmellose sodium NF Type A is commercially available under the trade name "Ac-di-sol".
Typical lubricants include magnesium stearate, stearic acid, hydrogenated vegetable oil or talc.
Flavoring agents include those described in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp.
1288-1300.
Typical sweeteners include saccharin, Aspartame, or edible mono- or disaccharides such as glucose or sucrose.
Dyes and pigments include those described in the Handbook of Pharmaceutical Excipients, pp. 81-90, 1986 by the American Pharmaceutical Association & the Pharmaceutical Society of Great Britain.
Typical preservatives include methyl paraben, propyl paraben, cetylpyridinium chloride, and the salts thereof, sorbic acid and the salts thereof, thimerosal, or benzalkonium chloride.
Enteric Coating:
Eudragit L-30-D(r), a methacrylic acid copolymer, manufactured by Rohm Pharma GmbH, Weiterstadt, West Germany, is a suitable enteric polymer. Eudragit L-30-D(r) has a ratio of free carboxyl groups to ester groups of approximately 1:1 and is freely soluble at pH 5.5 and above. In general, the greater the percentage of Eudragit L-30-D(r) contained in the enteric coating, the more proximal the release of active in the lower gastrointestinal tract. The location in the lower gastrointestinal tract at which the coating releases the compound can be manipulated by one skilled in the art through control of the composition and thickness of the applied enteric coating.
. Typically a plasticizer, such as those set forth above, is included.
Other additives such as talc or silica may be used as detackifiers to improve the coating process.
Subcoating:
Optionally a stability enhancing subcoat on the core tablet is used to minimize interaction between the compound of this invention and the enteric coating. This also permits utilization of a single 10-300 micron thick enteric film without affecting product stability. This subcoat inhibits migration of active ingredient from the core tablet into the enteric coating, thus improving shelf life and product stability, but the subcoat rapidly dissolves in intestinal fluid once the exterior enteric coating has been breached.
Typical subcoating polymers employable in this embodiment include hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, or polyvinylpyrrolidone.

Examples ~g;neral The following Examples refer to the Schemes.
Some Examples have been performed multiple times. In repeated Examples, reaction conditions such as time, temperature, concentration and the like, and yields were within normal experimental ranges. In repeated Examples where significant modifications were made, these have been noted where the results varied significantly from those described. In Examples where different starting materials were used, these are noted.
When the repeated Examples refer to a "corresponding" analog of a compound, such as a "corresponding ethyl ester", this intends that an otherwise present group, in this case typically a methyl ester, is taken to be the same group modified as indicated. For example, the "corresponding ethyl ester of compound 1" is HO~,,,~,. C02CH2CH3 O~' Exa le 1 Epoxy alcohol 1: Prepared from shikimic acid by the procedure of McGowan and Berchtold, "J. Org. Chem.", 46:2381 (1981).
~x~ple 2 Epoxy allyl ether 2: To a solution of epoxy alcohol 1 (2.37g, 14.08 mmol) in dry benzene (50 mL) was added thallium(I)ethoxide (1.01 mL) in one portion. After 2 hr the reaction was concentrated in vacuo and the residue dissolved in acetonitrile. Allyl iodide (3.0 mL) was added and the mixture was stirred in the dark for 16 h. The solids were filtered thru a celite pad and washed with chloroform. Concentration in vacuo followed by flash chromatography (40% EtOAc in hexane) gave 1.24 g (42°/~) of 2 as a pale viscous oil. 1H NMR (300 MHz, CDCl3): 8 6.75 (1H, m); 6.10-5.90 (1H, m, -CH=, allyl); 5.40-5.15 (2H, m, =CH2, allyl); 4.47-4.43 (1H, m); 4.30-4.15 (2H, m, -CH2-, allyl); 3.73 (3H, s); 3.55-3.50 (1H, m); 3.45-3.40 (1H, m); 3.15-3.00 (1H, dm, J = 19.5 Hz), 2.50-2.35 (1H, dm, J = 2.7,19.5 Hz).

Azido alcohol 3: Epoxide 2 (1.17 g, 5.57 mmol), sodium azide (1.82 g) and ammonium chloride (658 mg) were refluxed in MeOH/H20 (8:1) (35 mL) for 18 h. The reaction was then concentrated in vacuo and the residue partitioned between ethyl ether and water. The organic layer was washed with brine and dried. Concentration in vacuo gave 3 as a pale oil 1.3 g (92%) which was used without further purification. 1H NMR {300 MHz, CDCl3): 8 6.95-6.85 {1H, m); 6.00-5.85 (1H, m, -CH=, allyl); 5.35-5.25 (2H, m, =CH2, allyl);
4.25-4.10 (2H, m, -CH2-, allyl); 4.12 (1H, bt, J =4.2 Hz); 3.95-3.75 (2H, m);
3.77 (3H, s); 2.85 (1H, dd, j =5.3,18.3 Hz); 2.71 (1H, bs); 2.26 (1H, dd, J
=7.2,18.3 Hz).
sample 4 Aziridine 4: To a solution of alcohol 3 {637 mg, 2.52 mmol) in CH2C12 (20 mL) cooled to 0°C was added DMAP (few crystals) and triethyl amine (442 ~.L). MsCI (287 ~.L) was then added and the reaction stirred for 2 h at 0°C.
Volatiles were removed and the residue partitioned between ethyl ether and water. The organic layer was washed with saturated bicarbonate, brine and then dried. Concentration in vacuo gave 881 mg of crude mesylate. 1H
NMR (300 MHz, CDC13): 8 6.87-6.84 (1H, s); 6.00-5.85 (1H, m, -CH=, allyl);
5.40-5.25 (2H, m, =CH2, allyl); 4.72 (1H, dd, j = 3.9, 8.5 Hz); 4.32 {1H, bt, J =
3.9 Hz);
4.30-4.15 (2H, m, -CH2-, allyl); 3.77 (3H, s); 3.14 (3H, s); 2.95 (1H, dd, J =
5.7,18.6 Hz); 2.38 (1H, dd, j = 6.7,18.6 Hz).
The crude mesylate was dissolved in dry THF (20 mL) and treated with Ph3P (727 mg). After stirring for 3 h at room temperature, water (15 mL) and solid NaHC03 (1.35 g) was added and the mixture stirred overnight at room temperature. The reaction was then concentrated in vacuo and the residue partitioned between EtOAc, saturated bicarbonate and brine. The organic layer was separated and dried over MgS04. Concentration in vacuo and flash chromatography of the residue gave the aziridine 4 170 mg (33%) as a pale yellow oil. 1H NMR (300 MHz, CDCI3): 8 6.82-6.80~(1H, m); 6.04-5.85 (1H, m, -CH=, allyl); 5.35-5.20 {2H, m, =CH2, allyl); 4.39 {1H, bd, J =2.4 Hz);
4.20-4.05 (2H, m, -CH2-allyl); 3.73 (3H, s); 2.90-2.80 (1H, bd, J =18.9 Hz);
2.65-2.40 (2H, m).
N-acetyl aziridine 5: Aziridine 4 (I70 mg, 0.814 mmol) was dissolved in CH2C12 (2 mL) and pyridine (4 mL) and cooled to 0°C. Acetyl chloride (87 ~tL) was then added and the reaction stirred at 0°C for 1 h. Volatiles were removed in vacuo and the residue partitioned between ethyl ether, saturated bicarbonate and brine. The organic layer was separated and dried over MgS04. Concentration gave crude 5 196 mg (96%) which was used without further purification. IH NMR (300 MHz, CDC13): 8 6.88-6.86 {1H, m); 6.00-5.85 (1H, m, -CH=, allyl);,5.40-5.20 (2H, m, =CH2, allyl); 4.45-4.40 (1H, m); 4.16 (2H, d, J =6.0 Hz, -CH2-, allyl); 3.76 (3H, s); 3.00-2.95 (2H, m);
2.65 (1H, bd, J =18.5 Hz); 2.14 (3H, s).
Example 6 Azido allyl ether 6: Aziridine 5 (219 mg, 0.873 mmol), sodium azide (426 mg) and ammonium chloride (444 mg) in dry DMF (7 mL) was heated at 65°C under argon overnight. The reaction was poured into saturated bicarbonate/brine and extracted with ethyl ether several times. The combined ether layers were washed with brine and dried. Concentration followed by flash chromatography (EtOAc only) gave the azido amine 77 mg (35%) which was dissolved in CH2Cl2 (1 mL) and pyridine (1 mL) and cooled to 0°C. Acetyl chloride (38 ~.L) was added and after 45 min solid NaHC03 was added and the volatiles removed under vacuum. The residue was partitioned between EtOAc and brine. The organic layer was dried over MgS04 and concentrated in vacuo. Flash chromatography (EtOAc only) gave 6 90 mg (99%). IH NMR (500 MHz, CDC13): 8 6.86 (1H, bt, J =2.2 Hz); 5.95-5.82 (1H, m, CH=, allyl); 5.68 (1H, bd, J =7.3 Hz); 5.35-5.20 (2H, m, =CH2, allyl);
4.58-4.52 (1H, m); 4.22-4.10 (2H, m); 4.04 (1H, dd, J =5.9, 12.5 Hz); 3.77 (3H, s);
3.54-3.52 (1H, m); 2.89 (1H, dd, J = 5.9, I7.6 Hz); 2.32-2.22 (1H, m); 2.06 (3H, s).
Exa ale 7 Azido diol 7: To a solution of olefin 6 (90 mg, 0.306 mmol) in acetone (3 mL) and water (258 ~.L) was added N-methyl morpholine-N-oxide (39 mg) and Os04 (73 ~.L of a 2.5 '%~ w/w in t-butanol). The reaction was then stirred at room temperature for 3 days. Solid sodium hydrosulfite was added and after stirring for 20 min the reaction was filtered thru a celite pad and washed with copious amounts of acetone. Concentration in vacuo followed by flash chromatography (10% MeOH in CH2Cl2) gave the diol 7 50 mg (50%). IH NMR (300 MHz, CD3CN): 8 6.80-6.70 (1H, m); 4.20-4.15 (1H, bm);
3.95-3.80 (1H, m); 3.80-3.25 (6H, m); 3.70 (3H, s); 3.10 (1H, bs); 2.85 (1H, bs);
2.85-2.75 (IH, m); 2.30-2.15 (1H, m); 2.16 (1H, bs);1.92 (3H, s).

ample 8 Amino acid diol 8: A solution of the diol 7 (23 mg, 0.07 mmol) in THF _(1 mL) was treated with aq. KOH (223 ~L, of 0.40 M solution) at room temperature. After stirring for 1.5 h the reaction was acidified to pH=4 with Amberlite IR-120 (plus) ion exchange resin. The resin was filtered and washed with MeOH. Concentration in vacuo gave the crude carboxylic acid which was dissolved in ethanol (1.5 mL). To this solution was added Lindlar's catalyst (20 mg) and the reaction stirred over a hydrogen atmosphere (1 atm via a balloon) for 20 h. The reaction mixture was filtered thru a celite pad and washed with hot ethanol and water. The ethanol was removed under vacuum and the resulting aqueous layer lyophilized to give a mixture of the desired amino acid 8 and the starting azide 7 as a white powder. Compound 8: 1H NMR (500 MHz, D20): S 6.5 (1H, s); 4.24-4.30 (2H, m); 4.25-4.18 {1H, m); 3.90-3.55 (5H, complex m); 2.96-2.90 {1H, m); 2.58-2.50 (1H, complex m); 2.12 (3H, s).
E,xam~>le 9 Compound 62: A suspension of Quinic acid {60 g), cyclohexanone (160 mL) and toluenesulfonic acid {600 mg) in benzene (450 mL) was refluxed with Dean-Stark for 14 hrs. The reaction mixture was cooled to room temperature and poured into saturated NaHC03 solution (150 mL). The aqueous layer was extracted with CH2C12 (3x). The combined organic layers were washed with water (2x), brine (lx), and dried over Na2S04.
Concentration gave a whited solid, which was recrystallized from ether (75 g, 95%): 1H NMR (CDCl3) 8 4.73 (dd, J = 6.1, 2.5 Hz,1 H), 4.47 (ddd, J = 7.0, 7.0, 3.U Hz, 1H), 4.30 (ddd, J = 5.4, 2.6,1.4 Hz, l H), 2.96 (s,1H), 2.66 (d, J =
11.7 Hz, 1H), 2.40-2.15 (m, 3 H), 1.72-1.40 (m, 10 H).
Exam= l~ 10 Compound 63: To a solution of lactone 62 {12.7 g, 50 mmol) in methanol (300 mL) was added sodium methoxide (2.7 g, 50 mmol) in one portion. The mixture was stirred at room temperature for 3 hrs, and quenched with acetic acid (3 mL) and stirred for 10 min. The mixture was poured into saturated NH4C1 solution (300 mL), and extracted with CH2C12 (3x). The combined organic phase was washed with brine (1x), and dried over MgS04. Purification by flash column chromatography (Hexane/EtOAc = 1/1 to 1/2) gave diol (11.5 g, 80°/~) and starting material (1.2 g, 10%): 1H
NMR (CDCl3) 8 4.47 (ddd, J = 7.4, 5.8, 3.5 Hz, 1 H), 4.11 (m, l H), 3.98 (m,1 H), 3.81 (s, 3 H), 3.45 (s, l H), 2.47 (d, J = 3.3 Hz,1 H), 2.27 (m, 2 H), 2.10 (dd, J =
11.8, 4.3 Hz,1 H),1.92-1.26 (m,10 H).
Example 11 Compound 64: To a mixture of diol 63 (1.100 g, 3.9 mmol), molecule sieves (3 A, 2.2 g) and pyridine (1.1 g) in CH2Cl2 (15 mL) was added PCC (3.3 g, 15.6 mmol) in one portion. The mixture was stirred at room temperature for 26 hrs, and diluted with ether (30 mL). The suspension was filtered through a pad of celite, and washed with ether (2x20 mL). The combined ether was washed with brine (2x), and dried over MgS04. Concentration and purification was by flash column chromatography (Hexane/EtOAc =
3/1) gave the ketone (0.690 g, 67%): 1H NMR (CDCl3) S 6.84 (d, J = 2.8 Hz, l H), 4.69 (ddd, J = 6.4, 4.9, 1.6 Hz, l H), 4.30 (d, J = 5.0 Hz, 1 H), 3.86 (s, 3 H), 3.45 (d, J = 22.3 Hz, 1 H), 2.86 (m, 1 H),1.69-1.34 (m, 10 H).
Example 12 Compound 28: To a solution of ketone 64 (0.630 g, 2.4 mmol) in MeOH (12 mL) at 0°C was added NaBH4 in 30 min. The mixture was stirred for additional 1.5 hrs at 0°C, and quenched with 15 mL of saturated solution. The solution was extracted with CH2C12 (3x), and the combined organic extract was dried over MgS04. Purification by flash column chromatography (Hexane/EtOAc = 2/1) gave the alcohol (0.614 g, 97%): 1H
NMR (CDC13) 8 6.94 (d, J = 0.5 Hz, l H), 4.64 (ddd, J = 9.8, 6.7, 3.2 Hz, l H), 4.55 (dd, J = 7.1, 4.2 Hz, l H), 4.06 (m, l H), 3.77 (s, 3 H), 3.04 (dd, J = 16.5, 2.1 Hz, l H), 2.73 (d, J = 10.2 Hz, 1 H),1.94 (m, 1 H), 1.65-1.29 (m,10 H).
Compound 66: Alcohol 28 (2.93 g, 10.9 mmol) and toluenesulfonic acid (1.5 g) were dissolved in acetone (75 mL), and the mixture was stirred at room temperature for 15 hrs. The reaction was quenched with water (30 mL), and basified with concentrated NH3-H20 until PH = 9. Acetone was removed under reduced pressure, and the water phase was extracted with CH2C12 (3x). The combined organic extracts were washed with brine (lx), and dried over Na2S04. Concentration gave the desired product: 1H NMR
(CDC13) 8 7.01 (m, 1 H), 4.73 (m, 1 H), 4.42 (m, 1 H), 3.97 (m, 1 H), 3.76 (s, 3 H), 2.71-2.27 (m, 2 H), 2.02 (s, 3 H),1.98 (s, 3 H).
Example 14 Compound 67: To a solution of alcohol 66 (10.9 mmol) in CH2Cl2 (60 mL) at 0'C was added pyridine (4.4 mL, 54.5 mmol), followed by addition of trimethylacetyl chloride (2.7 mL, 21.8 mmol). The mixture was warmed to room ,temperature and stirred for 14 hrs. The mixture was diluted with CH2C12, and washed with water (2x), brine (1x), and dried over MgS04.
Purification by flash column chromatography (Hexane/EtOAc = 9/1) gave the diester (2.320 g, 68°/,): 1H NMR (CDC13) b 6.72 (m, 1 H), 5.04 (m, 1 H), 4.76 (m, l H), 4.40 (m,1 H), 3.77 (s, 3 H), 2.72-2.49 (m, 2 H),1.37 (s, 3 H),1.35 (s, 3 H),1.23 (s, 9 H).
p a 15 Compound 68: Diester 67 (2.32 g, 2.3 mmol) was dissolved in acetone/H20 (1/1, 100 mL) and heated at 55'C for 16 hrs. Solvents were removed, water (2 x 50 mL) was added and evaporated. Concentration with toluene (2 x 50 mL) gave diol, which was used without further purification:
1H NMR (CDC13) 8 6.83 (m, 1 H), 5.06 (m, 1 H), 4.42 (m, 1 H), 4.09 (m, l H), 3.77 (s, 3 H), 2.68-2.41 (m, 2 H), 1.22 (s, 9 H).
Compound 69: To a solution of diol 68 (0.410 g, 1.5 mmol) in THF (8 mL) at 0°C was added triethylamine (0.83 mL, 6.0 mmol), followed by slow addition of thionyl chloride (0.33 mL, 4.5 mmol). The mixture was warmed to room temperature and stirred for 3 hrs. The mixture was diluted with CHC13, and washed with water (3x), brine (lx), and dried over MgS04.
Purification by flash column chromatography (Hexanes/EtOAc = 5/1) gave a exo/endo mixture (0.430 g, 90°/.): 1H NMR (CDC13) 8 6.89-6.85 (m, 1 H), 5.48-4.84 {m, 3 H), 3.80, 3.78 (s, 3 H), 2.90-2.60 (m, 2 H), 1.25,1.19 (s, 9 H).
2S ExamplQ 17 Compound 70: The mixture of sulfone 69 (0.400 g, 1.3 mmol) and sodium azide (0.410 g, 6.29 mmol) in DMF (10 mL) was stirred for 20 hrs.
The reaction mixture was then diluted with ethyl acetate, washed with saturated NH4C1 solution, water, brine, and dried over MgS04.
Concentration gave the azide (0.338 g, 90°/~): 1H NMR (CDC13) S
6.78 (m, 1 H), 5.32 (m, 1 H), 4.20 (m, 1 H), 3.89 (m, 1 H), 3.78 (s, 3 H), 3.00-2.60 (m, 2 H), 1.21 (s, 9 H).

Compound 71: To a solution of alcohol 70 (0.338 g, 1.1 mmol) in CH2C12 (11 mL) at 0°C was added triethylamine (0.4 mL, 2.9 mmol), followed by slow addition of methylsulfonic chloride (0.18 mL, 2.3 mmol).
The mixture was stirred at 0°C for 30 min., and diluted with CH2C12. The organic layer was washed with water (2x), brine, and dried over MgS04.
Purification by flash column chromatography (Hexane/EtOAc = 3/1) gave the desired compound (0.380 g, 82°/~): 1H NMR (CDCl3) 8 6.82 (m, l H), 5.44 (m, l H), 4.76 (dd, J = 7.3,1.4 Hz,1 H), 4.48 (m, 1 H), 3.80 (s, 3 H), 3.11 (s, 3 H), 2.82-2.61 (m, 2 H), 1.21 (s, 9 H).
Compound 72: The mixture of azide 71 (0.380 g, 0.94 mmol) and triphenylphosphine (0.271 g, 1.04mmol) in THF (19 mL) was stirred for 2 hrs.
The reaction was quenched with water (1.9 mL) and triethylamine (0.39 mL, 2.82 mmol), and the mixture was stirred for 14 hrs. Solvents were removed under reduced pressure, and the mixture was used for next step. To a solution of above mixture in CH2Cl2 (20 mL) at 0°C was added pyridine (0.68 mL, 8.4 mmol), followed by slow addition of acetyl chloride (0.30 mL, 4.2 mmol). The mixture was stirred at 0°C for 5 min., and diluted with ethyl acetate. The mixture was washed with water {2x), brine (lx), dried over MgS04. Purification by flash column chromatography (Hexanes/EtOAc =
3/1) gave the aziridine (0.205 g, 83'%~): 1H NMR (CDC13) 8 7.19 (m, 1 H), 5.58 {m, l H), 3.77 (s, 3 H), 3.14 {m, 2 H), 2.85 (dd, J = 7.0, 1.6 Hz, 1 H), 2.34 (m, l H), 2.16{s,3H),1.14(s,9H).
Example 20 Compound 73: The mixture of aziridine 72 (0.200 g, 0.68 mmol), sodium azide (0.221 g, 3.4 mmol), and ammonium chloride (0.146 g, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 14 hrs. Then the mixture was diluted with ethyl acetate, and washed with water (5x), brine (1x), and dried over MgS04. Purification by flash column chromatography (hexanes/EtOAc = 2/1) gave desired product and deacetyl amine (0.139 g). The mixture was dissolved in acetic anhydride {2 mL), and stirred for 2 hrs. Excess anhydride was removed under reduced pressure, and give the desired product {149 mg): 1H NMR (CDCl3) 8 6.76 (m, l H), 5.53 (d, J = 8.5 Hz, 2 H), 5.05 (m, l H), 4.31 (m, 1 H), 4.08 (m, 1 H), 3.79 (s, 3 H), 2.91 (m, 1 H), 2.51 (m, l H), 1.99 (s, 3 H),1.20 (s, 9 H).

Exam~gle 21 Compound 74: A solution of potassium hydroxide in MeOH/H20 (0.5 M, 4.4 mL, 2.2 mmol) was added to ester 73 (149 mg, 0.44 mmol) and the mixture was stirred at room temperature for 3 hrs. The mixture was cooled to 0°C, and acidified with Amberlite (acidic) to PH = 3-4. The mixture was filtered, and washed with MeOH. Concentration gave the carboxylic acid as a white solid (73 mg, 69%): 1H NMR (CD30D) 8 6.62 (m, l H), 4.15 (m, l H), 3.95-3.72 (m, 2 H), 2.84 (dd, J = 6.7, L4 Hz, l H), 2.23 (m,1 H), 1.99 (s, 3 H).
~lple 22 Compound 75: The mixture of azide 74 (8 mg) and Pd-C (Lindlar) (15 mg) in ethanol (2 mL) was stirred under hydrogen for 16 hrs. The mixture was filtered through celite, washed with hot MeOH-H20 (1/1).
Concentration gave a solid. The solid was dissolved in water, and passed through a short C-8 column, and washed with water. Concentration gave a white solid (6 mg): 1H NMR (D20) S 6.28 (m, 1 H), 4.06-3.85 (m, 3 H), 2.83 (dd, J =17.7, 5.4 Hz, 1 H), 2.35 (m, 1 H), 2.06 (s, 3 H).
Example 23 Compound 76: Carboxylic acid 74 (68 mg, 0.28 mmol) and diphenyldiazomethane (61 mg, 0.31 mmol) were dissolved in ethanol (12 mL), and stirred for 16 hrs. The reaction was quenched with acetic acid (0.5 mL), and the mixture was stirred for 10 min. Solvents were removed under reduced pressure. Purification by flash column chromatography (EtOAc) gave the ester (56 mg, 50'%~): 1H NMR (CD30D) 8 7.36-7.23 (m, 10 H), 6.88 (s, 1 H), 6.76 (s, l H), 4.21 (m, 1 H), 3.93-3.79 (m, 2 H), 2.89 (dd, j = 17.7, 5.0 Hz, 1 H), 2.34 (m, 1 H), 2.00 (s, 3 H).
Examp~ 24 Compound 77: To a solution of alcohol 76 (20 mg, 0.05 mmol) in CH2CI2 (1 mL) was added pyridine (40 ~.L, 0.5 mmol), followed by addition of acetic anhydride (24 ~.L, 0.25 mmol). The mixture was stirred for 24 hrs, and solvents and reagents were removed under reduced pressure. Purification by flash column chromatography (Hexane/EtOAc = 1/2) gave the diester (20 mg, 91%): 1H NMR (CDCl3) 8 7.40-7.27 (m, 10 H), 6.95 (s, 1 H), 6.87 (m, l H), 5.60(m,lH),5.12{ddd,J=16.4,10.2,5.9Hz,lH),4.28(dd,J=20.0,9.4Hz,1 H),4.15(m,lH),2.93(dd,J=17.8,5.2Hz,lH),2.57(m,lH),2.09(s,3H),2.01 (s, 3 H).

ample 25 Compound 78: The mixture of diester 77 (20 mg, 0.045 mmol), anisole (50 p.L, 0.45 mmol), and TFA (1 mL) in CH2C12 (1 mL) was stirred for 20 min.
Solvents and reagents were removed under reduced pressure. Purification by flash column chromatography (EtOAc to EtOAc/AcOH = 100/1) gave the carboxylic acid (6 mg): 1H NMR (CDCl3) 8 6.85 (m, 1 H), 5.54 (m, l H), 5.12 (m, 1 H), 4.31-4.03 (m, 2 H}, 2.89 (m, 1 H), 2.60-2.41 (m, 1 H), 2.11 (s, 3 H), 2.03 (s, 3 H).
Compound 79: The mixture of azide 78 (6 mg, 0.02 mmol) and Pd-C
(Lindlar) (15 mg) in EtOH/H20 (2.2 mL, 10/1) was stirred under hydrogen for 3 hrs. The mixture was filtered through a pad of celite, washed with hot MeOH/H20 (1/1). Evaporation gave a white solid. The solid was dissolved in water, and passed through a C-8 column. Evaporation of water gave a white powder (3 mg): 1H NMR (D20) b 6.32 (m, 1 H), 5.06 (m, 1 H), 4.06 (t, J
= 10.4 Hz,1 H), 3.84 (m, 1 H), 2.83 (m, 1 H), 2.42 (m, 1 H}, 2.06 (s, 3 H), 2.00 (s, 3 H).
Compound 80: To a solution of alcohol 76 (35 mg, 0.086 mmol), Boc-glycine (30 mg, 0.172 mmol), and catalytic amount DMAP in CH2C12 (1 mL) was added DCC (35 mg, 0.172 mmol). The mixture was stirred for 30 min, and filtered and washed with CHCl3. The CHC13 solution was washed with water (2x). Concentration gave a white solid. Purification by flash column chromatography (Hexane/EtOAc = 1/2) gave product (30 mg): 1H NMR
(CDC13) S 7.39-7.26 (m, 10 H), 6.95 (s, 1 H), 6.86 (m, 1 H}, 5.77 (m, l H), 5.27 (m, 1 H), 4.99 (m,1 H), 4.18-4.01 (m, 2 H), 3.94-3.84 (m, 2 H), 2.96 (dd, J = 7.8, 5.9 Hz, l H), 2.57 (m,1 H), 2.02 (s, 3 H), 1.45 (s, 9 H).
Compound 81: The mixture of diester 80 (30 mg, 0.05 mmol), arusole (150 ~.L), and TFA (1 mL) in CH2Cl2 (1 mL) was stirred for 3 hrs. Solvents and reagents were evaporated . The mixture was dissolved in water, and washed with CHCl3 (3x). Water phase was evaporated to gave a white solid (15 mg): 1H NMR (CD30D) 8 6.73 (m, 1 H), 5.25-5.15 (m, l H), 4.35 (m, l H), 4.17 (m, l H), 3.82 (m, 2 H), 2.93 (dd, J =17.7, 5.6 Hz, 1 H), 2.42 (m, 1 H),1.97 (s, 3 H).

Fxamvle 29 Compound 82: The mixture of azide 81 (15 mg, 0.05 mmol) and Pd-C
(Lindlar) (30 mg) in EtOH/H20 (4 mL,1/1) was stirred under hydrogen for 3 hrs. ,The mixture was filtered through a pad of celite, and washed with hot MeOH/H20 (1/1). Concentration gave a glass-like solid. The solid was dissolved in water, and passed through C-8 column. Evaporation of water gave the amino acid: 1H NMR (D20) 8 6.68 (m, 1 H), 5.28 (m, 1 H), 4.29 (m, 1 H), 4.08-3.79 (m, 3 H), 2.85 (m, 1 H), 2.41 (m, 1 H), 2.04 (s, 3 H).
bis-Boc guanidinyl methyl ester 92: Treated according to the procedure of Kim and Qian, "Tetrahedron Lett.", 34:7677 (1993). To a solution of amine 91 (42 mg, 0.154 mmol), bis-Boc thiourea (43 mg, 0.155 mmol) and triethylamine (72 ~.L) in dry DMF {310 ~.L) cooled to 0°C was added mercury chloride (46 mg, 0.170 mmol) in one portion. After 30 min the reaction was warmed to room temperature and stirred for an additional 2.5 h. The reaction mixture was then filtered through a celite pad, concentrated and purified by flash column chromatography (100°/~ ethyl acetate) to give 70 mg (89%) of 92 as a colorless foam. 1H NMR (CDC13, 300 MHz): 811.37 (s,1H); 8.60 (d,1H, J = 7.8 Hz); 6.83 (t, 1H, J = 2.1 Hz); 6.63 (d,1H, J = 8.4 Hz); 4.76 (d,1H, J = 7.0 Hz); 4.71 (d,1H, j = 7.0 Hz); 4.45-4.10 (complex m, 2H); 3.76 (s, 3H); 3.39 (s, 3H); 2.84 (dd, 1H, J = 5.4, 17.4 Hz); 2.45-2.30 (rn, 1H);1.92 (s, 3H);1.49 (s,18H).
Example 31 bis-Boc guanidinyl carboxylic acid 93: To a solution of ester 92 (70 mg, 0.136 mmol) in THF (3 mL) cooled to 0°C was added aq. KOH (350 ~.L of a 0.476 M solution). The reaction was then warmed to room temperature and stirred for 2 h. The reaction was then acidified to pH = 4.5 with Amberlite IR-120 (plus) acidic resin. The resin was then filtered and washed with ethanol and H20. Concentration in vacuo gave 66 mg {97%) of carboxylic acid 93 as a white solid. 1H NMR (CDC13, 300 MHz): b 11.40 (br s,1H); 8.67 (d, 1H, J = 7.8 Hz); 6.89 (s,1H); 6.69 (br d,1H, J = 8.4 Hz); 4.77 (d,1H, J =
7.2 Hz);
4.70 (d,1H, J = 7.2 Hz); 4.40-4.15 (m, 2H); 3.39 (s, 3H); 2.84 (dd,1H, j =
4.8,17.1 Hz); 2.45-2.30 (m, 1H);1.95 (s, 3H);1.49 (s, 9H);1.48 (s, 9H).
Example 32 Guanidine carboxylic acid TFA salt 94: To a solution of bis-Boc s DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEiVIANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CEC! EST LE TOME ~ DE
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THiS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
'THAN ONE VOLUME
THIS IS VOLUME , I - OF
NOTE: For additional volumes-phase contact the Canadian Patem Office . ~'

Claims

What is claimed is:
1. A composition comprising a compound of formula (I) or (II):
wherein A1 is -C(J1)=, -N= or -N(O)=;
A2 is -C(J1)2-, -N(J1)-, -N(O)(J1)-, -S-, -S(O)-, -S(O)2- or -O-;
E1 is -(CR1R1)m1W1:
G1 is N3, -CN, -OH, -OR6a, -NO2, or -(CR1R1)m1W2:
T1 is -NR1W3, H, -R3, -R5, a heterocycle, or is taken together with U1 or G1 to form a group having the structure U1 is H, -R3 or -X1W6;
J1 and J1a are independently R1, Br, Cl, F, I, CN, NO2 or N3;
J2 and J2a are independently H or R1;
R1 is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -NO2, -OR6a, -OR1, -N(R1)2.
-N(R1)(R6b)2, -N(R6b)2, -SR1, -SR6a, -S(O)R1. -S(O)2R1, -S(O)OR1, -S(O)OR6a.
-S(O)2OR1, -S(O)2OR6a. -C(O)OR1 -C(O)R6c. -C(O)OR6a, -OC(O)R1.
-N(R1)(C(O)R1), -N(R6b)(C(O)R1), -N(R1)(C(O)OR1), -N(R6b)(C(O)OR1), -C(O)N(R1)2, -C(O)N(R(6b)(R1), -C(O)N(R6b)2, -C(NR6b)(N(R1)2), -C(N(R6b))(N(R1)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(R1))(N(R6b)2). -C(N(R6b))(N(R6b)2), -N(R1)C(N(R1))(N(R1)2).
-N(R1)C(N(R1))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R1)2).
-N(R6b)C(N(R1))(N(R1)2), -N(R6b)C(N(R6b))(N(R1)2)~
-N(R6b)C(N(R1))(N(R1)R6b)), -N(R1)C(N(R6b)(N(R1)(R6b))~

-N(R1)C(N(R1))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b)), -N(R6b)C(N(R1))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2), =O, =S, =N(R1), =N(R6b) or W5;
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
R6a is independently H or an ether- or ester-forming group;
R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6c is independently H or the residue of an amino-containing compound;
W1 is a group comprising an acidic hydrogen, a protected acidic group, or an R6c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom;
W3 is W4 or W5;
W4 is R5 or -C(O)R5, -C(O)W5, -SO2R5, or -SO2W5:
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(O)OR6a, -C(O)R6c, -C(O)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NR6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(O)R2;
X1 is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-, -N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-; and each m1 is independently an integer from 0 to 2;
provided, however, that compounds are excluded wherein:
(a) A1 is -CH= or -N= and A2 is -CH2-;
(b) E1 is COOH, P(O)(OH)2, SOOH, SO3H, or tetrazol;
(c) G1 is CN, N(H)R20, N3, SR20, OR20, guanidino, -N(H)CN

(d) T1 is -NHR20;
(e) R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or COOH group;
(f) J1 is H and J1a is H, F Cl, Br or CN;
(g) J2 is H and J2a is H, CN or N3;
(h) U1 is CH2YR20a, CHYR20aCH2YR20a or CHYR20aCHYR20aCH2YR20a:
(i) R20a is H or acyl having 1 to 4 carbon atoms;
{j) Y is O, S, H or NH;
(k) 0 to 2 YR20a are H, and (l) successive Y moieties in a U1 group are the same or different, and when Y is H then R20a is a covalent bond, and provided that if G1 is N3 then U1 is not -CH2OCH2Ph.
and the pharmaceutically acceptable salts and solvates thereof;
further excluded are compounds of the formula II wherein:
(a) A2 is O;
(b) E; is COON, P(O)(OH)2, NO2, SOOH, SO3H, tetrazole, CH2CHO, CHO, CH(CHO)2 or where E1 is COOH, P{O)(OH)2, SOOH or SO3H, an ethyl, methyl or pivaloyl ester thereof;
(c) G1 is hydrogen, N(R20a)2, SR20a or OR20a;
(d) T1 is -NHC(O)R20b, where R20b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR20a, OR20a, COOH or alkyl/aryl ester thereof, NO2, C(R20a)3, CH2COOH or alkyl/aryl ester thereof, CH2NO2 or CH2NHR20b;

(e) R20a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an NO2 group, an NH2 group or a COOH group;
(f) J1 is H and J1a is H, OR20a, F, Cl, Br, CN, NHR20a, SR20a or CH2X wherein X is NHR20a, halogen or OR20a;
(g) J2 is H or J2a is hydrogen, N(R20a)2, SR20a or OR20a;
(h) U1 is CH2YR20a, CHYR20CH2YR20a or CHYR20aCHYR20aCH2YR20a where Y is O, S or H, and successive Y moieties in U1 are the same or different and R20a represents a covalent bond when Y is hydrogen; and and pharmacologically acceptable salts or derivatives thereof;
and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
2. A composition comprising a compound of claim 1 and an enteric protectant.
3. A composition comprising an enterically protected compound of claim 1.
4. A composition comprising an enteric protectant and a compound of the formula:
wherein:
E1 is -CO2H, -CO2R5, -CO2R5aW5 or -CO2W5;
G1 is -N(R11)2, -N(R11)C(N(R11))(N(R11)2), or -C(R11)2-N(R11)2:
T1 is -NH(C(O)CH3), -NH(C(O)CH2F), -NH(C(O)CHF2), or -NH(C(O)CF3);
U1 is -OR4, -SR4, NHR4 or N(R4)2:
each R1 is independently H or alkyl of 1 to 12 carbon atoms;

each R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
each R3 is independently F, Cl, Br, I, -CN, N3, -NO2, -OR6a, -OR1, -N(R1)2, -N(R1)(R6b), -N(R6b)2, -SR1, -SR6a, -S(O)R1, -S(O)2R1, -S(O)OR1, -S(O)OR6a, -S(O)2OR1, -S(O)2OR6a,-C(O)OR1, -C(O)R6c, -C(O)CR6a, -OC(O)R1, -N(R1)(C(O)R1), -N(R6b)(C(O)R1), -N(R1)(C(O)OR1), -N(R6b)(C(O)OR1), -C(O)N(R1)2, -C(O)N(R6b)(R1), -C(O)N(R6b)2, -C(NR1)(N(R1)2), -C(N(R6b))(N(R1)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(R1))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R1)C(N(R1))(N(R1)2), -N(R1)C(N(R1))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R1)2), -N(R6b)C(N(R1))(N(R1)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(R1))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R1)(R6b)), -N(R1)C(N(R1))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b)), -N(R6b)C(N(R1))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2), =O, =S, =N(R1), =N(R6b) or W5;
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms; and R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups R6a is independently H or an ether- or ester-forming group;
R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6c is independently H or the residue of an amino-containing compound;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups; and R11 is independently H or R5, 5, The composition comprising a compound of claim 4 wherein E1 is C(O)OCH2CH3; G1 is NH2; T1 is NH(C(O)CH3); and U1 is OCH(CH2CH3)2, 6, A composition comprising an enterically protected compound of the formula:

.
7. The composition of claim 6 comprising a compound of the formula:
and an enteric coating.
8. A method of inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuraminidase with a composition comprising an enterically protected composition of claim 1.
9. The method of claim 8 wherein the neuraminidase is influenza neuraminidase in vivo.
10. A method for the treatment or prophylaxis of influenza infection in a host comprising administering to the host a therapeutically effective amount of a composition comprising an enterically protected compound of

claim 1.