ZA200103845B - Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in treatment of toxoplasmosis and in the treatment of cryptosporidiosis. - Google Patents

Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in treatment of toxoplasmosis and in the treatment of cryptosporidiosis. Download PDF

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ZA200103845B
ZA200103845B ZA200103845A ZA200103845A ZA200103845B ZA 200103845 B ZA200103845 B ZA 200103845B ZA 200103845 A ZA200103845 A ZA 200103845A ZA 200103845 A ZA200103845 A ZA 200103845A ZA 200103845 B ZA200103845 B ZA 200103845B
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South Africa
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use according
formula
compound
alkyl
independently
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ZA200103845A
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Clarence Nathaniel Ahlem
James Martin Frincke
Patrick T Prendergast
Krupakar Paul Thadikonda
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Hollis Eden Pharmaceuticals
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Description

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USE OF 17-KETOSTEROID COMPOUNDS AND DERIVATIVES,
METABOLITES AND PRECURSORS THEREOF IN TREATMENT OF
TOXOPLASMOSIS AND IN THE TREATMENT OF CRYPTOSPORIDIOSIS
BACKGROUND OF THE INVENTION
The present invention is directed to the use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the "compounds of the present invention" in treatment of toxoplasmosis and/or in treatment of cryptosporidiosis The present invention is also directed to the use of such compounds in combination with one or more additional compound (as described herein) in such treatments. The present invention is further directed to the use of such compounds (or combinations of compounds) for the manufacture of pharmaceutical formulations for treatment of such conditions. :
Cryptosporidium is an intestinal parasite that is the etiologic agent of cryptosporidiosis.
This parasite is a protozoan that has been found in humans and animals, and has been found to cause severe diarrhea (sometimes fatal). Cryptosporidium has been found to be extremely resistant to many known antibiotics. Persons with normal immune systems can suffer from f cryptosporidiosis, which is the apparent cause of many cases of diarrhea, and such persons usually : recover within two weeks. Persons with serious immune deficiency, such as AIDS patients, may ? 20 never recover from Cryptosporidiosis. This disease can spread from person to person or from animals to persons, and the incubation period appears to be two weeks or less. :
The Toxoplasma gondii protozoan is the etiologic agent of Toxoplasmosis. This sporozoa Co is an intracellular parasite that resides inside macrophages and has evolved a mechanism to avoid being killed by intracellular oxygen, metabolites and lysosomal enzymes.
The live parasite, Toxoplasma gondii, when ingested by a macrophage, forms a membrane : bound vesicle called a phagosome. This phagosome containing the Toxoplasma parasite can inhibit the fusion of lysosomes to the phagosome, which would cause its digestion and elimination.
However, if dead Toxoplasma parasites are ingested by macrophages, the phagosome thus resulting cannot prevent lysosome fusion, and parasite digestion. It is the function of the biosynthetic machinery of the parasite to synthesize molecules that block the ability of the lysosome to fuse with the Toxoplasma phagosome.
A number of steroid compounds and their uses have been described. See, e.g., U.S. patent numbers 4956355, 5859000, 4268441, 4666898, 5837269, 5827841, 5811418, 5824313, 5686438, 5635496, 5587369, 5583126, 5562910, 5532230, 5518725, 5736537, 5843932, 5837700, 5824671, 5807849, 5798347, 5780460, 5776923, 5728688, 5610150, 5593981, 5372996, 5110810, 5807848,
5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5292730, 5776921, 5641768, 5559107, 5478566, 5461042, 5407684, 5387583, 5277907, 5206008, 5077284, 5162198, 5660835, 5527789, 5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621, 5175154, 515703 1, 5028631, 5001119, 4898694, 5824668, 5710143, 5795880, 5527788, 5591736, 5861390 and PCT publication numbers WO 98/05338, WO 95/21617, WO 98/50040, WO 98/50041 and WO 97/48367.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, it now has been discovered that toxoplasmosis and cryptosporidiosis may be effectively treated with compounds (or pharmaceutically acceptable salts thereof) of the following formula 1 (and metabolites, analogs and precursors thereof):
Ry Ri X
Ry Q
Ry '
R, Ry Ry & i» a > fo 15 2 =) 10 ’ 8 Ry Ry } ’ Ra 3 4 3 Te 6 74, Ry R,
N ® Sd ~~
Ry
R4 Ry 1 wherein
Q) is -C(R})2- or -C(0)-;
Qgis-C(Ry)2-, -C(R1)(Y)-, -C(Y)- or -CHp-CH>-~;
Q3 is -H or -C(R)3-;
Q4 is -C(R1)2-, -C(O)-, hydroxyvinylidine (-CH(CH=CHOH)-) or methyl methylene (-
CH(CH)3-);
Qs is -C(R1)2- or -C(O)-;
X and Y independently are -OH, -H, lower alkyl (e.g., C1.¢ alkyl), -O-C(O)-Rs, -C(0)-ORs5, halogen (i.e., -F, -Cl, -Br or -I) or =O; each R] independently is -H, -F, -Cl, -Br, -I, -OH, C.¢ alkoxy, or C1.¢ alkyl;
Rj is -H, -OH, -F, -C], -Br, -1, C1.6 alkyl, C1. alkoxy, -OR3, an ester (e.g., -O-C(O)-Ry4 or -C(0)-0-Ry), a thioester (e.g., -O-C(S)-R4 or -C(S)-O-Ry), a thioacetal (e.g., -S-C(O)-R4 or - C(O)-S-Ry), a sulfate ester (e.g., -O-S(OX0)-O-Ry), a sulfonate ester (e.g., -O-S(0)-0-R4) or a a 3 (] carbamate (e.g., -O-C(0O)-NH-R4 or -NH-C(0)-O-Ry4) or Ry, together with the Ry that is bonded to the same carbon atom is =O;
R3 is -S(0)(0)-0OM, -5(0)(0)-0O-CH;-CH(O-C(0O)-Rg)-CHp-0-C(0)-Rg, -P(0)(0)-O-CH3-CH(O-C(0)-R7)-CH2-O-C(0)-R7, a glucuronide group of structure (A)
COOH
HaC lo} as
OH CH3 (A), or R3 is C).1g8 alkyl, Co.)8 alkenyl, C.1g8 alkynyl, a C).}g ester or a Cj.) g thioester, where any of the foregoing C.1g or C2.18 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selected -ORPR, (including -OH), -NHRPR (including -NHy) or -
SRPR, (including -SH) groups, or R3 is a C{.1§ fatty acid, C2.1¢ alkynyl, (J)n-phenyl-C1.5-alkyl, (J)n-phenyl-Co_s-alkenyl;
Ry is -H, a protecting group, optionally substituted C{.1§ alkyl, optionally substituted C5. 18 alkenyl, optionally substituted Co. 8 alkynyl, optionally substituted aryl, optionally substituted ~~ aryl-Cy¢ alkyl, optionally substituted aryl-C9_g alkenyl, optionally substituted aryl-Cp_g alkynyl, . optionally substituted heterocycle-C1_g alkyl, optionally substituted C;.¢ alkenyl-heterocycle, optionally substituted Cj_g alkynyl-heterocycle or an optionally substituted heterocycle, where any . of the foregoing moieties are optionally substituted at one, two, three, four, five or more carbon or hydrogen atoms with one or more independently selected -O-, -S-, -NRPR- (including -NH-), -NH-
C(0)-, -ORPR (including -OH), -NHRPR (including -NH>), -SRPR (including -SH), =O, =S, =N-
OH, -CN, -NO3, -F, -Cl, -Br or -I groups or atoms; : each Rs independently is straight or branched C1.14 alkyl; each Rg independently is straight or branched Cj.}4 alkyl; each R7 independently is straight or branched Cj. 14 alkyl or a glucuronide group of structure (A); each RPR independently is -H or an independently selected protecting group; nis, 1,2 or 3; each J independently is -F, -Cl, -Br, -1, C4 alkyl, C;.4 alkenyl, C1_4 alkoxy, carboxy, nitro, sulfate, sulfonyl, a C|.g carboxyl ester or a C_g sulfate ester;
M is hydrogen, sodium, _S(0)(0)-0-CHp-CH(O-C(0)-Rg)-CH2-0-C(O)-Rg, -P(0)(0)-O-
CHj-CH(O-C(0)-R7)-CH3-0-C(0O)-R7 or a glucuronide group of structure (A); and the dotted lines in formula 1 represent an optional double bond, provided that there are not double bonds at both the 4-5 and 5-6 positions and provided that when a double bond is present,
zero or 1 Rj group is bonded to carbon atoms at the -, 2-, 4-, 5-, 6- or 17 positions so that these carbon atoms are tetravalent; and the salts, stereoisomers, positional isomers, metabolites, analogs, precursors, hydrates, tautomers, ionized forms and solvates thereof. The formula 1 compounds are collectively referred herein to as the “compounds of the invention” or the “compounds of the present invention”.
Accordingly, the present invention provides a method for treating these parasitic infections which comprises administering to an afflicted host a therapeutically effective amount of a compound (or a pharmaceutically acceptable salt thereof) having the structure of formula 1,0ra metabolite or precursors thereof, as defined herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein and unless otherwise stated or implied by context, the following terms have the meanings defined here.
A “patient” or “subject” means a human or animal. Usually the animal is a vertebrate such } as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, felines, e.g., domestic cat, canines, e.g., dog, avians, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g. all of the above, but excluding one or more groups or species such as humans, primates or rodents. . “Alkyl” as used herein, unless stated to the contrary, is a C{-C] § hydrocarbon containing 1,2,3,4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal, secondary, tertiary, cyclic or mixed structures. Examples are -CH3, -CH2CH3, -CH2CH7CH3, ~
CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)32, -CH(CH3)CH2CH3, -C(CH3)3, - CH2CHCH2CHCH3, -CH(CH3)CHCHCH3, -CB(CH2CH3)2, -C(CH3)2CH)CH3, -
CH(CH3)CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH(CH3)CH2CH3, -CH2C(CH3)3, -
CH2CHCHCH2CHCH3, -CH(CH3)CH2CH2CH2CH3, -CH(CH2CH3)(CH2CH2CH3), -
C(CH3)2CH2CH2CH3, -CH(CH3)CH(CH3)CHCH3, -CH(CH3)CH2CH(CH3)2, -
C(CH3)(CH2CH3)2, -CH(CH2CH3)CH(CH3)2, -C(CH3)2CH(CH3)2, -CH(CH3)C(CH3)3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl- 1-propyl, 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl. “Alkenyl” as used herein, unless stated to the contrary, is C2-C]8 hydrocarbon comprising 1,2,3,4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal,
I+] iY secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more double bonds between adjacent carbon atoms. Examples are -CH=CH3, -CH=CHCH3, -CHCH=CHp, -
C(=CH3)(CH3), -CH=CHCH2CHj3, -CH2CH=CHCH3, -CH2CH2CH=CH3, -CH=C(CH3)p, -
CH C(=CH3)(CH3), -C(=CH2)CH2CH3, -C(CH3)=CHCH3, -CH(CH3)CH=CH3, - C=CHCH2CH,CH3, -CHCH=CHCH2CH3, -CHCH2CH=CHCH3, -CHCH2CH2CH=CH3, -
C(=CH)CHCH,CH3, -C(CH3)=CH2CHCH3, -CH(CH3)CH=CHCH3, -
CH(CH3)CHCH=CH2, -CH2CH=C(CH3)2, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent- 3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl. “Alkynyl” as used herein, unless stated to the contrary, is C2-C}g hydrocarbon comprising 1,2,3,4,5,6,7,8,9,10, 11, 12,13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal, secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more triple bonds between adjacent carbon atoms. Examples are -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -CH2CCCH3, -
CHCH2CCH, -CH(CH3)CCH, -CCCHCH2CH3, -CHRCCCHCH3, -CH2CH2CCCH3 and -
CH2CH2CH2CCH. “Halogen” or “halo” means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-1) and if more than one halogen is referred to (e.g., two or more variable groups may be a halogen), each ! halogen is independently selected. “Steroid nucleus” means 4 fused rings having the formula 1 structure, : “PEG” means an ethylene glycol polymer that contains about 20 to about 2000000 linked monomers, typically about 50-1000 linked monomers, usually about 100-300. Polyethylene glycols include PEGs containing various numbers of linked monomers, e.g., PEG20, PEG30,
PEG40, PEG60, PEG80, PEG100, PEG115, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG : 1000, PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000,
PEG11000, PEG12000, PEG2000000 and any mixtures thereof.
An "excipient" or a “carrier” means a component or an ingredient that is acceptable in the sense of being compatible with the other ingredients of compositions or formulations as disclosed herein and not overly deleterious to the patient or animal to which the formulation is to be administered. As used here, excipients and carriers include liquids, including benzyl benzoate, cottonseed oil, N,N-dimethylacetamide, a C5_}7 alcohol (e.g., ethanol), glycerol, peanut oil, a
PEG, vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil and vegetable oil. Excipients, as used herein may exclude solvents such as chloroform, dioxane or
DMSO. Excipients comprise one or more components typically used in the pharmaceutical formulation arts, e.g., fillers, binders, disintegrants and lubricants.
‘ v
Unless otherwise specified, expressions that refer to “a formula 1 compound”, a “compound of the invention”, a “compound of the present invention” and the like mean compositions or methods, e.g., methods to treat a Toxoplasmosis or a Cryptosporidiosis infection as disclosed herein, where one or more than one formula 1 compound is present, typically 1,2, 3 or 4, usually 1. “Alcohol” as used herein, includes excipients, means an alcohol that comprises a Ci-12 : - alkyl moiety substituted at one or more hydrogen atoms with one or more hydroxyl groups, usually . one, two or three. Alcohols include, e.g., ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s- butanol, ¢-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol, n- . 10 nonanol, n-decanol and benzyl alcohol. The carbon atoms in alcohols can be straight, branched or cyclic. Alcohol includes any subset of the foregoing, e.g., C24 alcohols (alcohols having 2, 3 or 4 carbon atoms). “Ester” means a moiety that comprises a -C(O)-O- structure, Typically, esters as used here -. comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), where the organic y moiety is bonded to a formula 1 steroid nucleus at R2 through the -C(O)-O- structure, €.g., organic . moiety-C(O)-O-steroid or organic moiety-O-C(O)-steroid. The organic moiety usually comprises . one or more of any of the organic groups described above, ¢.g., C1.20 alkyl moieties, C3_20 ) 3 alkenyl moieties, C2_0 alkynyl moieties, aryl moieties, Cg heterocycles or substituted ; 20 derivatives of any of these, e.g., comprising 1, 2, 3, 4 or more substituents, where each substituent - is independently chosen. Typical substitutions for hydrogen or carbon atoms in these organic groups include 1, 2, 3, 4 or more, usually 1, 2, or 3 -O-, -S-, -NRPR- (including -NH-), -C(0)-, =O, =S, -N(RPR); (including -NH3), -C(O)ORFR (including -C(O)OH), -OC(O)RPR (including -O-
C(0)-H), -ORFR (including -OH), -SRPR (including -SH), -NO3, -CN, -NHC(O)-, -C(O)NH-, -
OC(0)-, -C(0)O-, -0-A8, -S-A8, -C(0)-A8, -OC(0)-A8, -C(0)0-A8, =N-, -N=, =N-OH, -
OPO3(RPR);, -0S03H, or halogen moieties or atoms, where each RPR is -H, an independently selected protecting group or both RPR together comprise a protecting group, and A8 is C1.-g alkyl,
C>.g alkenyl, Cy_g alkynyl, C1.4 alkyl-aryl (e.g. benzyl), aryl (e.g. phenyl) or Cg_a allyl-Ca 5 heterocycle. Substitutions are independently chosen. The organic moiety includes compounds defined by the R4 variable. The organic moieties exclude obviously unstable moieties, e.g., -O-O-, except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for the one or more of the uses described herein. The substitutions listed above are typically substituents that one can use to replace one or more carbon atoms, e.g., -O- or -C(O)-, or one or more hydrogen atom, e.g., halogen, -NH», -OH or =O.
b] [ “Thioester’” means a moiety that comprises a -C(S)-O- structure. Typically, thioesters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon . atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula | steroid nucleus at R2 through the -C(S)-O- structure, e.g., organic moiety-C(S)-O-steroid or organic moiety-O-C(S)-steroid. The organic moiety usually comprises one or more of any of the organic groups described above, e.g., C1.20 alkyl moieties, C2_2¢ alkenyl moieties, C2.2¢ alkynyl moieties, aryl moieties, Cy_g heterocycles or substituted derivatives of any of these, e.g., comprising 1, 2, 3, 4 or more substituents, where each substituent is independently chosen.
Typical substitutions for hydrogen or carbon atoms in these organic groups include 1,2, 3, 4 or more, usually 1, 2, or 3 -O-, -S-, -NRPR- (including -NH-), -C(0)-, =O, =S, -N(RPRY, (including -
NH»), -C(0)ORPR (including -C(O)OH), -OC(O)RPR (including -0O-C(0)-H), -ORPR (including -
OH), -SRFR (including -SH), -NO3, -CN, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(0)O-, -O-A8S, -S-
AB, -C(0)-A8, -OC(0)-A8, -C(0)O-A8, =N-, -N=, =N-OH, -OPO3(RPR),, -0SO3H or halogen moieties or atoms, where each RPR is -H, an independently selected protecting group or both RPR together comprise a protecting group, and A8 is C1_g alkyl, C»_g alkenyl, C5_g alkynyl, Cj.4 : alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or C4 alkyl-C»_g heterocycle. Substitutions are : independently chosen. The organic moiety includes compounds defined by the R4 variable. The : organic moieties exclude obviously unstable moieties, e.g., -O-O-, except where such unstable : mdieties are transient species that one can use to make a compound with sufficient chemical ! 20 stability for the one or more of the uses described herein. The substitutions listed above are typically substituents that one can use to replace one or more carbon atoms, e.g., -O- or -C(O)-, or one or more hydrogen atom, e.g., halogen, -NH2, -OH or =O. : cL : “Thioacetal” means a moiety that comprises a -C(O)-S~ structure. Typically, thioacetals as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R2 through the -C(0)-S-~ structure, e.g., organic moiety-C(O)-S-steroid : or organic moiety-S-C(O)-steroid. The organic moiety is as described above for thioesters. “Carbamate” means an organic moiety as described for ester that comprises 1,2, 3, 4 or more -O-C(O)NRPR- structures where RPR is -H, a protecting group or an organic moiety as described for ester. Typically, carbamate groups as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms ’ (e.g., 0, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R2 through the -O-C(O)-NRPR- structure, e.g., organic moiety-NRPR-C(0)-O-steroid or organic moiety-O-C(O)-NRP R steroid. The organic moiety is as described above for thioesters.
. Y “Sulfate ester” means a moiety that comprises a -O-S(0)(0)-O- structure. Typically, sulfate esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R2 through the -O-S(0)(0)-O- structure, e.g. organic moiety-O-S(0)0)-O-steroid. The organic moiety is as described above for thioesters. “Sulfite ester” means a moiety that comprises a -O-5(0)-O- structure. Typically, sulfite esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2- 12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R2 through the -O-8(0)-O- structure, e.g., organic moiety-O-S(0O)-O-steroid. The organic moiety is as described above for thioesters,
The compositions disclosed herein optionally comprise salts of the formula 1 compounds that comprise an ionizable moiety or a polar moiety. As used herein, “salts” include complexes that comprise moieties of opposite charge. Ionizable moieties include -O-S(0)(0)-OH or a -NH> group at Ro and polar moieties include -OH. Salts include pharmaceutically acceptable salts that comprise, for example, an uncharged moiety or a monovalent anion moiety or a monovalent cation moiety. Salts include compounds derived by combination of appropriate anions such as inorganic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity. For example, one may form invention salts from acid addition of certain inorganic ) acids, e.g., HF, HCI, HBr, HI, H»SO4, H3PO4, to basic centers, typically amines that may be present in formula 1 compounds. Or one may use certain organic acids, e.g., organic sulfonic : acids, organic carboxylic acids in the same manner. Exemplary organic sulfonic acids include Cg. 16 aryl sulfonic acids, Cg.1¢ heteroaryl sulfonic acids and C1.1¢ alkyl sulfonic acids such as phenyl, a-naphthyl, B-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i- butyl, -butyl, pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acids include C1.16 alkyl, Cg-16 aryl carboxylic acids and C4-1 ¢ heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids. Many amino acids 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. Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used as synthetic intermediates for making other invention compounds.
i) G
Heterocycle. “Heterocycle” or “heterocyclic” 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. 1960, 82:5566; and U.S. patents 5763483 and 5811450, all of which are incorporated herein by reference.
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-1,5,2dithiazinyl, 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, B-carbolinyl, phenanthridinyl; acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, : quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, Co d 20 benzoxazolinyl, and isatinoyl. a. 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, 4-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 B—carboline. Typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. “Heteroaryl” means an aromatic ring or two or more fused rings that contain one or more aromatic rings where the ring or fused rings comprise 1, 2, 3 or more heteroatoms, usually oxygen (-O-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or C]_¢ alkyl, usually -H. : Examples are as described for heterocycle.
Protecting groups. Various groups that the formula 1 compounds may comprise include, e.g., substituted alkyl groups, substituted alkenyl groups, esters or substituted heterocycles, which -can contain one or more reactive moieties such as hydroxyl, or thiol. Intermediates used to make : 10 formula 1 compounds may be protected as is apparent in the art. Noncyclic and cyclic protecting groups and corresponding 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) (hereafter “Greene”). In the context of the present invention, these protecting groups are groups . that can be removed from the molecule of the invention without irreversibly changing the covalent 15 bond structure or oxidation/reduction state of the remainder of the molecule. For example, the protecting group, -X, that is bonded to a -OX or -NHX group can be removed to form -OH or -NH- , 2, respectively, without affecting other covalent bonds in the molecule. At times, when desired, ’ more than one protecting group can be removed at a time, or they can be removed sequentially. In ) . compounds of the invention containing more than one protecting group, the protecting groups are 20 the same or different. .
Protecting groups are intended to be removed by known procedures, although it will be understood that the protected intermediates fall within the scope of this invention. The removal of the protecting group may be arduous or straightforward, depending upon the economics and nature of the conversions involved. In general, one will use a protecting group with exocyclic amines or 25 with carboxyl groups during synthesis of a formula 1 compound. For most therapeutic applications amine groups should be deprotected. Protecting groups commonly are employed to protect against covalent modification of a sensitive group in reactions such as alkylation or acylation. Ordinarily, protecting groups are removed by, e.g. hydrolysis, elimination or aminolysis. Thus, simple functional considerations will suffice to guide the selection of a reversible or an irreversible 30 protecting group at a given locus on the invention compounds. Suitable protecting groups and criteria for their selection are described in T.W. Greene and P.G.M. Wuts, Eds. "Protective Groups in Organic Synthesis" 2nd edition, Wiley Press, at pps. 10-142, 143-174, 175-223, 224-276, 277- 308, 309-405 and 406-454, which is incorporated herein by reference.
Determination of whether a group is a protecting group is made in the conventional 35 manner, e.g. as illustrated by Kocienski, Philip I.; "Protecting Groups" (Georg Thieme Verlag
2 IN
Stuttgart, New York, 1994) (hereafter “Kocienski”), Section 1.1, page 2, and Greene Chapter 1, pages 1-9; and U.S. patent 5763483 and 5811450, all of which are incorporated herein by reference. In particular, a group is a protecting group if when, based on mole ratio, 90% of that protecting group has been removed by a deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone changes to their covalent bond structure or oxidation/reduction state other than those occasioned by the removal of the protecting group. When multiple protecting groups of the same type are present in the molecule, the mole ratios are determined when all of the groups of that type are removed.
When multiple protecting groups of different types are present in the molecule, each type of protecting group is treated (and the mole ratios are determined) independently or together with others depending on whether the deprotection reaction conditions pertinent to one type are also pertinent to the other types present. In one embodiment of the invention, a group is a protecting : group if when, based on mole ratio determined by conventional techniques, 90% of that protecting group has been removed by a conventional deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone irreversible changes to their covalent bond structure or oxidation/reduction state other than those : occasioned by the removal of the protecting group. Irreversible changes require chemical reactions ’ (beyond those resulting from aqueous hydrolysis, acid/base neutralization or conventional - separation, isolation or purification) to restore the covalent bond structure or-oxidation/reduction : 20 state of the deprotected molecule of the invention. - Protecting groups are also described in detail together with general concepts and specific : strategies for their use in Kocienski, Philip J.; "Protecting Groups" (Georg Thieme Verlag :
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, Chapter 6, Amino
Protecting Groups, pages 185-243, Chapter 7, Epilog, pages 244-252, and Index, pages 253-260, are incorporated with specificity in the context of their contents. More particularly, Sections 2.3
Silyl Ethers, 2.4 Alkyl) Ethers, 2.5 Alkoxyalkyl Ethers (Acetals), 2.6 Reviews (hydroxy and thiol : 30 protecting groups), 3.2 Acetals, 3.3 Silylene Derivatives, 3.4 1,1,3,3-
Tetraisopropyldisiloxanylidene Derivatives, 3.5 Reviews (diol protecting groups), 4.2 Esters, 4.3 2,6,7-Trioxabicyclo[2.2.2Joctanes [OBO] and Other Ortho Esters, 4.4 Oxazolines, 4.5 Reviews (carboxyl protecting groups), 5.2 O,0-Acetals, 5.3 S,S-Acetals, 5.4 O,S-Acetals, 5.5 Reviews (carbonyl protecting groups), 6.2 N-Acyl Derivatives, 6.3 N-Sulfonyl Derivatives, 6.4 N-Sulfenyl
Derivatives, 6.5 N-Alkyl Derivatives, 6.6 N-Silyl Derivatives, 6.7 Imine Derivatives, and 6.8
Reviews (amino protecting groups), are each incorporated with specificity where protection/deprotection of the requisite functionalities is discussed. Further still, the tables "Index to the Principal Protecting Groups" appearing on the inside front cover and facing page, "Abbreviations" at page xiv, and "reagents and Solvents" at page xv are each incorporated in their entirety herein at this location.
Typical hydroxy protecting groups are described in Greene at pages 14-118 and include
Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-
Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p- : :Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4- ” 10 .:Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2- chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4- methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl
S,S-Dioxido, 1-[(2-Chloro-4-methyl)phenyl}-4-methoxypiperidin-4-yl, 1,4-Dioxan-2-yl,
Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-
J . methanobenzofuran-2-yl); Substituted Ethyl Ethers (i-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- = 20 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’-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, alpha-Naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenyimethyl, 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-Phenyi)xanthenyl, 9-(9-Phenyl-10- oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers (Trimethylsilyl,
Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropyisily, 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-Oxopentanoate (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-Nitro-4- methylpentanoate, o-(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 hydroxy protecting groups include subtituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates. ’ + Typical 1,2- and 1,3-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene, 1- : : 20 Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide Ce (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, alpha- Methoxybenzylidene, !-(N,N-Dimethylamino)ethylidene Derivative, alpha-(N,N-
Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); and Silyl Derivatives (Di-t- butylsilylene Group, 1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene) Derivative, Tetra-t- butoxydisiloxane-1,3-diylidene Derivative, Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate, © Phenyl Boronate).
More typically, 1,2- and 1,3-diol protecting groups include epoxides and acetonides.
Typical amino protecting groups are described in Greene at pages 315-385 and include
Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl, 9(2-Sulfo)fluorcenylmethyl, 9-(2,7-
Dibromo)fluorenylmethyl, 2,7-Di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy))}- methyl, 4-Methoxyphenacyl); Substituted Ethyl (2,2,2-Trichoroethyl, 2-Trimethylsilylethyl, 2- Phenylethyl, 1-(1-Adamantyl)-1-methylethyl, 1,1-Dimethyl-2-haloethy], 1,1-Dimethyl-2,2-
s « 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)Imethyl, 4-Methylthiophenyl, 2,4-Dimethylthiophenyl, 2-
Phosphonioethyl, 2-Triphenylphosphonioisopropyl, 1,1-Dimethyl-2-cyanoethyl, m-Choro-p- acyloxybenzyl, p-(Dihydroxyboryl)benzyl, 5-Benzisoxazolylmethyl, 2-(Trifluoromethy!)-6- y 10 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 Derivative, N'-p-
Toluenesulfonylaminocarbonyl, N'-Phenylaminothiocarbonyl); Miscellaneous Carbamates (t- : -Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl, Cyclobutyl, Cyclohexyl, Cyclopentyl,
Cyclopropylmethyl, p-Decyloxybenzyl, Diisopropylmethyl, 2,2-Dimethoxycarbonylvinyl, o-(N,N- , Dimethylcarboxamido)benzyl, 1,1-Dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1- 2 Dimethylpropynyl, Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, . Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl, 1-Methylcyclohexyl, 1-Methyl- ) 1-cyclopropylmethyl, 1-Methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-Methyl-1-(p- . 20 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 Derivative, N-Benzoyl, N-p-Phenylbenzoyl); Amides With Assisted
Cleavage (N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl, N-Acetoacetyl, (N'-
Dithiobenzyloxycarbonylamino)acetyl, N-3-(p-Hydroxyphenyl)propionyl, N-3-(o-
Nitrophenyl)propionyl, N-2-Methyl-2-(o-nitrophenoxy)propionyl, N-2-Methyl-2-(o- phenylazophenoxy)propionyl, N-4-Chlorobutyryl, N-3-Methyl-3-nitrobutyryl, N-o-
Nitrocinnamoyl, N-Acetylmethionine Derivative, 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-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts,
» *
N-Benzyl, N-Di(4-methoxyphenyl)methy!, 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); Imine Derivatives (N-1,1-Dimethylthiomethylene,
N-Benzylidene, N-p-methoxybenylidene, N-Diphenylmethylene, N-(2-Pyridyl)mesityljmethylene, N,(N'N'-Dimethylaminomethylene, N,N'-Isopropylidene, N-p-Nitrobenzylidene, N-Salicylidene,
N-5-Chlorosalicylidene, N-(5-Chloro-2-hydroxyphenyl)phenylmethylene, N-Cyclohexylidene);
Enamine Derivative (N-(5,5-Dimethy)-3-oxo-1-cyclohexenyl)); N-Metal Derivatives (N-Borane
Derivatives, N-Diphenylborinic Acid Derivative, N-[Phenyl(pentacarbonyichromium- 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-Benzenesuifenyl, N-o-
Nitrobenzenesulfenyl, N-2,4-Dinitrobenzenesulfenyl, N-Pentachlorobenzenesulfenyl, N-2-nitro-4- methoxybenzenesulfenyl, N-Triphenylmethylsulfenyl, N-3-Nitropyridinesulfenyl); andN-Sulfonyl
Derivatives (N-p-Toluenesulfonyl, N-Benzenesulfonyl, N-2,3,6-Trimethyl-4-
ES methoxybenzenesulfonyl, N-2,4,6-Trimethoxybenzenesulfonyl, N-2,6-Dimethyl-4- ae methoxybenzenesulfonyl, N-Pentamethylbenzenesulfonyl, N-2,3,5,6,-Tetramethyl-4-
A methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6- Trimethylbenzenesulfonyl, N- te 2,6-Dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-Pentamethylchroman-6-sulfonyl, N- - :
SE 20 Methanesuilfonyl, N-.beta.-Trimethylsilyethanesulfonyl, N-9-Anthracenesuifonyl, N-4-(4', 8'- : oo Dimethoxynaphthylmethyl)benzenesulfonyl, N-Benzylsulfonyl, N-Trifluoromethylsulfonyl, N- i Phenacylsuifonyl).
Sa - More typically, amino protecting groups include carbamates and amides, still more typically, N-acetyl groups.
Stereoisomers. The formula 1 compounds include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diasteromeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be ] substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. Chiral centers may be found in invention compounds at, for example, Rl,
R2orR4 :
One or more of the following 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.
ro
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 that 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 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 3 10 general utility is chromatographic 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, which 1S is incorporated herein by reference. Examples of chiral columns that could be used to screen for : _the optimal separation technique would include Diacel Chriacel OD, Regis Pirkle Covalent D- : phenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D- 3 .DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column, :
Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Not all of these columns : 20 are likely to be effective with every racemic mixture. However, those skilled in the art understand 3 that a certain amount of routine screening may be required to identify the most effective stationary phase. When using such columns it is desirable 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 separating the conjugates by ordinary column chromatography. This isa very suitable method, particularly when the embodiment contains a free 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 inthe art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group.
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, 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
“ LY BN 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 5S 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 limited 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): Part 2, Resolution of Enantiomer Mixture, pages 217-435; more particularly, section 4,
Resolution by Direct Crystallization, pages 217-251, section 3, 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 mote particularly, section 5.1.4, Resolution of Alcohols, Transformation of Alcohols into Salt- : 20 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, all of which are incorporated herein by reference.
Embodiments include compositions that transiently occur when a method step or operation is performed. For example, when a formula | compound is contacted with an excipient, e.g., water, a cyclodextrin, a PEG, an alcohol, propylene glycol, benzyl alcohol or benzyl benzoate, the composition before addition of one ingredient with another is a non-homogenous mixture. As the ingredients are contacted, the mixture's homogeneity increases and the proportion of ingredients relative to each other approaches a desired value. Thus, some compositions as disclosed herein, optionally contain less than about 3% w/w water, e.g., less than 0.5% w/w water, can comprise about 0.0001-99% w/w of a formula 1 compound such as 16a-bromoepiandrosterone and one or more excipients. These transient compositions are intermediates that necessarily arise when one
« . makes an invention composition or formulation and they are included in invention embodiments to the extent that they are patentable.
Formula | compounds. The formula 1 compounds, or the “compounds of the invention”, are useful to treat a subject having, or prevent infection of a subject with, one or more
Toxoplasmosis or Cryptosporidium parasites. The present invention provides a new method for treating toxoplasmosis and/or cryptosporidiosis by administering compounds of the present invention, as discussed above, including compounds of formula 1 and pharmaceutically acceptable salts thereof,
For preferred formula 1 compounds, the Ry moiety bonded to the steroid ring is generally in the B-configuration, two Ry are bonded to Q7 and X is a double bonded oxygen moiety (=O).
Typically, one of the R| bonded to Q7 is hydrogen in the B-configuration, the other Rj bonded to
Q3 is hydrogen or a halogen, usually bromine, in the a-configuration and a double bond is present at the 5-6 positions. Such preferred compounds include dehydroepiandrosterone (“DHEA”) and 16a-bromodehydro-epiandrosterone (“Br-DHEA™).
Other preferred formula 1 compounds include 17-ketosteriods of formula 1 where a double bond is present at the 5-6 positions, X is =O, Q2 is -CHy- or -CHBr-, R3 is -H, or -
OR3 wherein Ry is -5(0)(0)-0H, -S(0)(0)-ONa, -S(0)(0)-0-CH3-CH(O-C(0)-Rg)-CH3-O-
C(O)-Rg (where R6 independently is C1.]4 straight or branched alkyl), -P(0)(0)-O-CH3-CH(O- )
C(O)R7)-CH3-0-C(0)-R7 (where R7 independently is a glucuronide group or C_14 straight or branched alkyl) or Rj is a glucuronide group. Other preferred compounds include compounds . having the formulas 20-43 rR, A X R rR, A X
Ry Ry
R Ry Ry R,
PEE | PE
Q, Qj,
Ry Ry R, Ry Ry Ry
Ry Ri Ry R; Ri Ry
Ri Ry Ry Ry
IR Ry Ry Ry Ry
Ri Ry Ry ™ 1 Ry Ry ™ 20 21
- G
R
Ry Ri X Ry TM X
R4 \ Qs R, R R4 Qs
Ry 1 Y
R Y R4
R Ry 1 Ry R R, Ry R ! Qa Ry ! Qs,
Ry R, Ry R,4 R
Ry R 1
Ry Ry R, R, 1 Ry
R R Ry Ry ! R ! Ry Ry 3 ¥ 1 R
Ri Ry, Ry Ry Ri Ry Ry Ry 22 23
R
Ry Ry Ry ™ X
R 1 Qs X R, } R Ry Qg
R 1
R : Ry R
Ry Ry YY Ry 1 Y
R4 Q Ry Qa . 3
R R Ry Ry 1 R 1 Ry R, k Ry
R, 1 Ry Ra 1
R Ry Ry Ry ! Ry R, R, R R4
R4 R, R, R, Ry R4 Ry 1 : S . 24 25 } Ry R4 x R. Ry x
R Ry Qg Ry Ry 1 Qg 1 Ry Ry R
R Ri R R 1 . ) rR 1 a 1 R R, 1 Ry ! 3 Ry Qs R
Ry Rs Ry R R
R Ry R 1 1 R 1 Ry 2 1 R, 1 Ry
Ri Ry f Ri R Ri 1
Ry R4 R, Rj Ry Ry 26 27
Ri Ri X rR, Ri x
Ry Qs Ry R4 Qe
Ri Y Ry y
R, | Ry R, Ri Rr,
Ri Qy R Ry Q R 3
Ry oe R; Ry Ry Ry
R, 1 R4 Rj R4 Ry
Ri Ry R R,
R4 1 Ry
Ry Ry Ri Ry Ry R4 28 29
Ry Ri
Ry Rq X 1
R Ri Qs R, R, Ri Q X 1
R
Ry R 1 R, 2
R R4 Y 1
R4 ! Qs, Ry Qa
R
R4 R4 Ri R4 R; | \ R,
Rz Ri R4 Ry 1
R
Ry R R4 Ry R, 1 1
R
R 1 Ry ! R1 R,4 R4 . 30 31
Ry Ri X
Ry Ri X 1
R, ! Qg R, R R4 Qs
Ry Ry R, 1 Rq
R R
R4 1 R4 R Ry R4 1 R
Ri Q4 Q,
R Ry
Ry Ri Ry Ry R Ru
R, R4 R, Rs 1
R4 ] 0 Ry Ry 0) 1 R
Ri Ry Ry Rs Ri R;, Ry Ri 32 33
”w [iY
Ry R4 X R, Ry X
R4 K Qs Ry Rq \ Qs
Ry Y Ry Y
R Ry Ri R4 R R4 Ri Ry 1 Qs R 1 Qs, R
R R
1 a R4 1 oo Ry
Rz 1 Ry Ro ! Rq
Ry [0] Ry R Oo
Ry 1
R4 R; R4 Ry Ry R, Ry R, 34 35
Ry Ri X Ry Ri X
Ry ! Qe Ry R4 Qs
Ry Rq
R rR Ri R, v R, Ri 1 Ry Y 1 Qj Q,
R R R
) 0 R, 1 R 1 R,
Ra 1 R4 Ra 1 R1
Rq So R; ! 6)
R 1
Ry Ry Ry Ra Ri R, Ry Ri : 5 36 37 : R R14 X R4 R4 X
Ry : Qg Ry Ry Qs
R4 Ry
Ry JR R R, [Ry R
Ry Ry
Qj, Ry R Qy Ry
R R R
1 R 1 R, 1 R 1 R4
Ra 1 R4 R2 ' Ry
R; 0 Ry (o]
Ry R, Rq Ri Ry Rq 38 39
Ry Ri X rR, Ry
Ry Qg R4 R4 : Qs n
Ry Ry
Ry 1 Ry Y Ry 1 Ry Y
R4 Ry
Qy R Qg R
R4 R4 Ry R,
Ra 1 Ry R; Ry Ry
Ry lo) Ry o
Ri Ry Ry R1 R, Ry 40 41
Ry Ri X Ry Rs X
R4 Qs Ri R4 Qe
Ry Ry
R,4 Rj
R R R R
R, 1 1 Y Ry 1 1 Y
Qa Q,
R
1 R4 Ry Ry R4 Ry
R, Ri Ry Ry Ri R,
Ri 0 Ry 0 : : Ri R, Ry Ri R, Ry 3 5 42 43 : wherein for each of structures 20-43 : Q3 and Qg are each -C(R1)3 wherein each R1 is independently selected; .
X and Y independently are -OH, -H, lower alkyl (e.g., C1_g alkyl), -C(0)-O-Rs;, -0-C(0)-
Rs, halogen or, X and Y together with the R at the same position independently are a ketone (=O); each R] is independently selected and has the definition given above; and
Ry and R35 have the definitions given above.
In some embodiments, the formula 1 compound has the structure 20-43 and 2,3, 4,5 or 6
Rj groups independently are -OH, halogen or alkoxy, and the remaining R are all hydrogen; R7 is -OH, an ester a thioester or a carbamate, or Ro, together with the Ry at the 3-position comprises =0; Y is -H, -OH, a halogen or -O-C(O)-Rs, or Y, together with the R at the 16-position comprises =O; X is -OH or -O-C(0)-Rs, or X, together with the Ry at the 17-position comprises =0; and Q3 and Qg independently are -CH3 or -CH2OH. Such embodiments include structure 20- 43 compounds where two -OH are present at the 3-position, the 16-position or at the 17-position.
v %
Preferred invention embodiments include compounds having the formula 44
CHy {
AIT wherein Y is hydrogen or bromine, R44 is -H, -S(0)(0)-OH, -5(0)(0)-ONa, -5(0)(0)-O-CHs- :
CH(O-C(0)-Rg)-CH3-0-C(0)-Rg, -P(0)(0)-0-CH3-CH(O-C(0)-R7)-CH2-0-C(O)-R7 or a glucuronide group of structure (A). In other preferred embodiments, Y and R44 in formula 44 are both hydrogen. An especially preferred compound is dehydroepiandrosterone (Y and Ry44 in formula 44 are both hydrogen and the double bond at the 5-6 position is present). In other embodiments, the compound is epiandrosterone (Y and R44 in formula 44 are both hydrogen and the double bond at the 5-6 position is absent). A 16-haloepiandrosterone with a F, Cl, Br or [ at the 16 position can also be used as an antiviral agent, e.g., 16a-bromoepiandrosterone. Other preferred compounds are (i) 16a-bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-3- sulfate (Y is -H and R44 is -S(O)(0)-OM in formula 44 are both hydrogen and the double bond at « the 5-6 position is present) and (iii) 5B-androstan-3p3-ol-17-one. Related embodiments comprise compounds related to formula 44 compounds comprise the formula 44 compounds wherein 1, 2, 3, ] 15 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently : selected -OH, -Br, -Cl, -F, -I, -OCH3 or -OC2Hj5 atoms or groups. .. In other embodiments, the 17-ketosteroids of formula | are dehydroepiandrosterone where :
R44 in formula 44 is a -5(0)(0)-0-CH3-CH(O-C(0)-Rg)-CH3-0-C(O)-R5, -P(O)(0)-O-CHp-
CH(O-C(0O)-R7)-CH»-0-C(0O)-R7 or a glucuronide group of structure (A), Y is hydrogen and the : 5-6 double bond is present. Other formula 44 compounds include conjugates of dehydroepiandrosterone wherein Y is hydrogen, a double bond is present at the 5-6 position and
R44 is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl sulfate, O- dihexadecylglycerol sulfate, hexadecane sulfonate, dioctadecanoylglycerol phosphate or O- hexadecylglycerol phosphate.
In another preferred aspect of the invention, the steroid of formula 1 is a compound of formula 45
CH, Rs2
POS wherein Rs is -H, -OH or =O; Rs is -Br, -Cl, -F or -I; R52 is -OH or =0; R4g is -H, -OH, or -
ORs3; and Rs3 is Cy.) 8 alkyl, C3.138 alkenyl, C3.1g alkynyl, a Cj_1g ester, a C1_1g thioester, wherein any of the foregoing Cy.18 or C2.1g groups is substituted at one or more hydrogen atoms with one or more independently selected -O-, -S-, -OH, -NH3 or -SH groups or Rs3 is a thioacetal, a sulfate ester, a sulfonate ester, a carbamate or a thioester. In one preferred aspect, R49 is -O-
C(0)-CH2-CH2-CH(R54)-CH(R55)-CHpR 56 wherein Rs4 is -NHp, -OH, -SH, -O-PO3, -SOj3 or -
OS03; Rss is -H, -NHp, -OH, -SH, -0-PO3, -SO3 or -OS03; and Rs is Cy.1g alkyl, Ca-18 alkenyl, C2_1 8 alkynyl, a C}.]g ester, a C}.1 g thioester, wherein any of the foregoing C 1-18 or
C2-18 groups is substituted at one or more hydrogen atoms with one or more independently ] selected -OH, -NHp, -SH or =O groups, and the precursors, metabolites and analogs thereof, .
Related embodiments comprise compounds related to formula 44 compounds comprise the formula 45 compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are } substituted with independently selected -OH, -Br, -Cl, -F, -I, -OCH3 or -OCoHj5 atoms or groups.
In other preferred embodiments, the formula 1 compounds have the formula 1B or 1C
X X fe Ry fe Ry
R; Ry IB or Re Ri 1C wherein each Rj independently is -H, -OH, a halogen, -CHCHj, -CHCHCH3, -CCH, -CCCH3, or, or, the other moiety that is bonded to the same carbon atom is absent and Ry is =O; Ry is -H, -OH, a halogen, Cj _g alkoxy, -S-C(O)-(CH2)p-R4, -C(0)-S-(CHp)-R4, -O-S(0)(0)-(CH2)m-R4, -O-
S(0)(0)-0-(CH2)m-R4, -O-C(0)-NH-(CHp)m-R4, -NH-C(0)-O-(CH2)-Rd, -0-C(S)-(CH)-
R4, -C(8)-O-(CH)m-R4, -O-C(0)-(CH2)1n-R4 or -C(0)-O-(CH2);m-R4; Ry is -H, -CHg, -CoHs, -C3H7, -CoH4O0H, -C3HgOH, -CHp-CH»-0-CH3, -CH3-CHjy-0-CHp-CH3, -CHy-CHj-0O-CH»-
CHOH, a C3.g alkenyl group, a C3.¢ alkynyl group, benzyl or phenyl, wherein the phenyl or benzyl groups are optionally substituted with 1, 2, or 3 independently selected halogen, C1_4 alkoxy, -OH, -SH, -O- or -NH- moieties; and Q3 and Qg independently are -H, -CH3 or -CHOH; and Q3 is -C(R1)7- or -CH2-CHp-. In these embodiments, Q3 and Qg are usually both in the p- configuration, typically they are -CH3, Q3 usually comprises -CH3-, -C(O)-, -CH(Br)-, -CH(I)-, or -CH(OH)- with the Br, I or OH moieties in the a-configuration, or Q) comprises =O, and R} at the 7-position is -H, -OH or =O. Related embodiments comprise compounds related to formula 44 compounds comprise the formula 1A or 1B compounds wherein 1,2, 3,4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently selected -OH, -Br, -Cl, -F, -1, -OCH3 or -OCoHj atoms or groups.
The formula 1 compounds can exist in a crystalline or polymorphic form.
Metabolites. Also falling within the scope of this invention are the in vivo metabolites of the compounds of the invention, 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 formula 1 compound, due to enzymatic or chemical processes. Accordingly, the invention includes novel and unobvious compounds produced by a : 15 process comprising contacting a compound of this invention with a subject, e.g., a human, rodent or a primate, 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) formula 1 compound, : administering it parenterally or orally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an : animal such as rat, mouse, guinea pig, primate, or to a human, allowing sufficient time for " . 20 metabolism to occur (typically about 30 seconds to about 30 hours) and isolating its conversion : i. products from the urine, blood or other biological samples. These products are easily isolated since k 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
HPLC, 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 therapeutic activity of their own.
The following description exemplifies embodiments of the formula 1 compounds.
Group 1. Exemplary embodiments include the formula 1 compounds named in table B based on the compound structure designations defined in table A. Each compound named in Table
B is depicted as a compound of formula 4
Qs y & (Ix
CT
Se
Ry 3 RiA where Q3 and Qg are both -CH3, Q4 is -CHj- and Rp, RA, and Y and X have the structures designated in Table A. The compounds named according to Tables A and B are referred to as “group 1” compounds.
Compounds named in Table B are designated by numbers assigned to Rp, Rj A, Y and X according to the following compound naming convention, R7.R1A.Y X, using the numbered chemical structures depicted in Table A. As shown in formula 4, Rj is in the 3B3-position and hydrogen fills the remaining valence or Rj is double bonded to the 3 carbon, RA is an R} group at the 7B-position or R1A is an R] group double bonded to the 7 carbon, Y is in the 16a-position and hydrogen fills the remaining valence or R3 is double bonded to the 16 carbon and X is in the 17B-~position and hydrogen fills the remaining valence or X is double bonded to the 17 carbon. ) 3 When Ry, R1A, Y or X is a divalent moiety, e.g., =O, the hydrogen at the corresponding position is absent. Thus, the group 1 compound named 1.2.1.1 specifies a formula 4 structure with a 3- : hydroxyl bonded to carbons at the 3- and 7-positions (the variable groups Ry and R1A respectively), an a-bromine bonded to carbon 16 (the variable group Y) and double bonded oxygen (=O) at carbon 17 (the variable group X), i.e., having the structure shown below.
CH, 0
Zar
HOM > I OH oy ~~ 1.2.1.1
TABLE A I —
R2 R1A 1 -OH 1 -H 2 =0 2 -OH 3 -O-P(0)(0)-OH 3=0
W ro 4 -O-P(0)(0)-0-CH,-CH(O-C(0)-CH3)-CH,-0-C(0)CH3 4 -CH3 -0-S(0)(0)-OH 5 -OCHj3 6 -0-S(0)(0)-0-Na* 6 -OCaHs 7 -0-S(0)(0)-0C;Hs 7 -OCH,CH,CH3 5 8 -0-S(0)(0)-0-CH,-CH(O-C(0)-CH3)-CHy-0O-C(O)CH;3 8 -OCH(CH3)CH3 9 -0-S(0)(0)-OCH,CHyCH,CHj 9 -OCH,CH,CH,CH;3 -0-S(0)(0)-OC(CH3)3 10 -OC(CH3)3
Y X
10 1 -Br 1=0 2 Cl 2 -OH 3-1 3-H 4 -F 4 -F 5-H 5 -Cl 6 -OH 6 -Br 7 =0 7-1 8 -0-C(0)-CH3 8 -O-C(O)-CH3 9 -0-C(0)-CH,CHs 9 -0-C(O)-CHpCH3 10 -0-C(0)-CHyCHyCH; 10 -O-C(0)-CHpCHpCH3____ : 20
TABLE B
1.1.1.1, 1.1.12, 1.1.1.3, 1.1.14, 1.1.1.5, 1.1.1.6, 1.1.1.7, 1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.22, . 1.1:2.3,1.124, 1.12.5, 1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3, 1.1.3.4, 1.13.5,1.1.3.6,1.1.3.7, 1.1.3.8, 1.1.3.9, 1.13.10, 1.1.4.1, 1.1.42, 1.1.43, 1.1.44, 1.1.4.5, 1.1.4.6, - 1.1.4.7,1.1.4.8,1.1.4.9,1.1.4.10,1.15.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7, 1.1.5.8, "1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1, 1.1.8.2, 1.1.8.3,1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9, 1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7, 1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4, 1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1, 1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 12.1.7,1.2.1.8,12.1.9,1.2.1.10,12.2.1,1.2.2.2,1.2.2.3,1.2.2.4,1.2.2.5, 1.2.2.6, 1.2.2.7, 1.2.2.8, 1.2.2.9,1.2.2.10, 1.23.1, 1.2.3.2, 1.23.3, 1.2.3.4, 1.2.3.5, 1.2.3.6, 12.3.7, 1.2.3.8, 1.2.3.9, 1.23.10, 12.4.1,12.42,1243,1.2.44,12.45,12.4.6,124.7,1.24.8,1.2.49,12.4.10, 1.2.5.1, 1.2.5.2, 12.53,1.2.54,12.5.5,1.2.5.6,1.2.5.7,1.2.5.8,1.2.5.9, 1.25.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.65,12.66,12.67, 1.2.68, 12.69, 126.10,1.2.7.1,12.7.2,1.2.73, 1.2.74, 1.2.7.5, 1.2.7.6,
1.2.7.7,1.2.78,1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3, 1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.89,12.8.10,1.2.9.1,1.2.9.2,1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9, 1.2.9.10, 1.2.10.1,1.2.102,1.2.103, 1.2.10.4, 1.2.10.5, 1.2.10.6, 1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 13.1.1,13.12,13.13,1.3.14,13.1.5,13.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1, 1.3.2.2,
1.323,1324,1325,1326,132.7,13.28,1.3.29,13.2.10,1.33.1, 1.3.3.2, 13.3.3, 1.3.3.4, 133.5,13.3.6,1.33.7,1.33.8,13.3.9, 1.33.10, 1.3.4.1, 1.342, 1.3.4.3, 1.3.4.4, 1.3.4.5, 1 3.4.6, 13.4.7,13.4.8,13.49,134.10,13.5.1,1.3.52,1.3.53,13.54,13.5.5,1.3.5.6, 13.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9, 1.3.6.10,
13.7.1,13.7.2,13.73,13.74,13.7.5,13.7.6, 1.3.7.7, 1.3.7.8,1.3.7.9,1.3.7.10, 1.3.8.1, 1.3.8.2,
} 10 13.83,13.84,1.3.8.5,1.3.8.6,1.3.8.7,1.3.8.8,1.3.89,1.3.8.10,1.3.9.1,1.3.9.2, 1.3.9.3, 1.3.9.4, 1.3.9.5,1.3.9.6,1.3.9.7,1.3.9.8,1.3.9.9, 1.3.9.10, 1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6,1.3.10.7, 1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.14, 1.4.1.5, 1 4.1.6, 14.1.7, 1.4.1.8,1.4.19,1.4.1.10, 1.4.2.1, 1.4.2.2, 1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 14.2.9,1.4.2.10,1.43.1,1.43.2,1.433,1.4.3.4,14.3.5,143.6,1.4.3.7,1.43.8, 1.4.3.9, 1.4.3.10,
14.4.1,14.42,1443,1.444,144.5,1446,1.44.7,1.4438,14.4.9,1.44.10, 1.4.5.1, 1.4.5.2, 1.45.3,1.4.54,1.455,1.45.6,1.45.7,1458, 1.459,1.4.5.10, 1.4.6.1, 1.4.6.2, 1.4.6.3, 1.4.6.4,
1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10, 1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6,
14.7.7,1.4.7.8,1.4.7.9, 1.47.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4, 1.4.8.5, 1.4.8.6, 1.4.8.7, 1.4.8.8, 1.4.8.9,1.4.8.10,1.49.1,1.492,1.4.93,1.49.4,1.4.9.5,1.49.6,1.49.7, 1.4.9.8, 1.4.9.9, 1.49.10,
1.4.10.1,1.4.102,1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6, 1.4.10.7, 1.4.10.8, 1.4.10.9, 1.4.10.10, : 15.1.1, 1.5.1.2, 1.5.1.3, 1.5.1.4, 1.5.1.5, 1.5.1.6, 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2, 1.52.3,1.524,1.52.5,1.52.6,1.5.2.7,1.52.8, 1.5.2.9, 1.5.2.10, 1.5.3.1, 1.5.3.2, 1.5.3.3, 1.5.3.4, 15.3.5,1.53.6,1.53.7,1.5.3.8,1.5.3.9, 1.53.10, 1.5.4.1, 1.5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6, 1.5.4.7,1.5.4.8,1.54.9, 1.54.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4, 1.5.5.5, 1.5.5.6, 1.5.5.7, 1.5.5.8,
1.5509,15.5.10,1.5.6.1,1.5.6.2,1.5.6.3,1.5.6.4,1.5.6.5,1.5.6.6,1.5.6.7, 1.5.6.8, 1.5.6.9, 1.5.6.10, 15.7.1,15.72,15.73,1.5.7.4,1.5.7.5,1.5.7.6, 1.5.7.7, 1.5.7.8, 1.5.7.9, 1.5.7.10, 1.5.8.1, 1.5.8.2, 1.5.83,1.5.84,1.5.85,1.58.6,1.5.8.7,1.5.8.8,1.5.89,1.5.8.10,1.59.1,1.5.9.2,1.5.9.3,1.59.4, 1.5.9.5.1.5.9.6, 1.59.7, 1.5.9.8, 1.5.9.9, 1.59.10, 1.5.10.1, 1.5.10.2, 1.5.10.3, 1.5.10.4, 1.5.10.5, 1.5.10.6, 1.5.10.7, 1.5.10.8, 1.5.10.9, 1.5.10.10, 1.6.1.1, 1.6.1.2, 1.6.1.3, 1.6.1.4, 1.6.1.5, 1.6.1.6,
1.6.1.7,1.6.1.8,1.6.1.9,1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3,1.6.2.4, 1.6.2.5, 1.6.2.6, 1.6.2.7, 1.6.2.8, 1.6.2.9,1.6.2.10,1.6.3.1, 1.6.3.2, 1.6.3.3, 1.63.4, 1.6.3.5, 1.6.3.6, 1.6.3.7, 1.6.3.8, 1.6.3.9, 1.63.10, 1.6.4.1,1.6.4.2,1.6.43,1.6.4.4,1.6.4.5,1.6.4.6, 1.6.4.7, 1.6.4.8,1.6.4.9,1.6.4.10, 1.6.5.1, 1.6.5.2, 1.6.5.3,1.6.5.4,1.6.5.5,1.6.5.6, 1.6.5.7, 1.6.5.8, 1.6.5.9, 1.6.5.10, 1.6.6.1, 1.6.6.2, 1.6.6.3, 1.6.6.4, 1.6.6.5, 1.6.6.6, 1.6.6.7, 1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1, 1.6.7.2, 1.6.7.3, 1.6.7.4, 1.6.7.5, 1.6.7.6,
1.6.7.7,1.6.7.8, 1.6.7.9, 1.6.7.10, 1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4, 1.6.8.5, 1.6.8.6, 1.6.8.7, 1.6.8.8,
1.6.8.9,1.6.8.10,1.6.9.1, 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5, 1.6.9.6, 1.6.9.7, 1.6.9.8, 1.6.9.9, 1.6.9.10, 1.6.10.1,1.6.10.2, 1.6.10.3, 1.6.10.4, 1.6.10.5, 1.6.10.6, 1.6.10.7, 1.6.10.8, 1.6.10.9, 1.6.10.10, 1.7.1.1,1.7.1.2,1.7.1.3, 1.7.1.4, 1.7.1.5, 1.7.1.6, 1.7.1.7, 1.7.1.8, 1.7.1.9, 1.7.1.10, 1.7.2.1, 1.7.2.2, 1.723,1.7.24,1.72.5,1.72.6,1.72.7,1.72.8,1.7.29, 1.72.10, 1.7.3.1, 1.7.3.2, 1.7.3.3, 1.7.3.4,
1.735,1.73.6,1.73.7,1.73.8,1.7.3.9,1.7.3.10, 1.7.4.1, 1.7.4.2, 1.7.4.3, 1.7.4.4, 1.7.4.5, 1.7.4.6, 1.74.7,1.7.4.8,1.7.49,1.7.4.10,1.7.5.1,1.7.52,1.753,1.7.54, 1.7.5.5, 1.7.5.6, 1.7.5.7, 1.75.8, 1.7.59, 1.7.5.10, 1.7.6.1, 1.7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 1.7.6.6, 1.7.6.7, 1.7.6.8, 1.7.6.9, 1.7.6.10, 1.7.7.1, 1.7.7.2,1.7.73, 1.7.7.4, 1.7.7.5, 1.7.7.6, 1.7.1.7, 1.1.1.8, 1.7.7.9, 1.7.7.10, 1.7.8.1, 1.7.8.2, 1.7.8.3,1.7.8.4,1.7.8.5,1.7.8.6,1.7.8.7, 1.7.8.8, 1.7.8.9, 1.7.8.10, 1.7.9.1, 1.7.9.2, 1.7.9.3, 1.7.9.4,
1.7.95,1.7.96,1.7.9.7,1.7.9.8, 1.7.9.9, 1.7.9.10, 1.7.10.1, 1.7.10.2, 1.7.10.3, 1.7.10.4, 1.7.10.5, 1.7.10.6, 1.7.10.7, 1.7.10.8, 1.7.10.9, 1.7.10.10, 1.8.1.1, 1.8.1.2, 1.8.1.3, 1.8.1.4, 1.8.1.5, 1.8.1.6, 1.8.1.7, 1.8.1.8, 1.8.1.9, 1.8.1.10, 1.8.2.1, 1.8.2.2, 1.8.2.3, 1.8.2.4, 1.8.2.5, 1.8.2.6, 1.8.2.7, 1.8.2.8, 1.8.2.9, 1.8.2.10, 1.8.3.1, 1.8.3.2, 1.8.3.3, 1.8.3.4, 1.8.3.5, 1.8.3.6, 1.8.3.7, 1.8.3.8, 1.8.3.9, 1.8.3.10, 1.8.4.1,1.8.4.2,1.84.3,1.8.4.4,1.8.4.5,1.8.4.6, 1.8.4.7,1.8.4.8, 1.8.4.9, 1.8.4.10, 1.8.5.1, 1.8.5.2,
1.8.5.3,1.8.54,1.8.55,1.8.5.6,1.8.5.7,1.8.5.8,1.8.5.9, 1.8.5.10, 1.8.6.1, 1.8.6.2, 1.8.6.3, 1.8.6.4, 1.8.6.5, 1.8.6.6, 1.8.6.7, 1.8.6.8, 1.8.6.9, 1.8.6.10, 1.8.7.1, 1.8.7.2, 1.8.7.3, 1.8.7.4, 1.8.7.5, 1.8.7.6, : 1.8.7.7,1.8.7.8, 1.8.7.9, 1.8.7.10, 1.8.8.1, 1.8.8.2, 1.8.8.3, 1.8.8.4, 1.8.8.5, 1.8.8.6, 1.8.8.7, 1.8.8.8,
’ 1.8.8.9,1.8.8.10,1.8.9.1,1.89.2, 1.89.3, 1.8.9.4, 1.8.9.5, 1.8.9.6, 1.8.9.7, 1.8.9.8, 1.8.9.9, 1.8.9.10, 1.8:10.1,1.8.10.2, 1.8.10.3, 1.8.10.4, 1.8.10.5, 1.8.10.6, 1.8.10.7, 1.8.10.8, 1.8.10.9, 1.8.10.10,
1.9.1.1,1.9.12,1.9.1.3,1.9.1.4,1.9.1.5,1.9.1.6,19.1.7, 1.9.1.8, 1.9.1.9, 1.9.1.10, 1.9.2.1, 1.9.2.2, - 19.23,1.92.4,1.9.2.5,1.9.2.6,1.92.7,1.92.8,192.9, 1.9.2.10,1.93.1, 1.9.3.2, 1.9.33, 1.9.3.4, : 1.9.35,19.3.6,1.9.3.7,1.9.3.8,1.9.3.9,1.9.3.10,1.9.4.1,1.94.2,1.9.4.3,1.9.44,1.9.45, 1.9.4.6, 1.9.47,19.48,194.9,19.4.10,195.1,1.9.52,1.9.5.3,1.9.54,1.9.5.5,1.9.5.6,1.9.5.7,1.9.5.8, 1.9.5.9,1.9.5.10,1.9.6.1, 1.9.6.2, 1.9.6.3, 1.9.6.4, 1.9.6.5,1.9.6.6, 1.9.6.7, 1.9.6.8, 1.9.6.9, 1.9.6.10,
1.9.7.1,19.7.2,19.7.3,1.9.7.4,19.7.5,1.9.7.6, 1.9.7.7, 1.9.7.8, 1.9.7.9, 1.9.7.10, 1.9.8.1, 1.9.8.2, 1.9.83,1.9.84,1.9.8.5,1.9.8.6,1.9.8.7,1.9.8.8, 1.9.8.9, 1.9.8.10, 1.9.9.1, 1.9.9.2, 1.9.9.3, 1.9.9.4, 1.9.9.5,1.9.9.6,1.9.9.7,1.9.9.8, 1.9.9.9, 1.9.9.10, 1.9.10.1, 1.9.10.2, 1.9.10.3, 1.9.10.4, 1.9.10.5, 1.9.10.6, 1.9.10.7, 1.9.10.8, 1.9.10.9, 1.9.10.10, 1.10.1.1, 1.10.1.2, 1.10.1.3, 1.10.1 4, 1.10.1.5, 1.10.1.6, 1.10.1.7, 1.10.1.8, 1.10.1.9, 1.10.1.10, 1.10.2.1, 1.10.2.2, 1.10.2.3, 1.10.2.4, 1.10.2.5,
1.10.2.6,1.10.2.7, 1.10.2.8, 1.10.2.9, 1.10.2.10, 1.10.3.1, 1.10.3.2, 1.10.3.3, 1.10.3.4, 1.10.3.5, 1.10.3.6, 1.10.3.7, 1.10.3.8, 1.10.3.9, 1.10.3.10, 1.10.4.1, 1.10.4.2, 1.10.4.3, 1.10.44, 1.10.4.5, 1.10.4.6, 1.10.4.7, 1.10.4.8, 1.10.4.9, 1.10.4.10, 1.10.5.1, 1.10.5.2, 1.10.5.3, 1.10.5.4, 1.10.5.5, 1.10.5.6, 1.10.5.7, 1.10.5.8, 1.10.5.9, 1.10.5.10, 1.10.6.1, 1.10.6.2, 1.10.6.3, 1.10.6.4, 1.10.6.5, 1.10.6.6, 1.10.6.7, 1.10.6.8, 1.10.6.9, 1.10.6.10, 1.10.7.1, 1.10.7.2, 1.10.7.3, 1.10.7.4, 1.10.7.5,
1.10.7.6,1.10.7.7,1.10.7.8, 1.10.7.9, 1.10.7.10, 1.10.8.1, 1.10.8.2, 1.10.8.3, 1.10.8.4, 1.10.8.5,
1.10.8.6,1.10.8.7, 1.10.8.8, 1.10.8.9, 1.10.8.10, 1.10.9.1, 1.10.9.2, 1.10.9.3, 1.10.94, 1.10.9.5, 1.10.9.6, 1.10.9.7, 1.10.9.8, 1.10.9.9, 1.10.9.10, 1.10.10.1, 1.10.10.2, 1.10.10.3, 1.10.10.4, 1.10.10.5, 1.10.10.6, 1.10.10.7, 1.10.10.8, 1.10.10.9, 1.10.10.10, 2.1.1.1, 2.1.1.2, 2.1.1.3, 2.1.1 4, 2.1.1.5,2.1.1.6,2.1.1.7,2.1.1.8,2.1.1.9,2.1.1.10,2.1.2.1,2.1.2.2,2.1.2.3, 2.1.2.4, 2.1.2.5, 2.12.6,
21.27,2.128,2.129,2.12.10,2.13.1,2.1.3.2,2.1.33,2.1.34,2.13.5,2.1.3.6,2.13.7, 2.13 8, 2.1.3.9,2.13.10,2.1.4.1,2.1.4.2, 2.1.4.3, 2.1.4.4, 2.1.4.5, 2.1.4.6, 2.1.4.7, 2.1.4.8, 2.1.4.9, 2.1 4.10, 2.1.5.1,2.15.2,2.1.5.3,2.1.5.4,2.1.5.5,2.1.5.6,2.1.5.7,2.1.5.8, 2.1.5.9, 2.1.5.10, 2.1.6.1, 2.1.6.2, 2.1.6.3,2.1.6.4,2.1.6.5,2.1.6.6,2.1.6.7,2.1.6.8,2.1.6.9, 2.1.6.10,2.1.7.1,2.1.7.2, 2.1.7.3, 2.1.7.4, 2.1.7.5,2.1.7.6,2.1.7.7,2.1.7.8,2.1.7.9,2.1.7.10,2.1.8.1,2.1.8.2, 2.1.8.3, 2.1.8.4, 2.1.8.5, 2.1.8.6,
2.1.8.7,2.1.8.8,2.1.8.9,2.1.8.10,2.1.9.1,2.1.9.2,2.1.9.3,2.1.9.4, 2.1.9.5, 2.1.9.6, 2.1.9.7, 2.1.9.8, 2.1.9.9,2.1.9.10, 2.1.10.1,2.1.10.2, 2.1.10.3, 2.1.10.4, 2.1.10.5, 2.1.10.6, 2.1.10.7, 2.1.10.8, 2.1.10.9,2.1.10.10,2.2.1.1,2.2.1.2,2.2.1.3,2.2.1.4,2.2.1.5,2.2.1.6, 2.2.1.7, 2.2.1.8, 2.2.1.9, 22.1.10,2.2.2.1,222.2,22.2.3,2.2.2.4,2.2.2.5,2.2.2.6,22.2.7,2.2.2.8,2.2.2.9,2.2.2.10, 2.2.3.1, 223.2,223.3,2234,223.5,223.6,223.7,2.2.3.8,2239,223.10,2.2.4.1,2.2.42, 2.2.43,
22.4.4,2245,2246,22.4.7,22.4.8,2249,224.10,225.1,2.2.5.2,2.2.53,2.2.5.4, 2.2.5.5, 2.2.5.6,2.2.5.7,2.2.5.8,2.2.59,2.2.5.10,2.2.6.1, 2.2.6.2, 2.2.6.3, 2.2.6.4, 2.2.6.5, 2.2.6.6, 2.2.6.7, 22.6.8,2.2.69,2.26.10,2.2.7.1,2.2.7.2,2.2.73,2.2.74,22.7.5,2.2.7.6,2.2.1.7,2.2.7.8,2.2.7.9, 22.7.10,2.2.8.1,2.2.8.2,2.2.8.3,2.2.8.4,2.2.8.5,2.2.8.6,2.2.8.7,2.2.8.8,2.2.8.9, 2.2.8.10, 2.2.9.1, : 2292,2293,2294,2.295,22.9.6,2.2.9.7,2.2.9.8,2.2.9.9,2.2.9.10,2.2.10.1, 2.2.10.2,
22.103,22.10.4,2.2.10.5,2.2.10.6, 2.2.10.7, 2.2.10.8, 2.2.10.9, 2.2.10.10, 2.3.1.1, 2.3.1.2, 23.13,23.14,23.15,23.1.6,23.1.7, 2.3.1.8, 23.19, 2.3.1.10, 2.3.2.1,2.3.2.2, 2.3.2.3, 2.3.2.4, 23.2.5,23.2.6,232.7,2.328,23.2.9,23.2.10,23.3.1,23.3.2,2.3.3.3,2.33.4,2.33.5,2.3.3.6, 23.3.7,2.33.8,233.9,2.3.3.10,2.3.4.1,2.3.42,2.3.43,2.3.4.4,2.3.45,2.3.4.6,2.3.4.7,2.3.4.8, 2.3.4.9,2.3.4.10,23.5.1,2.3.5.2,2.3.5.3,2.3.5.4,23.5.5,23.5.6,2.3.5.7, 2.3.5.8, 2.3.5.9, 2.3.5.10,
23.6.1,2.3.6.2,2.3.63,2.3.6.4,23.6.5,23.6.6,23.6.7,23.6.8,23.6.9,2.3.6.10,2.3.7.1, 23.7.2, 23.7.3,2.3.74,23.7.5,2.3.7.6,2.3.7.7,2.3.7.8,23.79,23.7.10,2.3.8.1,2.3.8.2, 2.3.83, 2.3.8.4, 2.3.8.5,2.3.8.6,2.3.8.7,2.3.8.8, 2.3.8.9, 2.3.8.10,2.3.9.1, 2.3.9.2, 2.3.9.3, 2.3.9.4, 2.3.9.5, 2.3.9.6, 2.3.9.7,2.3.9.8,2.399,2.3.9.10,2.3.10.1,2.3.10.2, 2.3.10.3, 2.3.10.4, 2.3.10.5, 2.3.10.6, 2.3.10.7, 2.3.10.8,2.3.10.9, 23.10.10, 2.4.1.1, 2.4.1.2, 2.4.1.3, 2.4.1.4, 2.4.1.5, 2.4.1.6, 2.4.1.7, 2.4.1.8,
24.19,24.1.10,24.2.1,2.422,2.423,24.2.4,2.4.2.5,2.4.2.6,2.4.2.7,2.4.2.8, 2.4.2.9, 2.4.2.10, 2.4.3.1,2.432,2433,24.34,2.4.3.5,243.6,243.7,243.8,2.4.3.9,2.4.3.10,2.4.4.1,2.4.4.2, 24.43,2444,244.52446,244.7,2.44.8,24.49,24.4.10,24.5.1,24.5.2,2.4.53,2.4.5.4, 2.4.55,2.4.5.6,2.45.7,2.4.5.8,2.4.5.9,2.45.10,2.4.6.1,2.4.62,24.6.3,2.4.6.4,2.4.6.5,2.4.6.6, 2.4.6.7,2.4.6.8,2.4.69,2.4.6.10,2.4.7.1,2.4.7.2,24.73,2.4.74,2.4.7.5,2.4.7.6, 2.4.7.7, 2.4.7.8,
24.79,24.7.10,2.4.8.1,2.4.8.2, 2.4.8.3, 2.4.8.4, 2.4.8.5, 2.4.8.6, 2.4.8.7, 2.4.8.8, 2.4.8.9, 2.4.8.10,
* »
249.1,2492,249.3,2494,24.95,24.9.6,249.7,2.4.9.8,2.49.9, 2.49.10, 2.4.10.1, 2.4.10.2,2.4.10.3,2.4.10.4, 2.4.10.5, 2.4.10.6, 2.4.10.7, 2.4.10.8, 2.4.10.9, 2.4.10.10, 2.5.1.1, 2.5.12,2.51.3,2.5.1.4,25.1.5,2.5.1.6,2.5.1.7,2.5.1.8, 2.5.1.9, 2.5.1.10, 2.5.2.1, 2.5.2.2, 2.5.2.3, 25.24,2525,252.6,25.2.7,252.8,2.52.9,25.2.10,2.53.1,2.5.3.2,2.5.3.3,2.5.3.4,253.5,
2536,253.7,2.53.8,2.539,253.10,2.54.1,2.54.2,2.54.3,2.5.4.4,2.5.45,2.54.6,2.54.7, 2.54.8,254.9, 2.5.4.10, 2.5.5.1,2.5.52,2.5.53,2.554,2.5.5.5,2.5.5.6, 2.5.5.7, 2.5.5.8, 2.5.5.9, 2.55.10,2.5.6.1,2.5.6.2,2.5.6.3,2.5.6.4,2.5.6.5,2.5.6.6,2.5.6.7,2.5.6.8, 2.5.6.9, 2.5.6.10, 2.5.7.1, 25.72,25.73,2.5.7.4,25.7.5,25.76,2.5.7.7,2.5.1.8,2.5.79,2.5.7.10,2.5.8.1,2.5.8.2,2.5.8.3, 2.5.8.4,2.58.5,2.5.8.6,2.5.8.7,2.5.8.8,2.5.89,2.5.8.10,2.59.1,2.59.2,2.59.3,2.59.4,2.5.9.5,
2.59.6,2.59.7,2.59.8,2.5.99,2.59.10,2.5.10.1,2.5.10.2, 2.5.10.3, 2.5.10.4, 2.5.10.5, 2.5.10.6, 2.5.10.7,2.5.10.8,2.5.10.9,2.5.10.10,2.6.1.1,2.6.1.2,2.6.1.3,2.6.1.4,2.6.1.5,2.6.1.6,2.6.1 7, 2.6.1.8,2.6.1.9,2.6.1.10,2.6.2.1,2.6.2.2,2.6.2.3,2.6.2.4,2.6.2.5,2.6.2.6, 2.6.2.7,2.6.2.8, 2.6.2.9, 2.6.2.10,2.6.3.1,2.6.3.2,2.6.3.3,2.6.3.4,2.6.3.5,2.6.3.6,2.6.3.7,2.6.3.8, 2.6.3.9,2.6.3.10, 2.6.4.1, 2.64.2,2.6.43,2.6.44,2.64.5,2.6.4.6,2.6.4.7,2.6.4.8,2.64.9,2.6.4.10,2.6.5.1,2.6.5.2,2.6.5.3,
2.6.5.4,2.6.5.5,2.6.5.6,2.6.5.7,2.6.5.8,2.6.5.9,2.6.5.10, 2.6.6.1, 2.6.6.2, 2.6.6.3, 2.6.6.4, 2.6.6.5,
2.6.6.6,2.6.6.7,2.6.6.8,2.6.6.9,2.6.6.10,2.6.7.1,2.6.7.2,2.6.7.3, 2.6.7.4, 2.6.7.5, 2.6.7.6, 2.6.7.7, : 2.6.7.8,2.6.7.9,2.6.7.10,2.6.8.1,2.6.8.2,2.6.8.3,2.6.8.4,2.6.8.5, 2.6.8.6,2.6.8.7,2.6.8.8,2.6.89, :
’ 2.6.8:10,2.6.9.1,2.6.9.2,2.6.9.3,2.6.9.4,2.6.9.5,2.6.9.6, 2.6.9.7, 2.6.9.8, 2.6.9.9, 2.6.9.10, 2.6.10.1, 2.6.10.2, 2.6.10.3, 2.6.10.4, 2.6.10.5, 2.6.10.6, 2.6.10.7, 2.6.10.8, 2.6.10.9, 2.6.10.10, y }
. 20 2.7.1.1,2.7.1.2,2.7.1.3,2.7.1.4, 2.7.1.5, 2.7.1.6, 2.7.1.7, 2.7.1.8, 2.7.1.9, 2.7.1.10, 2.7.2.1, 2.7.2.2, 2.72.3,2.7.2.4,2.72.5,2.72.6,27.2.7,2.7.2.8,2.7.2.9,2.7.2.10, 2.7.3.1, 2.73.2,2.7.3.3,2.73 4, 2.7.3.5,2.73.6,2.7.3.7,2.7.3.8,2.7.39,2.7.3.10,2.7.4.1,2.7.4.2, 2.74.3, 2.7.4 4, 2.7.4.5, 2.7.4.6, : 2.74.7,2.74.8,2.7.49,2.7.4.10,2.75.1,2.7.5.2,2.7.5.3,2.7.5.4, 2.7.5.5, 2.7.5.6, 2.7.5.7, 2.7.5.8, 2.7.5.9,2.7.5.10,2.7.6.1,2.7.6.2,2.7.6.3,2.7.6.4,2.7.6.5, 2.7.6.6, 2.7.6.7,2.7.6.8, 2.7.6.9, 2.7.6.10,
27.7.1,2.7.72,2.7.73,27.74,2.7.1.5,2.7.7.6,2.7.7.7,2.7.7.8,2.7.79, 2.7.7.10, 2.7.8.1, 2.7.8.2, 2.7.83,2.7.84,2.7.8.5,2.7.86,2.7.8.7,2.7.8.8,2.7.8.9,2.7.8.10,2.79.1,2.7.92,2.79.3, 2.79.4, 2.79.5,2796,2.7.9.7,2.7.9.8,2.7.9.9,2.7.9.10,2.7.10.1, 2.7.10.2, 2.7.10.3, 2.7.10.4, 2.7.10.5, 2.7.10.6,2.7.10.7,2.7.10.8, 2.7.10.9,2.7.10.10, 2.8.1.1, 2.8.1.2, 2.8.1.3,2.8.1.4, 2.8.1.5, 2.8.1.6, 2.8.1.7,2.8.1.8,2.8.1.9,2.8.1.10,2.82.1,2.82.2,2.8.2.3,2.8.2.4,2.8.2.5,2.8.2.6,2.8.2.7,2.8.2.8,
2.8.2.9,2.8.2.10,2.8.3.1,2.8.3.2,2.83.3,2.8.3.4,2.8.3.5,2.8.3.6,2.8.3.7,2.8.3.8,2.8.3.9, 2.83.10, 2.8.4.1,2.84.2,2.8.4.3,2.8.44,2.8.45,2.84.6,2.84.7,2.8.4.8,2.8.4.9,2.84.10,2.8.5.1,2.85.2, 2.8.5.3,2.8.5.4,2.8.5.5,2.8.5.6,2.8.5.7,2.8.5.8,2.8.5.9,2.8.5.10, 2.8.6.1, 2.8.6.2, 2.8.6.3, 2.8.6.4, 2.8.6.5,2.8.6.6,2.8.6.7,2.8.6.8, 2.8.6.9,2.8.6.10,2.8.7.1, 2.8.7.2, 2.8.7.3, 2.8.7.4, 2.8.7.5, 2.8.7.6, 2.8.7.7,2.8.7.8,2.8.7.9,2.8.7.10,2.8.8.1, 2.8.8.2, 2.8.8.3, 2.8.8 4, 2.8.8.5, 2.8.8.6, 2.8.8.7, 2.8.8.8,
2.8.89,2.8.8.10,2.89.1,2.89.2,2.89.3,2.8.9.4,2.89.5,2.8.9.6,2.8.9.7,2.8.9.8,2.8.9.9,2.8.9.10,
2.8.10.1,2.8.10.2, 2.8.10.3, 2.8.10.4, 2.8.10.5, 2.3.10.6, 2.8.10.7, 2.8.10.8, 2.8.10.9, 2.8.10.10, 29.1.1,2.9.1.2,2.9.1.3,2.9.1.4,29.1.5,2.9.1.6,2.9.1.7, 2.9.1.8,2.9.1.9, 2.9.1.10, 2.9.2.1, 2.9.2.2, 29.2.3,2.9.2.4,2.92.5,292.6,29.2.7,2.9.2.8,2.9.2.9,29.2.10,2.93.1,293.2,293.3,293 4, 2.93.5,2.93.6,2.9.3.7,2.9.3.8,2.9.3.9,29.3.10,2.9.4.1,2.9.4.2,2.9.4.3,2.9.4.4,2.9.4.5, 2.9.4.6,
204.7,29.4.8,29.49,29.410,295.1,29.52,2953,29.54,29.5.5,29.5.6,29.5.7,2.9.5.8, 2.9.5.9,2.9.5.10,2.9.6.1,2.9.62,2.9.6.3,2.9.6.4, 2.9.6.5, 2.9.6.6, 2.9.6.7, 2.9.6.8, 2.9.6.9, 2.9.6.10, 2.9.7.1,29.72,29.13,29.74,29.1.5,29.7.6,29.1.7,29.78,2.9.7.9,2.9.7.10,2.9.8.1, 2.9.8.2, 2.9.8.3,2.9.8.4,2.9.8.5,29.8.6,2.9.8.7,2.9.8.8,2.9.8.9,2.9.8.10,2.9.9.1,2.9.9.2, 2.9.9.3, 2.9.9.4, 29.9.5,299.6,2997,299.8,2999,299.10,29.10.1,29.10.2,2.9.10.3,2.9.10.4,2.9.10.5,
2.9.10.6,2.9.10.7,2.9.10.8, 2.9.10.9, 2.9.10.10, 2.10.1.1,2.10.1.2,2.10.1.3, 2.10.1.4, 2.10.15, 2.10.1.6,2.10.1.7,2.10.1.8, 2.10.19, 2.10.1.10, 2.10.2.1,2.10.2.2,2.10.2.3, 2.10.2.4, 2.10.2.5, 2.10.2.6,2.10.2.7,2.10.2.8,2.10.2.9,2.10.2.10,2.103.1,2.10.3.2,2.10.3.3,2.10.3.4,2.10.3.5, 2.10.3.6,2.10.3.7,2.10.3.8, 2.10.3.9, 2.103.10,2.10.4.1,2.10.4.2, 2.10.4.3, 2.10.4.4, 2.10.4.5, 2.10.4.6,2.10.4.7,2.10.4.8, 2.10.49, 2.10.4.10, 2.10.5.1, 2.10.5.2, 2.10.5.3, 2.10.5.4, 2.10.5.5,
2.10.5.6,2.10.5.7,2.10.5.8, 2.10.5.9, 2.10.5.10, 2.10.6.1, 2.10.6 2, 2.10.6.3, 2.10.6.4, 2.10.6.5, 2.10.6.6, 2.10.6.7, 2.10.6.8, 2.10.6.9, 2.10.6.10, 2.10.7.1, 2.10.7.2, 2.10.7.3, 2.10.74, 2.10.7.5, 2.10.7.6,2.10.7.7, 2.10.7.8, 2.10.7.9, 2.10.7.10, 2.10.8.1, 2.10.8.2, 2.10.8 3, 2.10.8.4, 2.10.8.5, 2.10.8.6,2.10.8.7, 2.10.8.8, 2.10.8.9, 2.10.8.10, 2.10.9.1, 2.10.9.2, 2.10.9.3, 2.10.9.4, 2.10.9.5, : 2.10.9.6,2.10.9.7, 2.10.9.8, 2.10.9.9, 2.10.9.10, 2.10.10.1, 2.10.10.2, 2.10.10.3, 2.10.10.4,
2.10.10.5,2.10.10.6, 2.10.10.7, 2.10.10.8, 2.10.10.9, 2.10.10.10, 3.1.1.1, 3.1.1.2, 3.1.1.3, 3.1.14, 3.1.15,3.1.1.6,3.1.1.7, 3.1.1.8, 3.1.1.9, 3.1.1.10,3.1.2.1,3.1.2.2, 3.1.2.3, 3.1.2.4, 3.1.2.5, 3.1.2.6, 3.12.7,3.1.2.8,3.1.29,3.1.2.10,3.1.3.1,3.1.3.2,3.1.3.3,3.1.3.4, 3.1.3.5, 3.1.3.6, 3.1.3.7, 3.1.3.8, 3.13.9,3.13.10,3.1.4.1,3.1.42,3.1.43,3.1.44,3.1.4.5,3.1.4.6,3.1.4.7,3.1.4.8, 3.1.4.9, 3.14.10, 3.15.1,3.1.5.2,3.1.53,3.1.5.4, 3.1.5.5, 3.1.5.6, 3.1.5.7, 3.1.5.8,3.1.5.9,3.1.5.10, 3.1.6.1, 3.1.6.2,
3.1.63,3.1.6.4,3.1.6.5,3.1.6.6,3.1.6.7,3.1.6.8,3.1.6.9, 3.1.6.10, 3.1.7.1,3.1.7.2,3.1.7.3, 3.1.7.4, 3.1.75,3.1.76,3.1.7.7,3.1.7.8,3.1.7.9, 3.1.7.10,3.1.8.1, 3.1.8.2, 3.1.8.3, 3.1.8.4, 3.1.8.5, 3.1.8.6, 3.1.8.7,3.1.8.8,3.1.89,3.1.8.10,3.1.9.1,3.1.9.2,3.1.9.3,3.1.9.4, 3.1.9.5, 3.1.9.6, 3.1.9.7, 3.1.9.3, 3.1.9.9,3.1.9.10,3.1.10.1,3.1.10.2, 3.1.10.3, 3.1.10.4, 3.1.10.5, 3.1.10.6, 3.1.10.7, 3.1.10.8,
3.1.109,3.1.10.10,3.2.1.1,3.2.12,3.2.1.3,3.2.1.4,3.2.1.5,3.2.1.6,3.2.1.7, 3.2.1 8, 3.2.1.9,
32.1.10,3.2.2.1,3.22.2,3.22.3,32.2.4,3.22.5,32.2.6,3.2.2.7,3.2.2.8,3.2.2.9,32.2.10, 3.2.3.1,
32.3.2,32.33,3234,32.3.5,3.23.6,3.23.7,323.8,3.239,3.23.10,3.2.4.1,3.2.42,3.2.43, 3.2.4.4,32.4.5,3.2.4.6,3.2.4.7,32.48,32.4.9,32.410,325.1,32.52,3253,3254,32.55, 3.2.5.6,3.2.5.7,3.2.5.8,3.2.5.9, 3.2.5.10,3.2.6.1,3.2.6.2,32.63,32.6.4,3.2.6.5,3.2.6.6,3.2.6 7, 3.2.6.8,3.2.6.9,3.2.6.10,3.2.7.1,3.2.7.2,3.2.7.3,3.2.74,32.75,3.2.7.6,3.2.7.7,3.2.7.8,3.2.79, 3.2.7.10,3.2.8.1,3.2.8.2,3.2.83,3.2.8.4,3.2.8.5,3.2.8.6,32.8.7,3.2.8.8,3.2.8.9,3.2.8.10, 3.2.9.1,
LX ¥ 3.2.92,3.2.9.3,3.2.9.4,32.9.5,3.2.9.6,3.2.9.7,3.2.9.8,3.2.9.9,3.2.9.10, 3.2.10.1, 3.2.10.2, 3.2.103,3.2.10.4, 3.2.10.5, 3.2.10.6, 3.2.10.7, 3.2.10.8, 3.2.10.9, 3.2.10.10, 3.3.1.1,3.3.1.2, 33.13,3.3.1.4,33.1.5,3.3.1.6,3.3.1.7, 3.3.1.8, 3.3.1.9, 3.3.1.10, 3.3.2.1, 3.3.2.2, 3.3.2.3, 3.3.2.4, 3.3.2.5,3.3.2.6,3.3.2.7,3.3.2.8,3.3.2.9, 3.3.2.10, 3.3.3.1, 3.3.3.2, 3.3.3.3, 3.3.3.4,3.3.3.5, 3.3.3.6, 33.3.7,333.8,333.9,3.33.10,33.4.1,33.4.2,334.3,33.44,33.4.5,33.4.6,33.4.7,33438, 3.3.4.9,3.3.4.10,3.3.5.1,3.3.5.2, 3.3.5.3, 3.3.5.4,3.3.5.5, 3.3.5.6, 3.3.5.7,3.3.5.8, 3.3.5.9, 3.3.5.10, 3.3.6.1,3.3.62,33.63,3.3.6.4,33.6.5,3.3.6.6,3.3.6.7,3.3.6.8,3.3.69,3.3.6.10,3.3.7.1,3.3.7.2, 3.3.73,3.3.7.4,33.7.5,3.3.7.6,3.3.7.7,33.7.8,3.3.7.9,3.3.7.10, 3.3.8.1,3.3.8.2, 3.3.8.3, 3.3.8 4, 3.3.8.5, 3.3.8.6, 3.3.8.7, 3.3.8.8, 3.3.8.9, 3.3.8.10, 3.3.9.1, 3.3.9.2, 3.3.9.3,3.3.9.4,33.9.5, 3.3.9.6, 3.3.9.7,3.3.9.8,3.3.9.9,3.3.9.10, 3.3.10.1,3.3.10.2, 3.3.10.3, 3.3.10.4, 3.3.10.5, 3.3.10.6, 3.3.10.7, 3.3.10.8,3.3.10.9,3.3.10.10, 3.4.1.1, 3.4.1.2, 3.4.1.3, 3.4.1.4,3.4.1.5,3.4.1.6,3.4.1.7,3.4.1.8, 3.4.1.9,3.4.1.10,3.4.2.1,3.42.2,3.4.23,3.42.4,3.42.5,3.4.2.6,3.42.7,3.4.2.8,3.4.2.9, 3.4.2.10, 3.43.1,3.43.2,3.43.3,3.43.4,343.5,3.4.3.6,3.4.3.7,3.4.3.8,3.4.3.9,3.43.10,3.4.4.1,3.4 4.2, 3.443,3.4.4.4,34.45,3.44.6,34.4.7,3.4.48,3.4.49,3.44.10,3.4.5.1,3.4.52,3.4.5.3,3.4.54, 1S 3.455,3.45.6,3.4.5.7,3.4.5.8,3.4.59,3.4.5.10,3.4.6.1,3.4.6.2,3.4.6.3,3.4.64,3.4.6.5,3.4.6.6, 3.4.6.7,3.4.6.8,3.4.6.9,3.4.6.10,34.7.1,3.4.7.2,3.4.7.3,3.4.74,3.4.7.5,3.4.7.6,3.4.7.7, 3.4.1.8, 3.4.7.9, 3.47.10, 3.4.8.1,3.4.8.2, 3.4.8.3, 3.4.8.4, 3.4.8.5, 3.4.8.6, 3.4.8.7, 3.4.8.8, 3.4.8.9, 3.4.8.10, ’ 3.49.1,3.492,3.49.3,3.49.4,3.49.5,3.4.96,3.49.7,3.4.9.8,3.4.99, 3.49.10, 3.4.10.1, : 3.4.10:2,3.4.10.3, 3.4.10.4, 3.4.10.5, 3.4.10.6, 3.4.10.7, 3.4.10.8, 3.4.10.9, 3.4.10.10, 3.5.1.1,
Co 20 3.5.12,3.5.1.3,3.5.1.4,3.5.1.5,3.5.1.6,3.5.1.7, 3.5.1.8, 3.5.1.9, 3.5.1.10, 3.5.2.1, 3.5.2.2,3.5.2.3, - : 3.52.4,3.525,3.52.6,3.52.7,3.5.2.8,3.5.2.9,3.5.2.10,3.5.3.1,3.5.3.2,3.5.3.3,3.5.3.4, 3.5.3.5, 3.5.3.6,3.53.7,3.5.3.8,3.53.9,3.5.3.10,3.5.4.1,3.54.2,3.54.3,3.5.4.4,3.5.4.5,3.5.4.6,3.54.7, : 354.8,3.549,3.54.10,3.55.1,3.5.5.2,3.5.5.3,3.5.5.4,3.5.5.5,3.5.5.6,3.55.7,3.5.5.8,3.55.9, 3.5.5.10,3.5.6.1, 3.5.6.2, 3.5.6.3, 3.5.6.4, 3.5.6.5, 3.5.6.6, 3.5.6.7, 3.5.6.8, 3.5.6.9, 3.5.6.10, 3.5.7.1, 3.572,3573,3.5.7.4,3.5.75,3.57.6,3.5.7.7,3.5.7.8,3.5.79,3.5.7.10,3.5.8.1,3.5.8.2, 3.5.8.3, 3.58.4,3.585,3.5.8.6,3.5.8.7,3.5.8.8,3.5.8.9,3.5.8.10,3.5.9.1,3.5.9.2,3.59.3,3.5.9.4,3.5.9.5, 3.5.9.6, 3.5.9.7,3.5.9.8,3.5.9.9,3.5.9.10,3.5.10.1, 3.5.10.2, 3.5.10.3, 3.5.10.4, 3.5.10.5, 3.5.10.6, 3.5.10.7, 3.5.10.8, 3.5.10.9, 3.5.10.10,3.6.1.1,3.6.1.2, 3.6.1.3, 3.6.1.4, 3.6.1.5, 3.6.1.6, 3.6.1.7, 3.6.1.8, 3.6.1.9, 3.6.1.10, 3.6.2.1, 3.6.2.2, 3.6.2.3,3.6.2.4, 3.6.2.5, 3.6.2.6, 3.6.2.7, 3.6.2.8, 3.6.2.9, 3.6.2.10,3.6.3.1,3.6.3.2,3.6.3.3,3.6.3.4,3.6.3.5,3.6.3.6,3.6.3.7,3.6.3.8,3.6.3.9,3.6.3.10,3.6 4.1, 3.6:42,3.6.43,3.6.4.4,3.64.5,3.6.46,3.6.4.7,3.6.48,3.6.49,3.6.4.10,3.6.5.1,3.6.5.2,3.6.53, 3.6.5.4, 3.6.5.5,3.6.5.6,3.6.5.7, 3.6.5.8, 3.6.5.9, 3.6.5.10, 3.6.6.1, 3.6.6.2, 3.6.6.3, 3.6.6.4, 3.6.6.5, 3.6.6.6, 3.6.6.7, 3.6.6.8, 3.6.6.9, 3.6.6.10, 3.6.7.1, 3.6.7.2, 3.6.7.3, 3.6.7.4, 3.6.7.5, 3.6.7.6, 3.6.7.7, 3.6.7.8,3.6.7.9,3.6.7.10, 3.6.8.1, 3.6.8.2, 3.6.8.3,3.6.8.4, 3.6.8.5, 3.6.8.6, 3.6.8.7, 3.6.8.8, 3.6.8.9, 3.6.8.10,3.6.9.1,3.6.9.2,3.6.9.3,3.6.9.4,3.6.9.5,3.6.9.6,3.6.9.7, 3.6.9.8, 3.6.9.9, 3.6.9.10,
* Ee
3.6.10.1,3.6.10.2, 3.6.10.3, 3.6.10.4, 3.6.10.5, 3.6.10.6, 3.6.10.7, 3.6.10.8, 3.6.10.9, 3.6.10.10, 3.7.1.1,3.7.1.2,3.7.1.3,3.7.1.4, 3.7.1.5, 3.7.1.6, 3.7.1.7,3.7.1.8, 3.7.1.9, 3.7.1.10, 3.7.2.1,3.7.2.2, 3.72.3,3.7.2.4,3.72.5,3.72.6,3.7.2.7,3.7.2.8, 3.72.9,3.7.2.10,3.73.1,3.7.3.2, 3.7.3.3, 3.734, 3.73.5,3.7.3.6,3.7.3.7,3.7.3.8,3.7.3.9,3.7.3.10,3.7.4.1,3.74.2,3.74.3,3.7.4.4,3.7.4.5, 3.7.4.6, 3747,3.74.8,3749,3.74.10,3.75.1,3.7.5.2,3.7.53,3.7.5.4,3.7.5.5,3.7.5.6,3.7.5.7, 3.7.5.8, 3.7.5.9,3.7.5.10,3.7.6.1,3.7.6.2,3.7.6.3,3.7.6.4, 3.7.6.5, 3.7.6.6, 3.7.6.7,3.7.6.8, 3.7.6.9, 3.7.6.10, 3.7.7.1,3.7.7.2,3.17.3,3.7.74,3.7.7.5, 3.7.7.6, 3.7.7.7,3.7.7.8, 3.7.7.9, 3.7.7.10, 3.7.8.1, 3.7.8.2, 3.7.8.3,3.7.8.4,3.7.8.5,3.7.8.6,3.7.8.7,3.7.8.8,3.7.8.9,3.7.8.10,3.7.9.1,3.7.9.2,3.7.9.3, 3.7.9.4, 3.7.9.5,3.7.9.6,3.79.7,3.7.9.8,3.7.9.9,3.7.9.10,3.7.10.1,3.7.10.2, 3.7.10.3, 3.7.10.4, 3.7.10.5,
3.7.10.6,3.7.10.7,3.7.10.8,3.7.10.9, 3.7.10.10, 3.8.1.1, 3.8.1.2, 3.8.1.3, 3.8.1.4, 3.8.1.5, 3.8.1.6, 3.8.1.7,3.8.1.8,3.8.1.9,3.8.1.10,3.8.2.1,3.8.2.2,3.8.2.3,3.8.2.4,3.8.2.5,3.8.2.6, 3.8.2.7, 3.8.2.8, 3.8.2.9,3.8.2.10,3.8.3.1,3.8.3.2,3.8.3.3,3.8.3.4,3.8.3.5,3.8.3.6,3.8.3.7,3.8.3.8, 3.8.3.9, 3.8.3.10, 3.84.1,3.8.4.2,3.843,3.8.4.4,3.84.5,3.8.4.6,3.84.7,3.84.8,3.8.4.9,3.8.4.10, 3.8.5.1, 3.8.5.2, 3.8.5.3,3.8.5.4,3.85.5,3.8.5.6,3.8.5.7,3.8.5.8,3.8.5.9,3.8.5.10, 3.8.6.1, 3.8.6.2, 3.8.6.3, 3.8.6.4,
3.8.6.5,3.8.6.6,3.8.6.7,3.8.6.8,3.8.6.9,3.8.6.10,3.8.7.1,3.8.7.2,3.8.7.3, 3.8.7.4, 3.8.7.5, 3.8.7.6, 3.8.7.7,3.8.7.8,3.8.7.9, 3.8.7.10, 3.8.8.1, 3.8.8.2, 3.8.8.3, 3.8.8.4, 3.8.8.5, 3.8.8.6, 3.8.8.7, 3.8.8.8, 3.8.8.9,3.8.8.10,3.8.9.1,3.8.9.2,3.8.9.3,3.8.9.4,3.8.9.5, 3.8.9.6, 3.8.9.7, 3.8.9.8, 3.8.9.9, 3.8.9.10, 3.8.10.1,3.8.10.2,3.8.10.3, 3.8.10.4, 3.8.10.5, 3.8.10.6, 3.8.10.7, 3.8.10.8, 3.8.10.9, 3.8.10.10, 3.9.1.1,3.9.1.2,3.9.1.3,3.9.1.4,3.9.1.5,3.9.1.6,3.9.1.7,3.9.1.8, 3.9.1.9, 3.9.1.10, 3.9.2.1, 3.9.2.2,
3.9.23,3.9.24,392.5,3.9.2.6,3.9.2.7,3.9.2.8,3.9.2.9,3.9.2.10,3.9.3.1,3.9.3.2, 3.9.3.3, 3.9.3.4, 3.9.3.5,3.9.3.6,3.9.3.7,3.9.3.8, 3.9.3.9, 3.93.10, 3.9.4.1,3.9.4.2,3.9.4.3,3.9.4.4,3.9.4.5,3.9.4.6, 39.4.7,3.9.4.8,3.94.9,3.9.4.10,39.5.1,3.9.5.2,3.9.5.3,3.9.5.4,3.9.5.5,3.9.5.6,3.9.5.7,3.9.5.8, 3.9.5.9,3.9.5.10,3.9.6.1,3.9.6.2,3.9.6.3, 3.9.6.4, 3.9.6.5, 3.9.6.6, 3.9.6.7,3.9.6.8, 3.9.6.9, 3.9.6.10, 3.9.7.1,3.9.7.2,39.73,3.9.7.4,3.9.7.5,39.7.6,3.9.7.7,3.9.7.8,3.9.7.9, 3.9.7.10, 3.9.8.1, 3.9.8.2,
3.9.8.3,3.9.8.4,3.9.8.5,3.9.8.6,3.9.8.7,3.9.8.8,3.9.8.9,3.9.8.10,3.9.9.1,3.9.9.2,3.9.9.3,3.9.9.4, 3.9.9.5,3.99.6,3.99.7,3.9.9.8,3.9.9.9,3.9.9.10,3.9.10.1,3.9.10.2, 3.9.10.3, 3.9.10.4, 3.9.10.5, 3.9.10.6,3.9.10.7,3.9.10.8, 3.9.10.9, 3.9.10.10, 3.10.1.1, 3.10.1.2, 3.10.1.3, 3.10.1 4, 3.10.1.5, 3.10.1.6.3.10.1.7, 3.10.1.8, 3.10.1.9, 3.10.1.10. 3.10.2.1, 3.10.2.2. 3.10.2.3, 3.10.2 4, 3.10.2.5, 3.10.2.6,3.10.2.7,3.10.2.8, 3.10.2.9, 3.10.2.10, 3.10.3.1, 3.10.3.2, 3.10.3.3, 3.10.3.4, 3.10.3.5,
3.10.3.6,3.10.3.7,3.10.3.8, 3.10.3.9, 3.10.3.10, 3.10.4.1,3.10.4.2, 3.10.4.3, 3.10.4.4, 3.10.4.5, 3.104.6,3.10.4.7,3.10.4.8,3.10.4.9,3.10.4.10, 3.10.5.1, 3.10.5.2, 3.10.5.3, 3.10.5.4, 3.10.5.5, 3.10.5.6,3.10.5.7,3.10.5.8,3.10.5.9, 3.10.5.10, 3.10.6.1, 3.10.6.2, 3.10.6.3, 3.10.6.4, 3.10.6.5, 3.10.6.6,3.10.6.7,3.10.6.8, 3.10.6.9, 3.10.6.10, 3.10.7.1, 3.10.7.2, 3.10.7.3, 3.10.7.4, 3.10.7.5, 3.10.7.6,3.10.7.7, 3.10.7.8, 3.10.7.9, 3.10.7.10, 3.10.8.1, 3.10.8.2, 3.10.8.3, 3.10.8.4, 3.10.8.5,
3.10.8.6,3.10.8.7,3.10.8.8, 3.10.8.9, 3.10.8.10, 3.10.9.1, 3.10.9.2, 3.10.9.3, 3.10.9.4, 3.10.9.5,
“® v
3.10.9.6,3.10.9.7,3.10.9.8, 3.10.9.9, 3.10.9.10, 3.10.10.1, 3.10.10.2, 3.10.10.3, 3.10.10.4, 3.10.10.5,3.10.10.6, 3.10.10.7, 3.10.10.8, 3.10.10.9, 3.10.10.10, 4.1.1.1, 4.1.1.2, 4.1.1.3, 4.1.1.4, 4.1.15,4.1.1.6,4.1.1.7,4.1.1.8,4.1.1.9, 4.1.1.10,4.1.2.1,4.1.2.2, 4.1.2.3, 4.1.2.4, 4.1.2.5, 4.1.2.6, 4.1.2.7,4.12.8,4.1.2.9,4.1.2.10,4.1.3.1,4.1.3.2, 4.1.3.3, 4.1.3.4, 4.1.3.5, 4.1.3.6, 4.1.3.7, 4.1.3.8,
4.139,4.13.10,4.1.4.1,4.1.42,4.143,4.1.4.4,4.1.45,4.14.6,4.1.4.7,4.1.4.8, 4.1.4.9, 4.1 4.10, 4.15.1,4.1.5.2,4.1.5.3,4.1.54,4.1.5.5,4.1.5.6,4.1.5.7,4.1.5.8,4.1.5.9, 4.1.5.10, 4.1.6.1, 4.1.6.2, 4.1.6.3,4.1.6.4,4.1.6.5,4.1.6.6,4.1.6.7, 4.1.6.8, 4.1.6.9,4.1.6.10, 4.1.7.1, 4.1.7.2, 4.1.7.3, 4.1.7.4, 4.1.75,4.1.7.6,4.1.7.7,4.1.7.8,4.1.7.9, 4.1.7.10, 4.1.8.1, 4.1.8.2, 4.1.8.3, 4.1.8.4, 4.1.8.5, 4.1.8.6, 4.18.7,4.1.8.8,4.1.89,4.1.8.10,4.1.9.1,4.1.9.2,4.19.3, 4.1.9.4, 4.1.9.5, 4.1.9.6, 4.1.9.7, 4.1.9.8,
4.1.99,4.1.9.10,4.1.10.1, 4.1.10.2, 4.1.10.3, 4.1.10.4, 4.1.10.5, 4.1.10.6, 4.1.10.7, 4.1.10.8, 4.1.10.5,4.1.10.10, 4.2.1.1, 4.2.1.2, 4.2.1.3,4.2.1.4,4.2.1.5,42.1.6,42.1.7,42.1.8,42.19, 4.2.1.10,4.2.2.1,4.2.2.2,4.2.2.3,4.22.4,42.2.5,422.6,42.2.7,42.2.8,42.29,422.10,4.2.3.1, 4232,4233,4234,4235,423.6,423.7,42.3.8,4239,423.10,4.2.4.1,4242, 424.3, 424.4,424.5,42.4.6,42.4.7,42.4.8,4249,42.4.10,42.5.1,4.2.52,42.53,4254,42.5.5,
4256,425.7,42.58,42.59,425.10,42.6.1,42.62,42.63,4.2.6.4,4.2.6.5,4.2.6.6,4.2.6.7, 42.6.8,42.69,4.2.6.10,4.2.7.1,4.2.72,42.7.3,42.74,42.75,42.76,42.7.7,42.7.8,4.2.7.9, 4.2.7.10,4.2.8.1,4.2.82,42.83,42.84,4285,4286,428.7,42.88,4.2.8.9,4238.10, 4.2.9.1,
) 4292,4293,4294,4295,4296,429.7,429.8,4299,4.29.10,4.2.10.1,42.102, 42.103,4.2.10.4,4.2.10.5,4.2.10.6,4.2.10.7,4.2.10.8, 4.2.10.9, 42.10.10, 4.3.1.1, 4.3.1.2,
: 20 43.13,43.14,43.15,4.3.1.6,43.1.7,4.3.1.8,4.3.1.9,4.3.1.10,4.3.2.1,4.3.2.2, 432.3,4.32.4,
: 4325,43.2.6,4.3.2.7,43.2.8,43.2.9,43.2.10,43.3.1,43.3.2,4.3.3.3,4.3.34,4.3.3.5,43.3.6, 433.7,43.3.8,4.3.3.9,433.10,4.3.4.1,43.4.2,43.43,43.44,43.45,43.4.6,43.47,43.4.8, - 43.4.9,43.4.10,43.5.1,43.5.2,4.3.5.3,435.4,43.5.5,43.5.6,4.3.5.7,4.3.5.8,4.3.5.9,43.5.10, - 4.3.6.1,4.3.6.2,4.3.6.3,4.3.6.4,4.3.6.5, 4.3.6.6,4.3.6.7,4.3.6.8,4.3.6.9,4.3.6.10,4.3.7.1, 43.72,
43.73,43.74,43.75,43.76,43.7.7,4.3.7.8,4.3.7.9,4.3.7.10, 4.3.8.1, 4.3.8.2, 4.3.8.3, 4.3.8.4, 4.3.8.5,4.3.8.6,4.3.8.7,4.3.8.8,4.3.8.9,4.3.8.10,43.9.1,43.9.2,4.3.9.3,4.3.9.4,439.5, 4.3.9.6, 4.3.9.7,4.3.9.8,4.3.9.9,43.9.10, 4.3.10.1, 4.3.10.2,4.3.10.3, 4.3.10.4, 4.3.10.5, 4.3.10.6, 4.3.10.7, 4.3.10.8,4.3.10.9,4.3.10.10,4.4.1.1,4.4.1.2,44.1.3,44.1.4,44.1.5,44.1.6,44.1.7,44.1 8, : 44.1.9,44.1.10,4.4.2.1,4.42.2,442.3,442.4,4425,442.6,442.7,442.8,4429,442.10,
443.1,443.2,4433,443.4,443.5,443.6,4.43.7,443.8,4439,443.10,44.4:1,4442, 44.43,44.4.4,44.45,44.4.6,444.7,444.8,4449,44.4.10,44.5.1,4452,4453,445.4, 44.5.5,445.6,4457,44.58,4459,445.10,44.6.1,44.6.2,446.3,44.64,4.46.5,4.4.6.6, 4.4.6.7,44.6.8,44.69,44.6.10,4.4.71,44.72,4473,44.74,44.75,4.4.7.6,4.4.7.7,4.4.7.8, 44.79,4.4.7.10,44.8.1,4.48.2,4483,44.84,4485,44.8.6,4.4.8.7,4.4.88,4.4.8.9,4.4.8.10,
4.49.1,4492,4493,4.49.4,4495,449.6,449.7,449.8,44.99, 4.49.10, 4.4.10.1,
Ng '
4.4.10.2,4.4.10.3,4.4.10.4,4.4.10.5, 4.4.10.6, 4.4.10.7, 4.4.10.8, 4.4.10.9, 4.4.10.10, 4.5.1.1, 4.5.1.2,4.5.1.3,4.5.1.4,4.5.1.5,4.5.1.6, 4.5.1.7, 4.5.1.8,4.5.1.9, 4.5.1.10,4.52.1,4.52.2, 452 3, 4524,45.25,4.526,452.7,45.2.8,4.529,4.52.10,4.53.1,45.3.2,4.53.3,4.53.4, 4.53.5, 453.6,45.3.7,4.538,453.9,453.10,4.54.1,4.542,454.3,4.54.4,454.5,45.4.6, 4.54.7,
4.54.8,4.549,454.10,455.1,4552,4553,45.54,4.55.5,45.5.6,4.5.5.7,4.5.5.8,4.5.5.9, 4.5.5.10,4.5.6.1,4.5.6.2,4.5.6.3,4.5.6.4,4.5.6.5,4.5.6.6, 4.5.6.7, 4.5.6.8, 4.5.6.9, 4.5.6.10, 4.5.7.1, 4.5.72,45.73,45.7.4,45.7.5,4.5.7.6,4.5.7.7,4.5.7.8,4.5.1.9,4.5.7.10,4.5.8.1,4.5.8.2, 4.5.8.3, 4.5.8.4,4.5.85,4.5.86,4.58.7,4.5.8.8,4.5.8.9,4.5.8.10,4.59.1,4.5.9.2,4.59.3,4.5.9.4, 4.59.5, 4.59.6,4.59.7,459.8,4.59.9,4.59.10,4.5.10.1,4.5.10.2, 4.5.10.3, 4.5.10.4, 4.5.10.5, 4.5.10.6,
4.5.10.7,4.5.10.8,4.5.10.9,4.5.10.10,4.6.1.1,4.6.12,4.6.1.3,4.6.1.4,4.6.1.5, 4.6.1.6, 4.6.1.7, 4.6.1.8,4.6.19,4.6.1.10,4.6.2.1,4.6.2.2,4.6.2.3,4.6.2.4,4.62.5,4.6.2.6,4.6.2.7,4.6.2.8, 4.6.2.9, 4.62.10,4.63.1,4.63.2,4.63.3,4.6.3.4,4.63.5,4.63.6,4.63.7,4.63.8,4.63.9,463.10,4.6.4.1, 4.6.4.2,4.643,4.64.4,464.5,464.6,464.7,464.8,4649,4.6.4.10,4.6.5.1,46.5.2,4.65.23, 4.6.5.4,4.6.5.5,4.6.5.6,4.6.5.7,4.6.5.8,4.6.5.9,4.6.5.10,4.6.6.1,4.6.62, 4.6.6.3, 4.6.6.4, 4.6.6.5,
4.6.6.6,4.6.6.7,4.6.6.8,4.6.6.9,4.6.6.10,4.6.7.1,4.6.7.2,4.6.7.3,4.6.7.4,4.6.7.5,4.6.7.6, 4.6.7.7, 4.6.7.8,4.6.7.9,4.6.7.10,4.6.8.1, 4.6.8.2, 4.6.8.3, 4.6.8.4, 4.6.8.5, 4.6.8.6, 4.6.8.7, 4.6.8.8, 4.6.8.9,
: 4.6.8.10,4.6.9.1,4.6.9.2,4.6.9.3,4.6.9.4, 4.6.9.5,4.6.9.6, 4.6.9.7, 4.6.9.8, 4.6.9.9, 4.6.9.10, : 4.6.10.1,4.6.10.2,4.6.10.3, 4.6.10.4, 4.6.10.5, 4.6.10.6, 4.6.10.7, 4.6.10.8, 4.6.10.9, 4.6.10.10, 4,7.1.1,4.7.12,4.7.1.3,4.7.1.4,4.7.1.5,4.7.1.6, 4.7.1.7, 4.7.1.8, 4.7.1.9, 4.7.1.10, 4.7.2.1, 4.7.2.2,
4.723,4.72.4,4725,472.6,4.72.7,4.7.2.8,4.729,4.72.10,4.73.1,4.7.3.2,4.7.3.3, 4.73 4, : 4.73.5,473.6,4.73.7,4.73.8,4.739,4.7.3.10,4.7.4.1,4.742,4.743,4.7.4.4,4.74.5, 4.7.4.6, 4.74.7,4.7.4.8,4.749,4.7.4.10,4.75.1,4.7.5.2,4.7.5.3,4.7.5.4,4.7.5.5, 4.7.5.6, 4.7.5.7,4.7.5.8, 4.7.5.9,4.7.5.10,4.7.6.1,4.7.6.2,4.7.6.3,4.7.6.4,4.7.6.5, 4.7.6.6, 4.7.6.7, 4.7.6.8, 4.7.6.9, 4.7.6.10, 4.7.7.1,4.7.72,4.1.13,4.7.7.4,4.7.7.5,4.1.7.6, 4.7.7.7, 4.7.7.8, 4.7.7.9, 4.7.7.10, 4.7.8.1, 4.7.8.2,
47.83,4.7.84,4785,4786,4.78.7,4.7.8.8,4.7.89,4.78.10,4.79.1,4.7.9.2,4.7.9.3, 4.7.9.4, 4.7.9.5,4.7.9.6,4.7.9.7,4.7.9.8,4.7.9.9,4.7.9.10,4.7.10.1, 4.7.10.2, 4.7.10.3, 4.7.10.4, 4.7.10.5, 4.7.10.6,4.7.10.7,4.7.10.8, 4.7.10.9, 47.10.10, 4.8.1.1, 4.8.1.2, 4.8.1.3, 4.8.1.4, 4.8.1.5, 4.8.1.6, 4.8.1.7.4.8.1.8.4.8.1.9,4.8.1.10.4.82.1,4.8.2.2,4.823,48.2.4,4.82.5,4.82.6,482.7,4.8238, 4829,4.82.10,4.83.1,4832,483.3,4.8.3.4,483.5,483.6,4.8.3.7,4.8.3.8,483.9,4.83.10,
4.84.1,4.842,4843,4844,484.5,4846,484.7,4848,4849,484.10,485.1,4.852, 4.8.5.3,4.8.5.4,4.8.5.5,4.8.5.6,4.8.5.7,4.8.58,4.8.5.9,4.85.10,4.8.6.1,4.8.6.2,4.8.6.3,4.8.6.4, 4.8.6.5,4.8.6.6,4.8.6.7,4.8.6.8,4.8.6.9,4.8.6.10,4.8.7.1,4.8.7.2,4.8.7.3,4.8.7.4,4.8.7.5,4.8.7.6, 4.8.7.7,4.8.7.8,4.8.7.9, 4.8.7.10, 4.8.8.1, 4.8.8.2, 4.8.8.3, 4.8.8.4, 4.8.8.5,4.8.8.6, 4.8.8.7, 4.8.8.8, 4.8.8.9,4.8.8.10,4.89.1,4.8.9.2,4.8.9.3,4.8.9.4,4.89.5,4.8.9.6,4.8.9.7, 4.8.9.8, 4.8.9.9, 4.8.9.10,
4.8.10.1,4.8.10.2,4.8.10.3,4.8.10.4, 4.8.10.5, 4.8.10.6, 4.8.10.7, 4.8.10.8, 4.8.10.9, 4.8.10.10,
¢ °
4.9.1.1,49.1.2,4.9.1.3,4.9.14,49.1.5,4.9.1.6,4.9.1.7,4.9.1.8, 4.9.1.9, 4.9.1.10, 4.9.2.1, 49.2.2, 4.9.23,49.2.4,49.25,4.9.2.6,49.2.7,49.2.8,4.9.2.9,4.9.2.10,4.93.1,493.2,4.93.3, 49.3.4, 4.9.3.5,4.9.3.6,4.9.3.7,4.9.3.8,49.3.9,493.10,4.94.1,49.4.2,494.3,49.4.4,4.9.4.5, 49.4.6, 4.9.4.7,49.4.8,49.49,4.9.4.10,49.5.1,49.5.2,49.53,4.9.54,49.5.5,4.9.5.6,4.9.5.7, 49.5.8,
4.9.59,49.5.10,4.9.6.1,4.9.6.2,4.9.6.3, 4.9.6.4, 4.9.6.5, 4.9.6.6, 4.9.6.7, 4.9.6.8, 4.9.6.9, 4.9.6.10, 49.7.1,49.72,49.73,49.74,49.75,49.7.6,4.9.7.7,49.7.8,4.9.79, 49.7.10, 4.9.8.1, 49.8.2, 49.8.3,4.9.8.4,498.5,49.8.6,49.8.7,49.8.8,4.9.89,4.9.8.10,4.9.9.1,49.9.2, 49.9.3, 49.9.4, 4995,4.9.9.6,4959.7,4.9.9.8,49.9.9,4.9.9.10, 49.10.1, 4.9.10.2, 49.10.3, 4.9.10.4, 4.9.10.5, 4.9.10.6,4.9.10.7, 4.9.10.8, 4.9.10.9, 4.9.10.10, 4.10.1.1, 4.10.1.2, 4.10.1.3, 4.10.1.4, 4.10.1.5,
4.10.1.6,4.10.1.7,4.10.1.8, 4.10.1.9, 4.10.1.10, 4.10.2.1, 4.10.2.2, 4.10.2.3, 4.10.2.4, 4.10.2.5, 4.10.2.6,4.10.2.7, 4.10.2.8,4.10.2.9, 4.10.2.10, 4.10.3.1, 4.10.3.2, 4.10.3.3, 4.10.3.4, 4.10.35, 4.10.3.6,4.103.7,4.10.3.8,4.103.9, 4.10.3.10, 4.10.4.1, 4.10.4.2, 4.10.4.3, 4.10.4.4, 4.10 4.5, 4.104.6,4.104.7,4.10.4.8,4.104.9,4.10.4.10, 4.10.5.1, 4.10.5.2, 4.10.5.3, 4.10.5.4, 4.10.5.5, 4.10.5.6,4.10.5.7,4.10.5.8, 4.10.5.9,4.10.5.10, 4.10.6.1, 4.10.6.2, 4.10.6.3, 4.10.6.4, 4.10.6.5,
4.10.6.6,4.10.6.7, 4.10.6.8, 4.10.6.9,4.10.6.10,4.10.7.1, 4.10.7.2, 4.10.7.3, 4.10.7.4, 4.10.7.5, 4.10.7.6,4.10.7.7, 4.10.7.8, 4.10.79, 4.10.7.10,4.10.8.1, 4.10.8.2, 4.10.83, 4.10.8.4, 4.10.8.5,
: 4.10.8:6,4.10.8.7,4.10.8.8,4.10.8.9, 4.10.8.10, 4.10.9.1, 4.10.9.2, 4.10.9.3, 4.10.9.4, 4.10.9.5,
’ 4.10.9:6,4.10.9.7, 4.10.9.8,4.10.9.9, 4.10.9.10, 4.10.10.1, 4.10.10.2, 4.10.10.3, 4.10.10.4,
- 4.10.10.5, 4.10.10.6, 4.10.10.7, 4.10.10.8, 4.10.10.9, 4.10.10.10, 5.1.1.1, 5.1.1.2, 5.1.1.3, 5.1.1.4,
“ ‘ 20 5.1.15,5.1.1.6,5.1.1.7, 5.1.1.8, 5.1.1.9, 5.1.1.10, 5.1.2.1, 5.1.2.2, 5.1.2.3, 5.1.2.4, 5.1.2.5, 5.1.2.6, -
= 51.2.7,5.1.2.8,5.1.2.9,5.1.2.10, 5.1.3.1, 5.1.3.2, 5.1.3.3, 5.1.3.4, 5.1.3.5, 5.1.3.6, 5.1.3.7, 5.1.3.8,
5.1.3.9,5.1.3.10,5.1.4.1,5.1.42,5.1.43,5.1.4.4,5.1.4.5,5.1.4.6,5.1.4.7, 5.1.4.8, 5.1.4.9, 5.14.10,
5.1.5.1,5.1.5.2,5.1.5.3,5.1.5.4, 5.1.5.5, 5.1.5.6, 5.1.5.7, 5.1.5.8, 5.1.5.9, 5.1.5.10, 5.1.6.1, 5.1.6.2, 5.1.6.3,5.1.6.4,5.1.6.5,5.1.6.6,5.1.6.7,5.1.6.8,5.1.6.9,5.1.6.10, 5.1.7.1, 5.1.7.2, 5.1.7.3, 5.1.7 4,
51.75,5.1.76,5.1.7.7,5.1.7.8, 5.1.7.9, 5.1.7.10, 5.1.8.1, 5.1.8.2, 5.1.8.3, 5.1.8.4, 5.1.8.5, 5.1.8.6, 5.1.8.7,5.1.8.8,5.1.89,5.1.8.10,5.1.9.1,5.1.9.2, 5.1.9.3, 5.1.9.4, 5.1.9.5, 5.1.9.6, 5.1.9.7, 5.1.9.8, 5.1.9.9,5.1.9.10,5.1.10.1, 5.1.10.2, 5.1.10.3, 5.1.10.4, 5.1.10.5, 5.1.10.6, 5.1.10.7, 5.1.10.8, 5.1.10.9,5.1.10.10, 5.2.1.1, 5.2.1.2,5.2.1.3,5.2.1.4, 5.2.1.5, 5.2.1.6, 5.2.1.7, 5.2.1.8, 5.2.1.9, 5.2.1.10,5.22.1,5.2.2.2,52.2.3,52.24,52.2.5,5.2.2.6,522.7,52.2.8, 52.2.9, 5.2.2.10, 5.2.3.1,
5232,5233,523.4,523.5,523.6,52.3.7,52.3.8,52.3.9,5.2.3.10,5.2.4.1,524.2,52.4.3,
- 5244,5245,5246,524.7,524.8,52.49,524.10,5.2.5.1,52.52,5253,52.54,525.5,
'5.2.5.6,52.5.7,5.2.5.8,5.2.59,5.2.5.10,5.2.6.1,5.2.6.2,52.6.3,5.2.6.4,5.2.6.5,52.6.6,52.6.7,
5.26.8,52.6.9,5.2.6.10,52.7.1,52.7.2,52.73,52.74,52.75,52.7.6,5.2.7.7,5.2.7.8,52.7.9, 5.2.7.10,5.2.8.1,5.2.8.2,5.2.8.3, 5.2.8.4, 5.2.8.5, 5.2.8.6, 5.2.8.7, 5.2.8.8, 5.2.8.9, 5.2.8.10, 5.2.9.1,
5292,5293,529.4,5295,529.6,529.7,529.8,65.299,5.2.9.10,5.2.10.1, 5.2.10.2,
5.2.10.3,5.2.10.4,5.2.10.5,5.2.10.6, 5.2.10.7, 5.2.10.8, 5.2.10.9, 5.2.10.10, 5.3.1.1, 5.3.1.2, 53.13,5.3.1.4,5.3.1.5,5.3.1.6,5.3.1.7,5.3.1.8,5.3.1.9,5.3.1.10, 5.3.2.1, 5.3.2.2, 5.3.2.3, 5.3.2.4, 5.32.5,53.2.6,5.3.2.7,5.3.2.8,5.3.2.9,53.2.10,53.3.1,5.3.3.2,53.3.3,5.3.3.4, 5.3.3.5, 5.3.3.6, 5.3.3.7,5.3.3.8,5.3.3.9,533.10,5.3.4.1,534.2,53.43,53.4.4,53.4.5,53.4.6,53.4.7, 5.3.4.8,
53.4.9,534.10,53.5.1,53.52,53.53,5.3.5.4,53.5.5,5.3.5.6, 5.3.5.7, 5.3.5.8, 5.3.5.9, 5.3.5.10, 5.3.6.1,5.3.6.2,5.3.6.3,5.3.6.4,53.6.5, 53.6.6, 5.3.6.7, 5.3.6.8, 5.3.6.9, 5.3.6.10, 5.3.7.1, 5.3.7.2, 5.3.7.3,53.7.4,5.3.7.5,53.7.6,5.3.7.7,5.3.7.8,5.3.7.9,5.3.7.10, 5.3.8.1, 5.3.8.2, 5.3.8.3, 5.3.8.4, 5.3.8.5,53.8.6, 5.3.8.7, 5.3.8.8, 5.3.8.9, 5.3.8.10, 5.3.9.1,5.3.9.2, 5.3.9.3, 5.3.9.4, 5.3.9.5, 5.3.9.6, 5.39.7,5.3.9.8, 5.3.9.9, 5.39.10, 5.3.10.1, 5.3.10.2, 5.3.10.3, 5.3.10.4, 5.3.10.5, 5.3.10.6, 5.3.10.7,
5.3.10.8,5.3.10.9,5.3.10.10, 5.4.1.1, 5.4.1.2, 5.4.1.3, 5.4.1.4, 5.4.1.5, 5.4.1.6, 5.4.1.7, 5.4.1.8, 5.4.1.9,5.4.1.10,5.4.2.1,5.4.22,5.4.2.3,5.4.2.4,5.4.2.5,5.4.2.6, 5.4.2.7,5.4.2.8, 5.4.2.9, 5.42.10, 5.43.1,543.2,5.4.33,543.4,54.3.5,54.3.6,54.3.7,543.8,5.43.9,5.4.3.10, 54.4.1, 5.4.4.2, 5.443,54.4.4,544.5,544.6,54.4.7,54.48,5.4.49,544.10,5.4.5.1,54.52,54.5.3, 5.4.5.4, . 5.4.5.5,5.4.5.6,5.4.5.7,5.4.5.8,54.5.9,5.4.5.10,5.4.6.1, 5.4.6.2, 5.4.6.3, 5.4.6.4, 5.4.6.5, 5.4.6.6, 5.4.6.7,54.6.8,54.69,54.6.10,54.7.1,5.4.72,5.473,54.74,54.7.5,5.4.7.6, 54.1.7, 5.4.1.8, 5.4.7.9,5.4.7.10,5.4.8.1,5.4.82,5.4.83,5.4.8.4,5.4.8.5,5.4.8.6, 5.4.8.7, 5.4.8.8, 5.4.8.9, 5.4.8.10, : 5.49.1,5.4.9.2,549.3,54.9.4,54.9.5,5.49.6,5.49.7,5.49.8, 5.4.9.9, 5.4.9.10, 5.4.10.1, 3 5.4.10.2,5.4.10.3,5.4.10.4, 5.4.10.5, 5.4.10.6, 5.4.10.7, 5.4.10.8, 5.4.10.9, 5.4.10.10, 5.5.1.1, : 5.5.1.2,5.5.1.3,5.5.14,5.5.1.5,5.5.1.6,5.5.1.7,5.5.1.8,5.5.1.9, 5.5.1.10, 5.5.2.1, 5.5.2.2, 5.5.2.3, 5.52.4,55.2.5,5526,5.52.7,5.5.2.8,5.5.2.9,5.52.10,5.5.3.1, 5.5.3.2, 5.5.3.3, 5.5.3.4, 5.5.3.5, 5.5.3.6,5.5.3.7,5.5.3.8,5.5.3.9,5.5.3.10,5.5.4.1,5.5.4.2,5.5.4.3,5.5.4.4, 55.4.5 55.4.6, 5.54.7, 5.5.4.8,5.5.4.9,5.5.4.10,5.5.5.1,5.5.5.2, 5.5.5.3, 5.5.5.4,5.5.5.5, 5.5.5.6, 5.5.5.7, 5.5.5.8, 5.5.5.9, 5.5.5.10,5.5.6.1, 5.5.6.2, 5.5.6.3, 5.5.6.4, 5.5.6.5, 5.5.6.6, 5.5.6.7, 5.5.6.8, 5.5.6.9, 5.5.6.10, 5.5.7.1, 5.5.7.2,5.5.7.3,5.5.74, 5.5.7.5, 5.5.1.6, 5.5.7.7, 5.5.1.8, 5.5.7.9, 5.5.7.10, 5.5.8.1, 5.5.8.2, 5.5.8.3, 5.5.8.4,5.5.8.5,5.5.8.6,5.5.8.7,5.5.8.8,5.5.8.9,5.5.8.10,5.5.9.1,5.5.9.2, 5.5.9.3, 5.5.9.4, 5.5.9.5, 5.5.9.6,5.5.9.7,5.5.9.8, 5.5.9.9, 5.5.9.10, 5.5.10.1, 5.5.10.2, 5.5.10.3, 5.5.10.4, 5.5.10.5, 5.5.10.6, 5.5.10.7,5.5.10.8,5.5.10.9, 5.5.10.10, 5.6.1.1, 5.6.1.2, 5.6.13, 5.6.1.4, 5.6.1.5, 5.6.1.6, 5.6.1.7, 5.6.1.8,5.6.1.9,5.6.1.10, 5.6.2.1, 5.6.2.2, 5.6.2.3, 5.6.2.4, 5.6.2.5, 5.6.2.6, 5.6.2.7, 5.6.2.8, 5.6.2.9, 5.6.2.10,5.6.3.1, 5.6.3.2, 5.6.3.3, 5.6.3.4, 5.6.3.5, 5.6.3.6, 5.6.3.7, 5.6.3.8, 5.6.3.9, 5.6.3.10, 5.6.4.1, 5.6.4.2,5.6.4.3,5.6.44,5.6.4.5 56.4.6,56.4.7,564.8,564.9,5.6.4.10,56.5.1,5.6.5.2,5.6.5.3, 5.6.5.4, 5.6.5.5, 5.6.5.6, 5.6.5.7, 5.6.5.8, 5.6.5.9, 5.6.5.10, 5.6.6.1, 5.6.6.2, 5.6.6.3, 5.6.6.4, 5.6.6.5, 5.6.6.6,5.6.6.7,5.6.6.8,5.6.6.9, 5.6.6.10, 5.6.7.1, 5.6.7.2, 5.6.7.3, 5.6.7.4, 5.6.1.5, 5.6.7.6, 5.6.7.7, 5.6.7.8,5.6.7.9, 5.6.7.10, 5.6.8.1, 5.6.8.2, 5.6.8.3, 5.6.8.4, 5.6.8.5, 5.6.8.6, 5.6.8.7, 5.6.8.8, 5.6.8.9, 5.6.8.10,5.6.9.1, 5.6.9.2,5.6.9.3,5.6.9.4,5.6.9.5,5.6.9.6,5.6.9.7, 5.6.9.8, 5.6.9.9, 5.6.9.10, 5.6.10.1,5.6.10.2,5.6.10.3, 5.6.10.4, 5.6.10.5, 5.6.10.6, 5.6.10.7, 5.6.10.8, 5.6.10.9, 5.6.10.10,
Y Y
5.7.1.1,5.7.1.2, 5.7.13, 5.7.14,5.7.1.5,5.7.1.6,5.7.1.7, 5.7.1.8, 5.7.1.9, 5.7.1.10, 5.7.2.1, 5.7.2.2, 5.7.2.3,5.7.2.4,5.7.2.5,5.7.2.6,5.7.2.7,5.7.2.8, 5.7.29, 5.7.2.10, 5.7.3.1, 5.7.3.2, 5.7.3.3, 5.7.3 4, 5.7.3.5,5.7.3.6,5.7.3.7,5.7.3.8,5.73.9,5.7.3.10,5.74.1,5.74.2,5.7.4.3,5.74.4,5.74.5, 5.7.4.6, 5.74.7,5.7.4.8,5.7.4.9,5.7.4.10,5.7.5.1,5.7.52,5.7.53,5.7.5.4,5.7.5.5, 5.7.5.6, 5.7.5.7,5.7.5.8, §.759,5.75.10,5.7.6.1,5.7.6.2,5.7.6.3,5.7.6.4,5.7.6.5, 5.7.6.6, 5.7.6.7, 5.7.6.8, 5.7.6.9, 5.7.6.10, 8.7.7.1,5.7.7.2,5.71.73,5.7.74,5.7.15, 5.1.7.6, 5.1.7.7,5.7.7.8, 5.1.7.9, 5.7.7.10, 5.7.8.1, 5.7.8.2, 5.7.83,5.7.84,5.7.8.5,5.7.8.6,5.7.8.7,5.7.8.8, 5.7.8.9, 5.7.8.10, 5.7.9.1, 5.7.9.2, 5.7.9.3, 5.7.9.4, 5.7.9.5,5.7.9.6,5.79.7,5.7.9.8,5.7.9.9, 5.7.9.10, 5.7.10.1, 5.7.10.2, 5.7.10.3, 5.7.10.4, 5.7.10.5, 5.7.10.6,5.7.10.7, 5.7.10.8, 5.7.10.9, 5.7.10.10, 5.8.1.1, 5.8.1.2, 5.8.1.3, 5.8.1.4, 5.8.1.5, 5.8.1.6, 5.8.1.7,5.8.1.8,58.1.9,58.1.10,5.8.2.1,5.8.2.2,5.8.2.3,5.8.2.4,5.8.2.5, 5.8.2.6, 5.8.2.7, 5.8.2.8, 5.8.2.9, 5.8.2.10, 5.8.3.1, 5.8.3.2,5.8.3.3,5.8.3.4,5.83.5,5.8.3.6,5.8.3.7, 5.8.3.8, 5.8.3.9, 5.8.3.10, 584.1,5842,5843,58.4.4,58.4.5,5.84.6,584.7,584.8,58.4.9,5.8.4.10,5.8.5.1,5.85.2, 5.8.5.3,5.8.54,5.8.5.5,5.8.5.6,58.5.7,5.8.5.8,5.8.5.9,5.8.5.10, 5.8.6.1, 5.8.6.2, 5.8.6.3, 5.8.6.4, 5.8.6.5,5.8.6.6,5.8.6.7,5.8.6.8, 5.8.6.9, 5.8.6.10, 5.8.7.1, 5.8.7.2, 5.8.7.3, 5.8.7.4, 5.8.7.5, 5.8.7.6, 5.8.7.7,5.8.7.8,5.8.79,5.8.7.10,5.8.8.1,5.8.8.2, 5.8.8.3, 5.8.8.4, 5.8.8.5, 5.8.8.6,5.8.8.7, 5.8.8.8, : 5.8.8.9,5.8.8.10,5.8.9.1,5.8.9.2,5.8.9.3,5.89.4,5.8.9.5,5.8.9.6,5.89.7,5.8.9.8, 5.8.9.9, 5.8.9.10, = 5.8.10.1;5.8.10.2,5.8.10.3, 5.8.10.4, 5.8.10.5, 5.8.10.6, 5.8.10.7, 5.8.10.8, 5.8.10.9, 5.8.10.10, = ) 5.9.1.1,59.1.2,59.1.3,59.1.4,59.1.5,59.16,59.1.7,59.1.8,5.9.1.9,5.9.1.10,5.9.2.1,59.2.2,
I 5923,5924,5925,59.2.6,59.2.7,59.2.8,59.29,59.2.10,593.1,5.9.3.2,59.3.3,5.9.34, ce 20 5.9.3.5,5.9.3.6,5.9.3.7,5.9.3.8,59.3.9,5.9.3.10, 5.9.4.1,5.9.4.2, 5.9.4.3, 5.9.4.4, 5.9.4.5, 5.9.4.6, - 5.9.4.7,5.9.4.8,59.4.9,59.4.10,595.1,59.52,595.3,59.54,595.5,5.9.5.6,5.9.5.7, 59.5.8, iS 5.9.5.9,5.9.5.10, 5.9.6.1, 5.9.6.2, 5.9.6.3, 5.9.6.4, 5.9.6.5, 5.9.6.6, 5.9.6.7, 5.9.6.8, 5.9.6.9, 5.9.6.10, - 5.9.7.1,5.9.7.2,5.9.7.3,5.9.7.4,59.7.5,5.9.7.6,59.7.7,5.9.7.8, 5.9.7.9, 5.9.7.10, 5.9.8.1, 5.9.8.2, 5.9.8.3,5.9.8.4,5.9.8.5,59.8.6,5.9.8.7,5.9.8.8,59.8.9,5.9.8.10,5.9.9.1, 5.9.9.2,5.9.9.3, 5.9.94, 599.5,599.6,59.9.7599.8,59.99,65.9.9.10, 5.9.10.1, 5.9.10.2, 5.9.10.3, 5.9.10.4, 5.9.10.5, 5.9.10.6,5.9.10.7, 5.9.10.8, 5.9.10.9, 5.9.10.10, 5.10.1.1, 5.10.1.2, 5.10.1.3, 5.10.1 .4, 5.10.1.5, 5.10.1.6,5.10.1.7, 5.10.1.8, 5.10.1.9, 5.10.1.10, 5.10.2.1, 5.10.2.2, 5.10.2.3, 5.10.2.4, 5.10.2.5, + 5.10.2.6,5.10.2.7,5.10.2.8, 5.10.2.9, 5.10.2.10, 5.10.3.1, 5.10.3.2, 5.10.3.3, 5.10.3.4, 5.10.3.5, : 5.10.3.6,5.10.3.7,5.10.3.8, 5.10.3.9, 5.10.3.10, 5.10.4.1, 5.10.4.2, 5.10.4.3, 5.10.4.4, 5.10.4.5, 5.104.6,5.10.4.7,5.10.4.8,5.10.4.9, 5.10.4.10, 5.10.5.1, 5.10.5.2, 5.10.5.3, 5.10.54, 5.10.5.5, : 5.10.5.6,5.10.5.7, 5.10.5.8, 5.10.5.9, 5.10.5.10, 5.10.6.1, 5.10.6.2, 5.10.6.3, 5.10.6.4, 5.10.6.5, 5.10.6.6,5.10.6.7, 5.10.6.8,5.10.6.9, 5.10.6.10, 5.10.7.1, 5.10.7.2, 5.10.7.3, 5.10.7.4, 5.10.7.5, 5.10.7.6, 5.10.7.7, 5.10.7.8, 5.10.7.9, 5.10.7.10, 5.10.8.1, 5.10.8.2, 5.10.8.3, 5.10.8 4, 5.10.8.5, 5.10.8.6,5.10.8.7,5.10.8.8, 5.10.8.9, 5.10.8.10, 5.10.9.1, 5.10.9.2, 5.10.9.3, 5.10.9.4, 5.10.9.5, 5.10.9.6,5.10.9.7,5.10.9.8,5.10.9.9, 5.10.9.10, 5.10.10.1, 5.10.10.2, 5.10.10.3, 5.10.10 4,
5.10.10.5, 5.10.10.6, 5.10.10.7, 5.10.10.8, 5.10.10.9, 5.10.10.10, 6.1.1.1, 6.1.1.2, 6.1.13,6.1.1.4, 6.1.1.5,6.1.1.6,6.1.1.7,6.1.1.8, 6.1.1.9, 6.1.1.10, 6.1.2.1, 6.1.2.2, 6.1.2.3, 6.1.2.4, 6.1.2.5, 6.1.2.6, 6.1.2.7,6.1.2.8,6.1.29,6.1.2.10,6.1.3.1,6.1.32, 6.1.33, 6.1.3.4,6.1.3.5,6.1.3.6, 6.1.3.7, 6.1.3.8, 6.13.9,6.13.10,6.1.4.1,6.1.42,6.1.4.3,6.1.4.4,6.1.45,6.1.4.6,6.1.4.7, 6.1.4.8, 6.1.4.9, 6.1 4.10, 6.15.1,6152,6153,6.1.54,6.1.55,6.1.5.6,6.1.5.7,6.1.5.8,6.1.5.9, 6.15.10, 6.1.6.1, 6.1.6.2, 6.1.6.3,6.1.6.4,6.1.6.5,6.1.6.6,6.1.6.7,6.1.6.8, 6.1.6.9, 6.1.6.10, 6.1.7.1, 6.1.7.2, 6.1.7.3, 6.1.74, 6.1.7.5,6.1.7.6,6.1.7.7,6.1.7.8,6.1.7.9,6.1.7.10, 6.1.8.1, 6.1.8.2, 6.1.8.3, 6.1.8.4, 6.1.8.5, 6.1.8.6, 6.1.8.7,6.1.8.8,6.1.8.9,6.1.8.10,6.1.9.1,6.1.9.2, 6.1.9.3, 6.1.9.4, 6.1.9.5, 6.1.9.6, 6.1.9.7, 6.1.9.8,
6.1.9.9, 6.19.10, 6.1.10.1, 6.1.10.2, 6.1.10.3, 6.1.10.4, 6.1.10.5, 6.1.10.6, 6.1.10.7, 6.1.10.8,
6.1.109,6.1.10.10,6.2.1.1,6.2.1.2, 6.2.1.3, 6.2.1.4, 6.2.1.5, 6.2.1.6, 6.2.1.7, 6.2.1.8, 6.2.1.9, 6.2.1.10,6.2.2.1,6.2.2.2,6.2.2.3,6.2.2.4,6.2.2.5,6.2.2.6,6.2.2.7, 6.2.2.8, 6.2.2.9, 6.2.2.10, 6.2.3.1, 6.2.3.2,6.2.3.3,6.23.4,6.23.5,6.2.3.6,6.2.3.7,6.2.3.8,6.2.3.9,6.2.3.10, 6.2.4.1, 6.2.4.2, 6.2.4.3, 6.2.4.4,6.2.4.5,6.2.4.6,6.2.4.7,6.2.4.8,6.2.4.9, 6.2.4.10, 6.2.5.1, 6.2.5.2, 6.2.5.3, 6.2.5.4, 6.2.5.5, 6.2.5.6, 6.2.5.7, 6.2.5.8, 6.2.5.9, 6.2.5.10, 6.2.6.1, 6.2.6.2, 6.2.6.3, 6.2.6.4, 6.2.6.5, 6.2.6.6, 6.2.6.7,
6.2.6.8,6.2.6.9,6.2.6.10,62.7.1, 6.2.7.2, 6.2.7.3, 6.2.7.4, 6.2.1.5,6.2.7.6, 6.2.7.7, 6.2.7.8, 6.2.7.9,
: 6.2.7.10,6.2.8.1,6.2.8.2, 6.2.8.3, 6.2.8.4, 6.2.8.5, 6.2.8.6, 6.2.8.7, 6.2.8.8, 6.2.8.9, 6.2.8.10, 6.2.9.1,
: 6.2.9.2,6.2.9.3, 6.2.9.4, 6.2.9.5, 6.2.9.6, 6.29.7, 6.2.9.8, 6.2.9.9, 6.2.9.10, 6.2.10.1, 6.2.10.2,
: 6.2.10.3, 6.2.10.4, 6.2.10.5, 6.2.10.6, 6.2.10.7, 6.2.10.8, 6.2.10.9, 6.2.10.10, 6.3.1.1, 6.3.1.2,
: 6.3.13,63.1.4,63.1.5,6.3.1.6,6.3.1.7, 6.3.1.8, 6.3.1.9, 6.3.1.10, 6.3.2.1, 6.3.2.2, 6.3.2.3, 63.2.4,
6.3.2.5,63.2.6,6.3.2.7,6.3.2.8,6.3.29,63.2.10,6.33.1,63.3.2,6.3.3.3,6.33.4,6.3.3.5, 63.3.6, 6.3.3.7,6.3.3.8,6.3.3.9,6.3.3.10,6.3.4.1,6.3.42,6.3.43,63.44, 6.3.4.5,6.3.4.6, 63.4.7, 63.4.8, 6.3.4.9,63.4.10,6.3.5.1, 6.3.5.2, 6.3.5.3, 6.3.5.4,6.3.5.5,63.5.6,6.3.5.7, 6.3.5.8, 6.3.5.9, 6.3.5.10, 6.3.6.1,63.6.2,6.3.6.3,6.3.6.4,6.3.6.5,6.3.6.6,6.3.6.7,6.3.6.8,6.3.6.9,63.6.10,63.7.1, 63.7.2, 6.3.73,63.74,63.75,63.7.6,63.7.7,6.3.7.8,6.3.7.9, 6.3.7.10, 6.3.8.1, 6.3.8.2, 6.3.8.3, 6.3.8.4,
6.3.8.5,6.3.8.6,63.8.7,63.8.8,6.3.8.9,63.8.10,63.9.1,63.9.2 6.3.9.3,63.9.4,63.9.5,63.9.6, 6.3.9.7,6.3.9.8, 6.3.9.9, 6.3.9.10, 6.3.10.1, 6.3.10.2, 6.3.10.3, 6.3.10.4, 6.3.10.5, 6.3.10.6, 6.3.10.7, 6.3.10.8, 6.3.10.9, 6.3.10.10, 6.4.1.1, 6.4.1.2, 6.4.1.3, 6.4.1.4, 6.4.1.5, 6.4.1.6, 6.4.1.7, 6.4.1.8, 6.4.1.9,6.4.1.10,64.2.1, 64.22, 6423 642.4 6425 642.6 642.7,6428 6429, 642.10, 6.43.1,64.3.2,6.4.33,6434,64.3.5,64.3.6,6.4.3.7,6.43.8,64.3.9,6.4.3.10,6.4.4.1,6.4.4.2,
6.4.43,64.44,64.4.5,644.6,64.4.7,64.4.8, 64.4.9,6.4.4.10,6.4.5.1,6.452, 64.53, 64.54, 6.4.5.5, 6.4.5.6, 6.4.5.7, 6.4.5.8, 6.4.5.9, 6.4.5.10, 6.4.6.1, 6.4.6.2, 6.4.6.3, 6.4.6.4, 6.4.6.5, 6.4.6.6, 6.4.6.7,6.4.6.8, 6.4.6.9, 6.4.6.10,6.4.7.1,6.4.7.2,6.4.73, 64.7.4, 6.4.1.5, 6.4.7.6, 6.4.7.7, 6.4.7.8, 6.4.7.9,6.4.7.10,6.4.8.1, 6.4.8.2, 6.4.8.3,6.4.8.4, 6.4.8.5, 6.4.8.6, 6.4.8.7, 6.4.8.8, 6.4.8.9, 6.4.8.10, 6.4.9.1,64.9.2,64.9.3,6.494,64.9.5,649.6,64.9.7,64.9.8, 6.4.9.9, 6.49.10, 6.4.10.1,
6.4.102,6.4.10.3,6.4.10.4,6.4.10.5, 6.4.10.6, 6.4.10.7, 6.4.10.8, 6.4.10.9, 6.4.10.10, 6.5.1.1,
6.5.1.2,6.5.1.3,6.5.1.4, 6.5.1.5, 6.5.1.6, 6.5.1.7, 6.5.1.8, 6.5.1.9, 6.5.1.10, 6.5.2.1, 6.5.2.2, 6.5.2.3, 6.5.2.4,6.52.5,6.52.6,6.5.2.7,6.5.2.8,6.5.2.9, 6.52.10, 6.53.1, 6.5.3.2, 6.5.3.3, 6.5.3.4, 6.5.3.5, 6.5.3.6,6.5.3.7,6.53.8, 6.5.3.9, 6.5.3.10, 6.5.4.1, 6.5.4.2, 6.5.4.3, 6.5.4.4, 6.5.4.5, 6.5.4.6, 6.5.4.7, 6.5.4.8,6.5.4.9,6.5.4.10,6.55.1,6.5.5.2,6.55.3,6.5.5.4,6.5.5.5,6.5.5.6, 6.5.5.7, 6.5.5.8, 6.5.5.9, 6.5.5.10,6.5.6.1,6.5.6.2,6.5.6.3,6.5.6.4,6.5.6.5, 6.5.6.6,65.6.7,6.5.6.8,6.5.6.9,6.5.6.10,6.5.7.1, 6.5.7.2,6.5.7.3,6.5.7.4, 6.5.1.5, 6.5.7.6, 6.5.7.7, 6.5.7.8, 6.5.7.9, 6.5.7.10, 6.5.8.1, 6.5.8.2, 6.5.8.3, 6.5.8.4,6.5.8.5,6.5.8.6, 6.5.8.7, 6.5.8.8, 6.5.8.9, 6.5.8.10, 6.59.1, 6.5.9.2, 6.5.9.3, 6.59.4, 6.5.9.5, 6.5.9.6, 6.5.9.7, 6.5.9.8, 6.5.9.9, 6.5.9.10, 6.5.10.1, 6.5.10.2, 6.5.10.3, 6.5.10.4, 6.5.10.5, 6.5.10.6, 6.5.10.7, 6.5.10.8, 6.5.10.9, 6.5.10.10, 6.6.1.1, 6.6.1.2, 6.6.1.3, 6.6.1.4, 6.6.1.5, 6.6.1.6, 6.6.1.7, 6.6.1.8,6.6.1.9,6.6.1.10,6.6.2.1, 6.6.2.2, 6.6.2.3, 6.6.2.4, 6.6.2.5, 6.6.2.6, 6.6.2.7, 6.6.2.8, 6.6.2.9, 6.6.2.10, 6.6.3.1, 6.6.3.2, 6.6.3.3, 6.6.3.4, 6.6.3.5, 6.6.3.6, 6.6.3.7, 6.6.3.8, 6.6.3.9, 6.6.3.10, 6.6.4.1, 6.6.4.2,6.6.4.3,6.6.4.4, 6.6.4.5, 6.6.4.6, 6.6.4.7, 6.6.4.8, 6.6.4.9, 6.6.4.10, 6.6.5.1, 6.6.5.2, 6.6.5.3, 6.6.5.4, 6.6.5.5, 6.6.5.6, 6.6.5.7, 6.6.5.8, 6.6.5.9, 6.6.5.10, 6.6.6.1, 6.6.6.2, 6.6.6.3, 6.6.6.4, 6.6.6.5, 6.6.6.6, 6.6.6.7, 6.6.6.8, 6.6.6.9, 6.6.6.10, 6.6.7.1, 6.6.7.2, 6.6.7.3, 6.6.7.4, 6.6.7.5, 6.6.7.6, 6.6.7.7, 6.6.7.8,6.6.7.9, 6.6.7.10, 6.6.8.1, 6.6.8.2, 6.6.8.3, 6.6.8.4, 6.6.8.5, 6.6.8.6, 6.6.8.7, 6.6.8.8, 6.6.8.9, 6.6.8.10, 6.6.9.1, 6.6.9.2, 6.6.9.3, 6.6.9.4, 6.6.9.5, 6.6.9.6, 6.6.9.7, 6.6.9.8, 6.6.9.9, 6.6.9.10, & © 6.6.10.1,6.6.10.2, 6.6.10.3, 6.6.10.4, 6.6.10.5, 6.6.10.6, 6.6.10.7, 6.6.10.8, 6.6.10.9, 6.6.10.10,
Sa 6.7.1.1,6.7.1.2,6.7.1.3,6.7.1.4, 6.7.1.5, 6.7.1.6, 6.7.1.7, 6.7.1.8, 6.7.1.9, 6.7.1.10, 6.7.2.1, 6.7.2.2, = 6.7.2.376.7.2.4,6.7.2.5,6.7.2.6,6.7.2.7,6.7.2.8, 6.7.2.9, 6.1.2.10, 6.7.3.1, 6.7.3.2, 6.7.3.3, 6.7.3.4,
EE 20 6.7.3.5,6.7.3.6,6.7.3.7,6.1.3.8,6.7.3.9,6.7.3.10,6.74.1,6.7.4.2, 6.7.4.3, 6.7.4.4, 6.7.4.5, 6.7.4.6, - 2. 6.7.4.76.7.4.8,6.7.4.9,6.7.4.10,6.7.5.1,6.7.52,6.75.3,6.7.5.4,6.7.5.5, 6.7.5.6, 6.7.5.7, 6.7.5.8, : 6.7.5.9/6.7.5.10, 6.7.6.1, 6.7.6.2, 6.7.6.3,6.7.6.4, 6.7.6.5,6.7.6.6, 6.7.6.7, 6.7.6.8, 6.7.6.9, 6.7.6.10, . 6.7.7.1,6.7.7.2,6.7.7.3,6.7.74,6.7.7.5, 6.7.7.6, 6.7.7.7, 6.1.7.8, 6.1.1.9, 6.7.7.10, 6.7.8.1, 6.7.8.2, 6.7.8.3,6.7.8.4,6.7.8.5,6.7.8.6, 6.7.8.7, 6.7.8.8, 6.7.8.9, 6.7.8.10, 6.7.9.1, 6.7.9.2, 6.7.9.3, 6.7.9.4, : 6.7.9.5,6.7.9.6,6.7.9.7,6.7.9.8, 6.7.9.9, 6.7.9.10,6.7.10.1, 6.7.10.2, 6.7.10.3, 6.7.10.4, 6.7.10.5, 6.7.10.6, 6.7.10.7, 6.7.10.8, 6.7.10.9, 6.7.10.10, 6.8.1.1, 6.8.1.2, 6.8.1.3, 6.8.1.4, 6.8.1.5, 6.8.1.6, 6.8.1.7,6.8.1.8, 6.8.1.9, 6.8.1.10, 6.8.2.1, 6.8.2.2, 6.8.2.3, 6.8.2.4, 6.8.2.5, 6.8.2.6, 6.8.2.7, 6.8.2.8, 6.82.9,6.8.2.10, 6.8.3.1, 6.8.3.2, 6.8.3.3, 6.8.3.4, 6.8.3.5, 6.8.3.6, 6.8.3.7, 6.8.3.8, 6.8.3.9, 6.8.3.10, 6.8.4.1, 6.8.4.2, 6.8.4.3, 6.8.4.4, 6.8.4.5, 6.8.4.6, 6.8.4.7, 6.8.4.8, 6.8.4.9, 6.8.4.10, 6.8.5.1, 6.8.5.2, 6.8.5.3, 6.8.5.4, 6.8.5.5, 6.8.5.6, 6.8.5.7, 6.8.5.8, 6.8.5.9, 6.8.5.10, 6.8.6.1, 6.8.6.2, 6.8.6.3, 6.8.6.4, "6.8.6.5, 6.8.6.6, 6.8.6.7, 6.8.6.8, 6.8.6.9, 6.8.6.10, 6.8.7.1, 6.8.7.2, 6.8.7.3, 6.8.7.4, 6.8.7.5, 6.8.7.6, 6.8.7.7, 6.8.7.8, 6.8.7.9, 6.8.7.10, 6.8.8.1, 6.8.8.2, 6.8.8.3, 6.8.8.4, 6.8.8.5, 6.8.8.6, 6.8.8.7, 6.8.8.8, 6.8.8.9, 6.8.8.10, 6.8.9.1, 6.8.9.2, 6.8.9.3, 6.8.9.4, 6.8.9.5, 6.8.9.6, 6.8.9.7, 6.8.9.8, 6.8.9.9, 6.8.9.10, 6.8.10.1, 6.8.10.2, 6.8.10.3, 6.8.10.4, 6.8.10.5, 6.8.10.6, 6.8.10.7, 6.8.10.8, 6.8.10.9, 6.8.10.10, 6.9.1.1,69.1.2,69.1.3,6.9.1.4, 6.9.1.5, 6.9.1.6, 6.9.1.7, 6.9.1.8, 6.9.1.9, 6.9.1.10, 6.9.2.1, 6.9.2.2,
» *
6.9.2.3,6.9.2.4,6.9.2.5,69.2.6,692.7,6.9.2.8,692.9,692.10,693.1,6932,6933, 693 4, 6.9.3.5,6.9.3.6, 6.9.3.7, 6.9.3.8,6.9.3.9,6.93.10,6.9.4.1,69.4.2,69.43,69.44,69.4.5, 6.9.4.6, 6.9.4.7,69.4.8,6.9.4.9,69.4.10,69.5.1, 6.9.5.2, 6.9.53,6.9.54,69.5.5,6.9.5.6, 6.9.5.7, 6.9.5.8, 6.9.5.9, 6.9.5.10,6.9.6.1,6.9.6.2,6.9.6.3, 6.9.6.4, 6.9.6.5, 69.6.6, 6.9.6.7, 6.9.6.8,6.9.6.9, 6.9.6.10, 697.1,69.7.2,69.7.3,69.7.4,69.7.5,69.7.6,6.9.7.7,6.9.7.8, 69.7.9, 6.9.7.10, 6.9.8.1, 6.9.8.2, 6.9.8.3,6.9.8.4,6.9.8.5,6.9.8.6,6.9.8.7,6.9.8.8,6.9.8.9, 6.9.8.10,6.9.9.1,6.9.9.2, 69.9.3, 6.9.9.4, 6.9.9.5, 6.9.9.6, 6.9.9.7, 6.9.9.8, 6.9.9.9, 6.9.9.10, 6.9.10.1, 6.9.10.2, 6.9.10.3, 6.9.10.4, 6.9.10.5, 69.106, 6.9.10.7, 6.9.10.8, 6.9.10.9, 6.9.10.10, 6.10.1.1, 6.10.1.2, 6.10.13, 6.10.1.4, 6.10.1.5, 6.10.16, 6.10.1.7, 6.10.1.8, 6.10.1.9, 6.10.1.10, 6.10.2.1, 6.10.2.2, 6.10.2.3, 6.10.2.4, 6.10.2.5,
6.10.2.6,6.10.2.7, 6.10.2.8, 6.10.2.9, 6.10.2.10, 6.10.3.1, 6.10.3.2, 6.10.3.3, 6.10.3.4, 6.10.3.5, 6.10.36, 6.10.3.7, 6.10.3.8, 6.10.3.9, 6.10.3.10, 6.10.4.1, 6.10.4.2, 6.10.4.3, 6.10.4.4, 6.10.4.5, 6.10.4.6,6.10.4.7,6.10.4.8, 6.10.4.9, 6.10.4.10, 6.10.5.1, 6.10.5.2, 6.10.5.3, 6.10.5.4, 6.10.5.5, 6.10.5.6, 6.10.5.7, 6.10.5.8, 6.10.5.9, 6.10.5.10, 6.10.6.1, 6.10.6.2, 6.10.6.3, 6.10.6.4, 6.10.6.5,
: '6.10.6.6, 6.10.6.7, 6.10.6.8, 6.10.6.9, 6.10.6.10, 6.10.7.1, 6.10.7.2, 6.10.7.3, 6.10.7.4, 6.10.7.5,
.6.10.7.6, 6.10.7.7, 6.10.7.8, 6.10.7.9, 6.10.7.10, 6.10.8.1, 6.10.8.2, 6.10.8.3, 6.10.8.4, 6.10.8.5,
6.10.8.6, 6.10.8.7, 6.10.8.8, 6.10.8.9, 6.10.8.10, 6.10.9.1, 6.10.9.2, 6.10.9.3, 6.10.9.4, 6.10.9.5,
; 6.10.9.6, 6.10.9.7, 6.10.9.8, 6.10.9.9, 6.10.9.10, 6.10.10.1, 6.10.10.2, 6.10.10.3, 6.10.10.4,
: 6.10.10.5, 6.10.10.6, 6.10.10.7, 6.10.10.8, 6.10.10.9, 6.10.10.10, 7.1.1.1, 7.1.1.2, 7.1.1.3, 7.1.1.4,
i 7.1.1.5, 7.1.1.6, 7.1.1.7, 7.1.1.8, 7.1.1.9, 7.1.1.10, 7.1.2.1, 7.1.2.2, 7.1.2.3, 7.1.2.4, 7.1.2.5, 7.1.2.6,
- 20 7.1.2.7,7.12.8,7.1.2.9,7.1.2.10,7.1.3.1,7.1.32, 7.1.33, 7.1.3.4, 7.1.3.5, 7.1.3.6, 7.1.3.7, 7.1.3.8, 7.13.9,7.13.10, 7.1.4.1, 7.1.4.2, 7.1.4.3, 7.1.4.4, 7.1.4.5,7.1.4.6, 7.1.4.7, 7.1.4.8, 7.1.4.9, 7.14.10, 7.15.1,7.1.5.2, 7.1.53, 7.1.5.4, 7.1.5.5, 7.1.5.6, 7.1.5.7, 7.1.5.8, 7.1.5.9, 7.1.5.10, 7.1.6.1, 7.1.6.2, 7.1.63,7.1.6.4,7.1.6.5, 7.1.6.6, 7.1.6.7, 7.1.6.8, 7.1.6.9, 7.1.6.10, 7.1.7.1, 7.1.7.2, 7.1.7.3, 7.1.7.4, 7.1.75,7.1.7.6, 7.1.7.7, 7.1.7.8, 7.1.7.9, 7.1.7.10, 7.1.8.1, 7.1.8.2, 7.1.8.3, 7.1.8.4, 7.1.8.5, 7.1.8.6,
7.1.8.7,7.1.8.8,7.1.8.9, 7.1.8.10, 7.1.9.1, 7.1.9.2, 7.1.9.3, 7.1.9.4, 7.1.9.5, 7.1.9.6, 7.1.9.7, 7.1.9.8, 7.1.9.9, 7.19.10, 7.1.10.1, 7.1.10.2, 7.1.10.3, 7.1.10.4, 7.1.10.5, 7.1.10.6, 7.1.10.7, 7.1.10.8, 7.1.109, 7.1.10.10, 7.2.1.1, 7.2.1.2, 7.2.1.3, 7.2.1.4, 72.1.5, 7.2.1.6, 7.2.1.7, 7.2.1.8, 7.2.1.9, 72.1.10,722.1,7222,7223,7224,7225,722.6,122.7,7228,72.2.9,7.2.2.10, 7.2.3.1. 7232,7.2.33,7.23.4,72.3.5,72.3.6,7.23.7,72.3.8,72.3.9,723.10,724.1,7.2.4.2,7.2.43,
7.2.4.4,72.45,72.46,72.4.7,72.48,7.2.49,72.4.10,725.1,7.252,72.53,7.2.54,7.2.5.5, 72.5.6,72.5.7,7.2.5.8,72.59,7.2.5.10,7.2.6.1,7.2.6.2, 7.2.6.3, 7.2.6.4, 7.2.6.5, 7.2.6.6, 1.2.6.7, 72.6.8,7.2.69,7.2.6.10,72.7.1,72.1.2,7.2.1.3,7.2.7.4,12.7.5,72.7.6, 72.7.7, 7.2.7.8, 7.2.7.9, 7.2.7.10,7.2.8.1,7.2.8.2,72.83,7.2.8.4,7.2.8.5,7.2.8.6,7.2.8.7, 7.2.8.8, 7.2.8.9, 7.2.8.10, 7.2.9.1, 7.2.92,7293,7.29.4,7.2.9.5,7.2.9.6,7.29.7,7.2.9.8,7.2.9.9, 7.29.10, 7.2.10.1, 7.2.10.2,
7.2.103,7.2.10.4,7.2.10.5, 7.2.10.6, 7.2.10.7, 7.2.10.8, 7.2.10.9, 7.2.10.10, 7.3.1.1, 7.3.1.2,
wy 0 7.3.13,7.3.14,73.1.5,73.1.6, 73.1.7, 7.3.1.8, 7.3.1.9, 7.3.1.10, 7.3.2.1, 7.3.2.2, 7.3.2.3, 7.3.2.4, 73.25,73.2.6,7.3.2.7,7.3.2.8, 73.2.9, 7.3.2.10, 7.3.3.1, 7.3.3.2, 7.3.3.3, 7.3.3.4, 7.3.3.5, 7.3.3.6, 7.33.7,73.3.8,733.9,73.3.10,7.3.4.1,73.42,7.34.3,73.4.4,7.3.4.5,7.3.4.6,73.4.7, 7.3.4.8, 7.349,73.4.10,73.5.1,7.3.5.2,7.3.5.3,73.5.4,7.3.5.5,7.3.5.6, 7.3.5.7, 7.3.5.8, 7.3.5.9, 7.3.5.10, 7.3.6.1,73.6.2,7.3.6.3,7.3.6.4,7.3.6.5, 7.3.6.6, 7.3.6.7, 7.3.6.8, 7.3.6.9, 7.3.6.10, 7.3.7.1, 7.3.7.2, 7.373,73.74,73.7.5,73.7.6,7.3.7.7, 7.3.7.8, 7.3.7.9, 7.3.7.10, 7.3.8.1, 7.3.8.2, 7.3.8.3, 7.3.8.4, 7.3.8.5,7.3.8.6,7.3.8.7, 7.3.8.8, 7.3.8.9, 7.3.8.10, 7.3.9.1, 7.3.9.2, 7.3.9.3, 7.3.9.4, 7.3.9.5, 7.3.9.6, 7.3.9.7,7.3.9.8,7.3.9.9,7.3.9.10, 7.3.10.1, 7.3.10.2, 7.3.10.3, 7.3.10.4, 7.3.10.5, 7.3.10.6, 7.3.10.7, 7.3.10.8, 7.3.10.9, 7.3.10.10, 7.4.1.1, 7.4.1.2, 7.4.1.3, 7.4.1.4, 74.15, 7.4.1.6, 7.4.1.7, 7.4.1.8, 7.4.19,74.1.10,74.2.1,742.2,7423,742.4,74.2.5,742.6,74.2.7,7.42.8,74.29,7.4.2.10, : 743.1,7.43.2,743.3,74.3.4,74.3.5,743.6,7.43.7,743.8,743.9,74.3.10,744.1,744.2, 74.43,7444,7445,74.4.6,74.4.7,744.8,7.44.9,744.10,7.45.1,7452,74.53,7454, 7.4.55,745.6,745.7,7458,74.59,74.5.10,74.6.1,7.4.6.2,7.4.6.3,7.4.6.4,7.4.6.5,7.4.6.6, 7.4.6.7,7.4.6.8,7.4.69,74.6.10,74.7.1,74.7.2,74.73,74.74,7.4.75,7.4.7.6,74.7.7,74.7.8, 7.479,74.7.10,74.8.1,748.2,74.83,74.84,74.8.5,7.48.6,7.4.8.7,7.4.8.8,7.4.8.9, 7.48.10, 7.49.1,749.2,7493,74.9.4,749.5,749.6,749.7,7498,7.49.9,7.4.9.10,7.4.10.1, 3 7.4.102,7.4.10.3,7.4.10.4, 7.4.10.5, 7.4.10.6, 7.4.10.7, 7.4.10.8, 7.4.10.9, 7.4.10.10, 7.5.1.1,
S 7.5.1.2,7513,75.14,75.15,75.1.6,7.5.1.7,7.5.1.8,7.5.19,7.5.1.10, 7.5.2.1, 7.5.2.2, 7.5.2.3, + + 7.52.4,7525,752.6,75.2.7,7.52.8,7.52.9,7.5.2.10, 7.53.1, 7.5.3.2, 7.5.3.3, 7.5.3.4, 7.5.3.5, be 20 7.53.6,7.53.7,7.53.8,7.53.9,7.5.3.10,7.54.1,7.54.2,7.54.3,7.54.4,7.54.5,7.5.4.6,7.5.4.7, i. 7.5.4.8,7.549,754.10,7.5.5.1,7.552,7.553,7.5.5.4,7.5.5.5,7.5.5.6,7.5.5.7,7.5.5.8, 7.5.5.9, : i 7.5.5.10,7.5.6.1,7.5.6.2,7.5.6.3,7.5.6.4,7.5.6.5, 7.5.6.6, 7.5.6.7, 7.5.6.8, 7.5.6.9, 7.5.6.10, 7.5.7.1, ; 15.72,75.73,7.5.74,75.7.5,7.5.16,7.5.7.7,7.5.1.8,7.5.79,7.5.7.10, 7.5.8.1, 7.5.8.2, 7.5.8.3, 7.5.8.4,7.5.8.5,7.58.6,7.5.8.7,7.5.8.8,7.5.89,7.5.8.10, 7.5.9.1, 7.5.9.2, 7.5.9.3, 7.5.9.4, 7.5.9.5, 7.59.6,7.59.7,7.59.8,7.59.9,7.5.9.10, 7.5.10.1, 7.5.10.2, 7.5.10.3, 7.5.10.4, 7.5.10.5, 7.5.10.6, 7.5.10.7,7.5.10.8, 7.5.10.9, 7.5.10.10, 7.6.1.1, 7.6.1.2, 7.6.1.3, 7.6.1.4, 7.6.1.5, 7.6.1.6, 7.6.1.7, 7.6.1.8,7.6.1.9,7.6.1.10,7.6.2.1,7.6.2.2,7.6.2.3,7.6.2.4,7.6.2.5,7.6.2.6,7.6.2.7,7.6.2.8, 7.6.2.9, 7.62.10,7.6.3.1,7.6.3.2,7.6.3.3,7.6.3.4,7.6.3.5, 7.6.3.6, 7.6.3.7, 7.6.3.8, 7.6.3.9, 7.6.3.10, 7.6.4.1, -7.6.42,7.643,7.64.4,7.6.45,7.64.6,7.64.7,764.8,76.4.9,7.6.4.10,7.6.5.1,7.6.5.2, 7.6.5.3, 7.6.54,7.6.5.5,7.6.5.6,7.6.5.7,7.6.5.8,7.6.5.9,7.6.5.10,7.6.6.1,7.6.6.2,7.6.6.3, 7.6.6.4, 7.6.6.5, 7.6.6.6, 7.6.6.7, 7.6.6.8, 7.6.6.9, 7.6.6.10, 7.6.7.1, 7.6.7.2, 7.6.7.3, 7.6.74, 7.6.7.5, 7.6.1.6, 7.6.7.7, 7.6.7.8,7.6.7.9,7.6.7.10,7.6.8.1,7.6.8.2, 7.6.8.3, 7.6.8.4, 7.6.8.5, 7.6.8.6, 7.6.8.7, 7.6.8.8, 7.6.8.9, 7.6.8.10,7.6.9.1,7.6.9.2,7.6.9.3,7.6.9.4, 7.6.9.5, 7.6.9.6, 7.6.9.7, 7.6.9.8, 7.6.9.9, 7.6.9.10, 7.6.10.1,7.6.10.2,7.6.10.3, 7.6.10.4, 7.6.10.5, 7.6.10.6, 7.6.10.7, 7.6.10.8, 7.6.10.9, 7.6.10.10, 7.71.1,77.12,7.713,7.7.14,7715,77.1.6,7.7.1.7,7.7.1.8,7.7.19,7.7.1.10, 7.7.2.1, 7.72.2,
7.72.3,7.72.4,7.72.5,7.72.6,7.72.7,7.7.2.8,7.7.2.9, 7.72.10, 7.73.1, 7.73.2, 1.73.3, 7.73.4, 7.73.5,7.73.6,7.73.7,7.73.8,7.73.9,7.73.10, 1.7.4.1, 7.74.2, 7.7.4.3, 7.7.4.4, 1.7.4.5, 7.7.4.6, 7.74.7,1.74.8,7.749,7.74.10,7.75.1, 7.75.2, 7.7.5.3, 7.1.5.4, 7.7.5.5, 7.7.5.6, 1.7.5.7, 7.7.5.8, 7.1.5.9,7.7.5.10,7.7.6.1, 7.7.6.2, 7.7.6.3, 7.7.6.4, 1.7.6.5, 7.1.6.6, 1.7.6.7, 1.7.6.8, 7.7.6.9, 7.7.6.10,
777.1,7.7.7.2,7.1.13,71.7.4,1.7.1.5,7.1.7.6,1.7.1.7,7.1.1.8, 7.7.7.9, 7.7.7.10, 7.7.8.1, 7.7.8.2, 7.7.83,7.7.8.4,7.7.8.5,7.7.8.6, 7.7.8.7, 7.7.8.8, 7.7.8.9, 7.78.10, 7.7.9.1, 7.7.9.2, 7.7.9.3, 7.7.9.4, 7.7.9.5,7.7.9.6,7.7.9.7, 7.7.9.8, 7.7.9.9, 7.7.9.10, 7.7.10.1, 7.7.10.2, 7.7.10.3, 7.7.10.4, 7.7.10.5, 7.7.10.6,7.7.10.7, 7.7.10.8, 7.7.10.9, 7.7.10.10, 7.8.1.1, 7.8.1.2, 7.8.1.3, 7.8.1.4, 7.8.1.5, 7.8.1.6, 7.8.1.7,7.8.1.8,7.8.1.9,7.8.1.10, 7.8.2.1, 7.8.2.2, 7.8.2.3, 7.8.2.4, 7.8.2.5, 7.8.2.6, 7.8.2.7, 7.8.2.8, : 10 7.829,7.82.10,7.83.1,7.8.32,7.83.3,7.8.3.4,7.8.3.5, 7.8.3.6, 7.8.3.7, 7.8.3.8, 7.8.3.9, 7.8.3.10, 7.8.4.1,7.8.4.2,7.8.4.3,7.8.4.4,7.8.4.5,7.8.4.6,7.8.4.7,7.84.8,7.8.4.9, 7.84.10, 7.8.5.1, 7.8.5.2, 7.8.5.3,7.8.5.4, 7.8.5.5, 7.8.5.6, 7.8.5.7, 7.8.5.8, 7.8.5.9, 7.85.10, 7.8.6.1, 7.8.6.2, 7.8.6.3, 7.8.6.4, 7.8.6.5, 7.8.6.6, 7.8.6.7, 7.8.6.8, 7.8.6.9, 7.8.6.10, 7.8.7.1, 7.8.7.2, 7.8.7.3, 7.8.7.4, 7.8.7.5, 7.8.7.6, 7.8.7.7,7.8.7.8,7.8.7.9, 7.8.7.10, 7.8.8.1, 7.8.8.2, 7.8.8.3, 7.8.8.4, 7.8.8.5, 7.8.8.6, 7.8.8.7, 7.8.8.8,
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. 79.2.3,7.9.2.4,7.92.5,79.2.6,7.9.2.7,7.9.2.8, 7.9.2.9, 7.92.10, 7.9.3.1, 7.9.3.2, 7.9.3.3, 7.9.3 4, : 7.9.3.5,7.9.3.6,7.9.3.7,7.9.3.8,7.9.3.9,7.9.3.10, 7.9.4.1,7.9.4.2, 7.9.43, 7.9.4.4, 7.9.4.5, 7.9.4.6,
79.4.7,79.4.8,7.9.49,79.4.10,7.9.5.1,7.9.5.2, 7.9.53, 7.9.5.4, 7.9.5.5, 7.9.5.6, 7.9.5.7, 7.9.5.8, : 7.9.5.9,7.9.5.10,7.9.6.1,79.6.2,7.9.6.3,7.9.6.4,7.9.6.5, 7.9.6.6, 7.9.6.7, 7.9.6.8, 7.9.6.9, 7.9.6.10, 7.9.7.1,7.9.7.2,7.9.7.3,79.7.4,7.9.7.5,7.9.7.6, 7.9.7.7, 7.9.7.8, 7.9.7.9, 7.9.7.10, 7.9.8.1, 7.9.8.2, 7.9.8.3,7.9.8.4,7.9.8.5,7.9.8.6,7.9.8.7, 7.9.8.8, 7.9.8.9, 7.9.8.10, 7.9.9.1, 7.9.9.2, 7.9.9.3, 7.9.9.4, 7.9.9.5,7.9.9.6,7.9.9.7,7.9.9.8, 7.9.9.9, 7.99.10, 7.9.10.1, 7.9.10.2, 7.9.10.3, 7.9.10.4, 7.9.10.5,
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SU 8.3.1.3,8.3.1.4,83.1.5,8.3.1.6, 8.3.1.7, 8.3.1.8, 8.3.1.9, 8.3.1.10, 8.3.2.1, 8.3.2.2, 8.3.2.3, 8.3.2.4, a 8.3.2.5,8.3.2.6,8.3.2.7,8.3.2.8,83.2.9,8.3.2.10, 83.3.1, 83.3.2, 8.3.3.3, 8.3.3.4, 8.3.3.5, 83.3.6, bo. 20 8.3.3.7,83.3.8,83.3.9,83.3.10,83.4.1,83.4.2,83.43,83.44,83.45,83.4.6,834.7,83.48, oe 8.3.4.9;8.3.4.10,8.3.5.1, 8.3.5.2, 8.3.5.3, 8.3.5.4, 8.3.5.5, 8.3.5.6, 8.3.5.7, 8.3.5.8, 8.3.5.9, 8.3.5.10, : 83.6.1,8.3.6.2,8.3.6.3,83.6.4,83.6.5 83.6.6 83.6.7,83.6.8,83.69,83.6.10,83.7.1,83.7.2, : ; 8.3.7.3,83.7.4,8.3.7.5,8.3.7.6, 8.3.7.7, 8.3.7.8, 83.7.9, 8.3.7.10, 8.3.8.1, 8.3.8.2, 8.3.8.3, 8.3.8.4, 8.3.8.5,8.3.8.6,8.3.8.7,8.3.8.8,8.3.8.9,8.3.8.10,83.9.1,83.9.2,83.9.3,83.94, 83.9.5, 83.9.6, 8.3.9.7,83.9.8,8.3.9.9,8.3.9.10,8.3.10.1,83.10.2, 8.3.10.3, 8.3.10.4, 8.3.10.5, 8.3.10.6, 8.3.10.7, 8.3.10.8, 8.3.10.9, 8.3.10.10, 8.4.1.1, 8.4.1.2, 8.4.1.3, 8.4.1.4, 8.4.1.5, 8.4.1.6, 8.4.1.7, 8.4.1.8, 8.4.1.9,84.1.10,8.4.2.1,8.4.2.2,8.4.2.3,84.2.4,84.25,84.2.6,8.4.2.7,8.4.2.8, 8.4.2.9, 8.4.2.10, 8.4.3.1,8.4.3.2,843.3,8.4.3.4,843.5, 843.6, 843.7,84.3.8,84.3.9,84.3.10,84.4.1, 8.4.4.2, 8.4.43,8.4.4.4,8.4.4.5 8.4.4.6,844.7,84.4.8 84.4.9 84.4.10,8.4.5.1,84.5.2, 84.5.3, 8.4.5.4, 8.4.5.5,84.5.6,8.4.5.7, 8.4.5.8, 8.4.5.9, 8.4.5.10,8.4.6.1, 8.4.6.2, 8.4.6.3, 8.4.6.4, 8.4.6.5, 8.4.6.6, 8.4.6.7,8.4.6.8,8.4.6.9,8.4.6.10,84.7.1,8.4.72,8.4.73, 8.4.7.4, 8.4.7.5,8.4.7.6, 8.4.7.7, 8.4.7.8, 8.4.7.9,8.4.7.10,8.4.8.1, 8.4.8.2, 8.4.83, 8.4.8.4, 8.4.8.5, 8.4.8.6, 8.4.8.7,8.4.8.8, 8.4.8.9, 8.4.8.10, 8.49.1,84.9.2,8.493,84.9.4,849.5, 84.9.6, 849.7,8.4.9.8, 8.4.9.9, 8.49.10, 8.4.10.1, 8.4.10.2, 8.4.10.3, 8.4.10.4, 8.4.10.5, 8.4.10.6, 8.4.10.7, 8.4.10.8, 8.4.10.9, 8.4.10.10, 8.5.1.1, 85.1.2,85.1.3,8.5.1.4, 8.5.1.5, 8.5.1.6, 8.5.1.7, 8.5.1.8, 8.5.1.9, 8.5.1.10, 8.5.2.1, 8.5.2.2, 8.5.2.3,
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R841 8842, 8843 8844 8845 8846 884728428840 2824108851 8852, 8.8.5.3, 8.8.5.4, 8.8.5.5, 8.8.5.6, 8.8.5.7, 8.8.5.8, 8.8.5.9, 8.8.5.10, 8.8.6.1, 8.8.6.2, 8.8.6.3, 8.8.6.4, 8.8.6.5,8.8.6.6,8.8.6.7, 8.8.6.3, 8.8.6.9, 8.8.6.10, 8.3.7.1,8.8.7.2, 8.8.7.3, 8.8.7.4, 8.3.7.5, 8.8.7.6, 8.8.7.7, 8.8.7.8, 8.8.7.9, 8.8.7.10, 8.8.8.1, 8.8.8.2, 8.8.8.3, 8.8.8.4, 8.8.8.5, 8.8.8.6, 8.8.8.7, 8.8.8.8, 8.8.8.9, 8.8.8.10, 8.8.9.1, 8.8.9.2, 8.8.9.3, 8.8.9.4, 8.8.9.5, 8.8.9.6, 8.8.9.7, 8.8.9.8, 8.8.9.9, 8.8.9.10, 8.8.10.1,8.8.10.2, 8.8.10.3, 8.8.10.4, 8.8.10.5, 8.8.10.6, 8.8.10.7, 8.8.10.8, 8.8.10.9, 8.8.10.10, 89.1.1,89.1.2,8.9.1.3,89.1.4,8.9.1.5,8.9.1.6,8.9.1.7, 89.1.8, 8.9.1.9, 8.9.1.10, 8.9.2.1, 8.9.2.2, 89.23 8924, 68925 89.26 89.2.7 89.2.8,8929,89.2.10,89.3.1,8.9.3.2,893.3,89.34,
4 ¢ 8.9.3.5,8.9.3.6,8.9.3.7,8.9.3.8,8.9.3.9,8.9.3.10, 8.9.4.1, 8.9.4.2, 8.9.4.3, 8.9.4.4, 8.9.4.5,8.9.4.6, 8.9.47,89.4.8,8949,89.4.10,89.5.1,8.9.5.2,8.9.53,8.9.5.4,89.5.5,8.9.5.6, 8.9.5.7, 8.9.5.8, 8.9.5.9,8.9.5.10,8.9.6.1,8.9.6.2, 8.9.6.3, 8.9.6.4, 8.9.6.5, 8.9.6.6, 8.9.6.7, 8.9.6.8, 8.9.6.9, 8.9.6.10, 8.9.7.1,8.9.7.2,8.9.7.3,8.9.7.4,8.9.7.5,8.9.7.6, 8.9.7.7, 8.9.7.8, 8.9.7.9, 8.9.7.10, 8.9.3.1, 8.9.8.2, 89.83,89.84,8.9.8.5,8.9.8.6,8.9.8.7, 8.9.8.8, 8.9.8.9, 8.9.8.10, 8.9.9.1, 8.9.9.2, 8.9.9.3, 8.9.9.4, 8.9.95,8.9.9.6,8.9.9.7,8.9.9.8,8.9.9.9, 8.9.9.10, 8.9.10.1, 8.9.10.2, 8.9.10.3, 8.9.10.4, 8.9.10.5, 8.9.10.6, 8.9.10.7, 8.9.10.8, 8.9.10.9, 8.9.10.10, 8.10.1.1, 8.10.1.2, 8.10.1.3, 8.10.1.4, 8.10.1.5, 8.10.1.6, 8.10.1.7, 8.10.1.8, 8.10.1.9, 8.10.1.10, 8.10.2.1, 8.10.2.2, 8.10.2.3, 8.10.2.4, 8.10.2.5, 8.10.2.6, 8.10.2.7, 8.10.2.8, 8.10.2.9, 8.10.2.10, 8.10.3.1, 8.10.3.2, 8.10.3.3, 8.10.3.4, 8.10.3.5, 8.10.3.6,8.10.3.7, 8.10.3.8, 8.10.3.9, 8.10.3.10, 8.10.4.1, 8.10.4.2, 8.10.4.3, 8.10.4.4, 8.10.4.5, 8.10.4.6, 8.10.4.7, 8.10.4.8, 8.10.4.9, 8.10.4.10, 8.10.5.1, 8.10.5.2, 8.10.5.3, 8.10.5.4, 8.10.5.5, 8.10.5.6, 8.10.5.7, 8.10.5.8, 8.10.5.9, 8.10.5.10, 8.10.6.1, 8.10.6.2, 8.10.6.3, 8.10.6.4, 8.10.6.5, 8.10.6.6, 8.10.6.7, 8.10.6.8, 8.10.6.9, 8.10.6.10, 8.10.7.1, 8.10.7.2, 8.10.7.3, 8.10.7.4, 8.10.7.5, 8.10.7.6, 8.10.7.7, 3.10.7.8, 8.10.7.9, 8.10.7.10, 8.10.8.1, 8.10.8.2, 8.10.8.3, 8.10.8 .4, 8.10.8.5, 8.10.8.6, 8.10.8.7, 8.10.8.8, 8.10.8.9, 8.10.8.10, 8.10.9.1, 8.10.9.2, 8.10.9.3, 8.10.9.4, 8.10.9.5, : 8.10.9.6, 8.10.9.7, 8.10.9.8, 8.10.9.9, 8.10.9.10, 8.10.10.1, 8.10.10.2, 8.10.10.3, 8.10.10.4, . 8.10.10.5, 8.10.10.6, 8.10.10.7, 8.10.10.8, 8.10.10.9, 8.10.10.10, 9.1.1.1, 9.1.1.2, 9.1.1.3, 9.1.1.4, . 9.1.15,9.1.1.6,9.1.1.7,9.1.1.8,9.1.1.9,9.1.1.10,9.1.2.1,9.1.2.2,9.1.2.3,9.1.2.4,9.1.2.5, 9.1.2.6, 9.1.2.7,9.1.2.8,9.1.2.9,9.1.2.10,9.1.3.1,9.1.3.2,9.1.3.3,9.1.3.4, 9.1.3.5, 9.1.3.6, 9.1.3.7, 9.1.3.8,
FON 20 9.1.3.9,9.1.3.10,9.1.4.1,9.1.4.2,9.1.43,9.1.4.4,9.1.45,9.1.4.6,9.1.4.7,9.1.4.8, 9.1.4.9, 9.14.10,
Ll 9.1.5.1,9.1.52,9.1.5.3,9.1.5.4,9.1.5.5,9.1.5.6,9.1.5.7,9.1.5.8, 9.1.5.9, 9.1.5.10, 9.1.6.1, 9.1.6.2, 9.1.6.3,9.1.6.4,9.1.6.5,9.1.6.6,9.1.6.7,9.1.6.8, 9.1.6.9, 9.1.6.10, 9.1.7.1, 9.1.7.2, 9.1.7.3, 9.1.7 4, ! 9.1.7.5,9.1.7.6,9.1.7.7,9.1.7.8,9.1.7.9,9.1.7.10, 9.1.8.1, 9.1.8.2, 9.1.8.3, 9.1.8.4, 9.1.8.5, 9.1.8.6, 9.1.8.7,9.1.8.8,9.1.8.9,9.1.8.10,9.1.9.1,9.1.9.2,9.1.9.3,9.1.9.4, 9.1.9.5, 9.1.9.6, 9.1.9.7, 9.1.9.8, 9.1.99,9.1.9.10,9.1.10.1,9.1.10.2, 9.1.10.3,9.1.10.4, 9.1.10.5, 9.1.10.6, 9.1.10.7, 9.1.10.8, 9.1.10.9,9.1.10.10,9.2.1.1,9.2.1.2, 9.2.1.3, 9.2.1.4, 9.2.1.5, 9.2.1.6, 9.2.1.7, 9.2.1.8, 9.2.1.9, 9.2.1.10,9.2.2.1,9.2.2.2,9.2.23,9.2.2.4,9.2.2.5,9.2.2.6,9.2.2.7,9.2.2.8,9.2.2.9,9.2.2.10, 9.2.3.1, 9.23.2,9.23.3,9.2.3.4,9.23.5,9.2.3.6,9.2.3.7,9.2.3.8,9.2.3.9,9.2.3.10,9.2.4.1,9.2.4.2,9.2.4 3, 9.244,9245,924.6,9.24.7,9.2.48,9249,9.2.4.10,9.25.1,9.2.5.2,9.2.5.3,9.2.54,9.2.5.5, 30. 9.2.5.6,9.2.5.7,9.2.5.8,9.2.5.9,9.2.5.10,9.2.6.1,9.2.6.2,9.2.6.3, 9.2.6.4, 9.2.6.5, 9.2.6.6, 9.2.6.7, 9.2.6.8,92.69,9.2.6.10,9.2.7.1,9.2.7.2,9.2.73,9.2.74,92.7.5,9.2.7.6,9.2.7.7,9.2.7.8, 92.7.9, 9.2.7.10,9.2.8.1,9.2.8.2,9.2.8.3,9.2.8.4,9.2.8.5,9.2.8.6,9.2.8.7,9.2.8.8, 9.2.8.9,9.2.8.10, 9.2.9.1, 9.2.9.2,9.2.93,9.29.4,925.5,9.29.6,929.7,9.2.9.8,9.2.9.9,9.2.9.10, 9.2.10.1, 9.2.10.2, 9.2.10.3,9.2.10.4,9.2:10.5, 9.2.10.6,9.2.10.7, 9.2.10.8, 9.2.10.9, 9.2.10.10, 9.3.1.1, 9.3.1.2, 93.13,93.14,93.15,9.3.1.6,93.1.7,9.3.1.8,9.3.1.9,9.3.1.10,9.3.2.1,9.3.2.2,9.3.2.3, 9.3.2.4,
Ee 9.3.2.5,93.2.6,9.3.2.7,9.3.2.8,9.3.29,932.10,933.1,933.2,933.3,9.3.3.4,933.5,9.3 36, 9.3.3.7,93.3.8,9.33.9,933.10,93.4.1,9.34.2,93.43,93.4.4,93.4.5,93.456,934.7, 93.438, 9.3.49,93.4.10,9.3.5.1,9.3.5.2,93.53,93.54,9.3.55,93.5.6,9.3.5.7,93.5.8, 9.3.5.9, 9.3 5.10, 9.3.6.1,9.3.62,9.3.6.3,93.6.4,9.3.6.5,93.6.6,9.3.6.7,9.3.68,93.6.9,93.6.10,9.37.1,93.7.2, : 5 93.73,93.74,93.75,93.7.6,9.3.7.7,9.3.7.8,9.3.7.9,9.3.7.10,93.8.1,9.3.82, 9.3.8.3, 9.3.8.4, 9.3.8.5,9.3.8.6,93.8.7,9.3.8.8,93.89,93.8.10,9.3.9.1,93.9.2,93.9.3,9.3.9.4,9.39.5,9.3.9.6, 9.3.9.7,93.9.8,9.3.9.9,9.3.9.10,9.3.10.1,93.10.2,9.3.103,93.10.4, 93.10.5, 9.3.10.6, 9.3.10.7, 9.3.10.8,9.3.10.9,93.10.10,9.4.1.1,9.4.1.2,9.4.13,9.4.1.4,9.4.1.5, 9.4.1.6, 9.4.1.7, 9.4.1.8, 9.4.1.9,9.4.1.10,9.4.2.1,9.4.22,9.42.3,9.42.4,94.2.5,9.4.2.6,9.4.2.7,9.4.2.8, 9.4.2.9, 9.42.10, 9.43.1,9432,9.4.33,9.434,9.43.5,9.4.3.6,9.4.3.7,9.4.3.8,9.43.9,9.43.10,9.4.4.1,9.4.4.2, 9.4.4.3,9.4.4.4,9.44.5,9.4.4.6,9.4.4.7,9.4.4.8,9.4.49,9.4.4.10,9.4.5.1,9.4.52,9.4.5.3,9.4.5.4, 9.4.5.5,9.4.5.6,9.4.5.7,9.4.5.8,9.4.5.9,9.4.5.10,9.4.6.1,9.4.6.2, 9.4.6.3, 9.4.6.4, 9.4.6.5, 9.4.6.6, 9.4.6.7,9.4.6.8,9.4.6.9,9.4.6.10,9.4.7.1,9.4.7.2,9.4.7.3,9.4.7.4,9.4.7.5,9.4.7.6, 9.4.1.7, 9.4.7.8, 9.4.7.9,9.4.7.10,9.4.8.1, 9.4.8.2, 9.4.8.3,9.4.8.4,9.4.8.5,9.4.8.6, 9.4.8.7, 9.4.8.8, 9.4.8.9, 9.4.3.10, 94.9.1,9.49.2,9.493,9.494,9.49.5,9.4.9.6,9.49.7,9.49.8,9.4.9.9,9.4.9.10, 9.4.10.1, 9.4.10.2,9.4.10.3,9.4.10.4, 9.4.10.5, 9.4.10.6, 9.4.10.7, 9.4.10.8, 9.4.10.9, 9.4.10.10, 9.5.1.1, - 9.5.12,9.5.1.3,9.5.1.4, 9.5.1.5, 9.5.1.6, 9.5.1.7, 9.5.1.8, 9.5.1.9, 9.5.1.10, 9.5.2.1, 9.5.2.2, 9.5.2.3, . 9.5.2.4,9.5.2.5,9.5.2.6, 9.5.2.7, 9.5.2.8, 9.5.2.9, 9.5.2.10, 9.5.3.1, 9.5.3.2, 9.5.3.3, 9.5.3.4, 9.5.3.5,
B 9.5.3.6,9.5.3.7,9.53.8,9.5.3.9,9.5.3.10,9.5.4.1,9.5.4.2,9.54.3, 9.5.4.4, 9.5.4.5,9.5.4.6,9.5.4.7, : 20 9.5.4.8,9.5.4.9,9.5.4.10, 9.5.5.1, 9.5.5.2, 9.5.5.3, 9.5.5.4, 9.5.5.5, 9.5.5.6, 9.5.5.7, 9.5.5.8, 9.5.5.9, 9.5.5.10,9.5.6.1,9.5.6.2, 9.5.6.3, 9.5.6.4,9.5.6.5,9.5.6.6,9.5.6.7, 9.5.6.8, 9.5.6.9, 9.5.6.10, 9.5.7.1, 9.5.7.2,9.5.7.3,9.5.74,9.5.7.5,9.5.7.6, 9.5.7.7, 9.5.7.8,9.5.79, 9.5.7.10, 9.5.8.1, 9.5.8.2, 9.5.8.3, 9.5.8.4,9.5.8.5,9.5.8.6,9.5.8.7, 9.5.8.8, 9.5.8.9, 9.5.8.10, 9.5.9.1, 9.5.9.2, 9.5.9.3, 9.5.9.4, 9.5.9.5, 9.5.9.6,9.5.9.7,9.59.8,9.5.9.9,9.5.9.10,9.5.10.1,9.5.10.2, 9.5.10.3, 9.5.10.4, 9.5.10.5, 9.5.10.6, 9.5.10.7,9.5.10.8,9.5.10.9,9.5.10.10, 9.6.1.1, 9.6.1.2, 9.6.1.3, 9.6.1.4, 9.6.1.5, 9.6.1.6, 9.6.1.7, 9.6.1.8,9.6.1.9,9.6.1.10, 9.6.2.1, 9.6.2.2,9.6.2.3, 9.6.2.4, 9.6.2.5, 9.6.2.6, 9.6.2.7, 9.6.2.8, 9.6.2.9, 9.6.2.10,9.6.3.1,9.6.3.2,9.6.3.3,9.6.3.4,9.6.3.5, 9.6.3.6, 9.6.3.7, 9.6.3.8, 9.6.3.9, 9.63.10, 9.6.4.1, 5.6.4.2,9.6.43,5.644,9.64.5,9.6.4.6,964.7,0648 0649 064.10,065.1, 0652 06523, 9.6.5.4,9.6.5.5,9.6.5.6,9.6.5.7,9.6.5.8, 9.6.5.9, 9.6.5.10,9.6.6.1, 9.6.6.2, 9.6.6.3, 9.6.6.4, 9.6.6.5, 9.6.6.6,9.6.6.7,9.6.6.8,9.6.69, 9.6.6.10,9.6.7.1,9.6.7.2, 9.6.7.3, 9.6.7.4, 9.6.1.5, 9.6.7.6, 9.6.7.7, 9.6.7.8, 9.6.7.9, 9.6.7.10, 9.6.8.1, 9.6.8.2, 9.6.8.3, 9.6.8.4, 9.6.8.5, 9.6.8.6, 9.6.8.7, 9.6.8.8, 9.6.8.9, 9.6.8.10,9.69.1,9.6.9.2, 9.6.9.3,9.6.9.4, 9.6.9.5, 9.6.9.6, 9.6.9.7, 9.6.9.8, 9.6.9.9, 9.6.9.10, 9.6.10.1,9.6.10.2, 9.6.10.3, 9.6.10.4, 9.6.10.5, 9.6.10.6, 9.6.10.7, 9.6.10.8, 9.6.10.9, 9.6.10.10, 9.7.1.1,9.7.1.2,9.7.13,9.7.1.4,9.7.1.5,9.7.1.6,9.7.1.7,9.7.1.8,9.7.1.9,9.7.1.10,9.7.2.1,9.7.2.2, 9.7.23,9.7.2.4,9.7.2.5,9.7.2.6,9.7.2.7,9.7.2.8,9.7.2.9,9.7.2.10,9.7.3.1,9.7.3.2, 9.7.3.3, 9.7.3.4,
EY KJ
9.7.3.5,9.7.3.6,9.7.3.7,9.7.3.8,9.73.9,9.7.3.10,9.7.4.1,9.7.4.2, 9.7.4.3, 9.7.4.4,9.7.4.5, 9.7.4.6, 9.7.4.7,9.7.4.8,9.7.4.9,9.7.4.10,9.7.5.1,9.7.5.2,9.7.5.3,9.7.5.4, 9.7.5.5, 9.7.5.6, 9.7.5.7, 9.7.5.8, 9.7.5.9,9.7.5.10,9.7.6.1,9.7.6.2,9.7.6.3, 9.7.6 .4,9.7.6.5, 9.7.6.6, 9.7.6.7, 9.7.6.8, 9.7.6.9, 9.7.6.10, 9.7.7.1,9.7.7.2,9.7.7.3,9.7.7.4,9.1.1.5,9.7.7.6,9.7.7.7,9.7.7.8, 9.7.7.9, 9.7.7.10,9.7.8.1, 9.7.8.2, 9.7.83,9.7.84,9.7.8.5,9.7.8.6,9.7.8.7,9.7.8.8, 9.7.8.9, 9.7.8.10, 9.7.9.1, 9.7.9.2, 9.7.9.3, 9.7.9.4, 9.79.5,9.7.9.6,9.7.9.7,9.7.9.8,9.7.9.9, 9.7.9.10, 9.7.10.1, 9.7.10.2, 9.7.10.3, 9.7.10.4, 9.7.10.5, 9.7.10.6,9.7.10.7,9.7.10.8, 9.7.10.9, 9.7.10.10, 9.8.1.1, 9.8.1.2, 9.8.1.3, 9.8.1.4, 9.8.1.5, 9.8.1.6, 9.8.1.7,9.8.1.8,9.8.1.9,9.8.1.10,9.8.2.1,9.82.2,9.8.2.3,9.8.2.4,9.8.2.5,9.8.2.6,9.8.2.7, 9.8.2.8, 9.8.2.9,9.8.2.10,9.8.3.1,9.8.3.2,9.83.3,9.8.3.4,9.83.5,9.8.3.6,9.8.3.7,9.8.3.8,9.8.3.9,9.8.3.10, 9.84.1,9.84.2,9.84.3,9.84.4,9.84.5,9.8.4.6,9.84.7,9.84.8,9.84.9,9.8.4.10,9.85.1,9.8.5.2, 9.8.5.3,9.8.5.4,9.8.5.5,9.8.5.6,9.8.5.7,9.8.5.8,9.8.5.9,9.8.5.10, 9.8.6.1, 9.8.6.2, 9.8.6.3, 9.8.6.4, 9.8.6.5,9.8.6.6,9.8.6.7,9.8.6.8,9.8.6.9,9.8.6.10,9.8.7.1,9.8.7.2,9.8.7.3,9.8.7.4,9.8.7.5, 9.8.7.6, 9.8.7.7,9.8.7.8,9.8.7.9,9.8.7.10,9.8.8.1,9.8.8.2,9.8.8.3,9.8.8.4, 9.8.8.5, 9.8.8.6, 9.8.8.7, 9.8.8.8, 9.8.8.9,9.8.8.10,9.8.9.1,9.8.9.2,9.89.3,9.8.9.4,9.83.9.5,9.8.9.6, 9.8.9.7, 9.8.9.8, 9.8.9.9, 9.8.9.10, 9.8.10.1,9.8.10.2,9.8.10.3, 9.8.10.4, 9.8.10.5, 9.8.10.6, 9.8.10.7, 9.8.10.8, 9.8.10.9, 9.8.10.10, 9.9.1.1,9.9.1.2,9.9.1.3,9.9.1.4,9.9.1.5,9.9.1.6,9.9.1.7,9.9.1.8,9.9.1.9,9.9.1.10, 9.9.2.1, 9.9.2.2, 99.23,99.24,992.5,992.6,99.2.7,9.9.2.8,9.92.9,9.9.2.10,9.9.3.1,9.9.3.2,9.9.3.3, 9.9.3.4, 9.9.3.5,9.9.3.6,9.9.3.7,9.9.3.8,9.93.9,9.9.3.10,9.9.4.1,9.9.4.2, 9.9.4.3, 9.9.4.4,9.9.4.5, 9.9.4.6, 99.47,99.4.8,99.49,994.10,99.5.1,9.9.5.2,9.9.53,9.9.54,9.9.5.5,9.9.5.6,9.9.5.7, 9.9.5.8, : 20 9.9.5.9,99.5.10,9.9.6.1,9.9.6.2,9.9.6.3, 9.9.6.4, 9.9.6.5, 9.9.6.5, 9.9.6.7, 9.9.6.8, 9.9.6.9, 9.9.6.10, 99.7.1,99.7.2,99.7.3,9.9.7.4,9.9.7.5,9.9.7.6,9.9.7.7,9.9.7.8,9.9.7.9,9.9.7.10,9.9.8.1, 9.9.8.2, 9.9.8.3,9.9.8.4,9.9.8.5,9.9.8.6,9.9.8.7,9.9.8.8,9.9.8.9,9.9.8.10, 9.9.9.1,9.9.9.2, 9.9.9.3, 9.9.9.4, 9.995,9.99.6,99.9.7,9.9.9.8,9.9.9.9,9.9.9.10,9.9.10.1, 9.9.10.2, 9.9.10.3, 9.9.10.4, 9.9.10.5, 9.9.10.6,9.9.10.7, 9.9.10.8, 92.9.10.9,9.9.10.10, 9.10.1.1, 9.10.1.2, 9.10.1.3, 9.10.1.4, 9.10.1.5, 9.10.16,9.10.1.7,9.10.1.8, 9.10.1.9,9.10.1.10, 9.10.2.1,9.10.2.2, 9.10.2.3, 9.10.24, 9.10.2.5, 9.10.2.6,9.10.2.7,9.10.2.8, 9.10.2.9, 9.10.2.10,9.10.3.1,9.10.3.2, 9.10.3.3, 9.10.3 .4, 9.10.3.5, 9.10.3.6,9.10.3.7,9.10.3.8, 9.10.3.9,9.10.3.10,9.10.4.1,9.10.4.2, 9.10.4 .3, 9.10.4 4, 9.10.4.5, 9.10.4.6,9.10.4.7,9.10.4.8, 9.10.4.9,9.10.4.10, 9.10.5.1,9.10.5.2, 9.10.5.3,9.10.5.4, 9.10.5.5, 9.10.5.6,9.10.5.7,9.10.5.8,9.10.5.9,9.10.5.10, 9.10.6.1,9.10.6.2, 9.10.6.3, 9.10.6 .4, 9.10.6.5, 9.10.6.6,9.10.6.7,9.10.6.8,9.10.6.9,9.10.6.10, 9.10.7.1, 9.10.7.2, 9.10.7.3, 9.10.7 4, 9.10.7.5, 9.10.7.6,9.10.7.7,9.10.7.8, 9.10.7.9, 9.10.7.10, 9.10.81, 9.10.8.2, 9.10.8.3, 9.10.8.4, 9.10.8.5, 9.10.8.6,9.10.8.7,9.10.8.8,9.10.8.9,9.10.8.10,9.10.9.1,9.10.9.2,9.10.9.3, 9.10.9.4, 9.10.9.5, 9.10.9.6,9.10.9.7,9.10.9.8,9.10.9.9, 9.10.9.10, 9.10.10.1,9.10.10.2, 9.10.10.3, 5.10.10.4, 9.10.10.5, 9.10.10.6, 9.10.10.7, 9.10.10.8, 9.10.10.9, 9.10.10.10, 10.1.1.1, 10.1.1.2, 10.1.1.3, 10.1.14,10.1.1.5,10.1.1.6, 10.1.1.7, 10.1.1.8, 10.1.1.9, 10.1.1.10, 10.1.2.1, 10.1.2.2, 10.1.2.3,
10.1.2.4,10.1.2.5, 10.1.2.6, 10.1.2.7, 10.1.2.8, 10.1.2.9, 10.1.2.10, 10.1.3.1, 10.1.3.2, 10.1.3.3, 10.1.3.4,10.1.3.5,10.1.3.6, 10.1.3.7, 10.1.3.8, 10.1.3.9, 10.1.3.10, 10.1 4.1, 10.1.4.2, 10.14.33, 10.1.4.4,10.1.4.5,10.1.4.6, 10.1.4.7, 10.1.4.8, 10.1.4.9, 10.1.4.10, 10.1.5.1, 10.1.5.2, 10.1.53, 10.1.5.4,10.1.5.5, 10.1.5.6, 10.1.5.7, 10.1.5.8, 10.1.5.9, 10.1.5.10, 10.1.6.1, 10.1.6.2, 10.1.6.3,
10.1.6.4,10.1.6.5, 10.1.6.6, 10.1.6.7, 10.1.6.8, 10.1.6.9, 10.1.6.10, 10.1.7.1, 10.1.7.2, 10.1.7.3, 10.1.7.4,10.1.7.5, 10.1.7.6, 10.1.7.7, 10.1.7.8, 10.1.7.9, 10.1.7.10, 10.1.8.1, 10.1.8.2, 10.1.8.3,
) 10.1.8.4,10.1.8.5, 10.1.8.6, 10.1.8.7, 10.1.8.8, 10.1.8.9, 10.1.8.10, 10.1.9.1, 10.1.9.2, 10.1.9.3, 10.1.9.4,10.1.9.5, 10.1.9.6, 10.1.9.7, 10.1.9.8, 10.1.9.9, 10.1.9.10, 10.1.10.1, 10.1.10.2, 10.1.10.3, 10.1.10.4,10.1.10.5, 10.1.10.6, 10.1.10.7, 10.1.10.8, 10.1.10.9, 10.1.10.10, 10.2.1.1, 10.2.1.2,
] 10 10.2.1.3,10.2.1.4,10.2.1.5,10.2.1.6, 10.2.1.7, 10.2.1.8, 10.2.1.9, 10.2.1.10, 10.2.2.1, 10.2.2.2,
10.2.2.3,10.2.2.4,10.2.2.5,10.2.2.6, 10.2.2.7,10.2.2.8, 10.2.2.9, 10.2.2.10, 10.2.3.1, 10.2.3 2, 10.2.3.3,10.2.3.4,10.2.3.5,10.2.3.6, 10.2.3.7, 10.2.3.8, 10.2.3.9, 10.2.3.10, 10.2.4.1, 10.2.4.2, 102.4.3,10.2.4.4,10.2.4.5,10.2.4.6,10.2.4.7,10.2.4.8,10.2.4.9, 10.2.4.10, 10.2.5.1, 10.2.5.2, 10.2.5.3,10.2.5.4,10.2.5.5, 10.2.5.6, 10.2.5.7, 10.2.5.8, 10.2.5.9, 10.2.5.10, 10.2.6.1, 10.2.6.2,
10.2.6.3,10.2.6.4,10.2.6.5, 10.2.6.6, 10.2.6.7, 10.2.6.8, 10.2.6.9, 10.2.6.10, 10.2.7.1, 10.2.7.2,
10.2.7.3, 10.2.7.4, 10.2.7.5, 10.2.7.6, 10.2.7.7, 10.2.7.8, 10.2.7.9, 10.2.7.10, 10.2.8.1, 10.2.8.2,
10.2.3.3,10.2.8.4,10.2.8.5, 10.2.8.6, 10.2.8.7, 10.2.8.8, 10.2.8.9, 10.2.8.10, 10.2.9.1, 10.2.9.2, 10.2.9.3,10.2.9.4,10.2.9.5, 10.2.9.6, 10.2.9.7, 10.2.9.8, 10.2.9.9, 10.2.9.10, 10.2.10.1, 10.2.10.2, 10.2.10.3, 10.2.10.4, 10.2.10.5, 10.2.10.6, 10.2.10.7, 10.2.10.8, 10.2.10.9, 10.2.10.10, 10.3.1.1,
i 20 103.1.2,10.3.1.3,10.3.1.4,103.1.5, 10.3.1.6, 10.3.1.7, 10.3.1.8, 10.3.1.9, 10.3.1.10, 10.3.2.1, : 10.3.2.2,10.3.2.3,10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 10.3.2.8, 10.3.2.9, 10.3.2.10, 10.3.3.1, 10.3.3.2,10.3.3.3, 10.3.3.4, 10.3.3.5, 10.3.3.6, 10.3.3.7, 10.3.3.8, 10.3.3.9, 10.3.3.10, 10.3.4.1, 10.3.4.2,10.3.4.3,10.3.4.4, 10.3.4.5, 10.3.4.6, 10.3.4.7, 10.3.4.8, 10.3.4.9, 10.3.4.10, 10.3.5.1, 10.3.5.2,10.3.5.3, 10.3.5.4, 10.3.5.5, 10.3.5.6, 10.3.5.7, 10.3.5.8, 10.3.5.9, 10.3.5.10, 10.3.6.1,
10.3.6.2,10.3.6.3, 10.3.6.4, 10.3.6.5, 10.3.6.6, 10.3.6.7, 10.3.6.8, 10.3.6.9, 10.3.6.10, 10.3.7.1, 10.3.7.2,10.3.7.3, 10.3.7.4, 10.3.7.5, 10.3.7.6, 10.3.7.7, 10.3.7.8, 10.3.7.9, 10.3.7.10, 10.3.8.1, 10.3.8.2,10.3.8.3,10.3.8.4, 10.3.8.5, 10.3.8.6, 10.3.8.7, 10.3.8.8, 10.3.8.9, 10.3.8.10, 10.3.9.1, 10.3.9.2,10.3.9.3.10.3.9.4, 10.3.9.5, 10.3.9.6, 10.3.9.7, 10.3.9.8. 10.3.9.9. 10.3.9.10, 10.3.10.1, 10.3.10.2, 10.3.10.3, 10.3.10.4, 10.3.10.5, 10.3.10.6, 10.3.10.7, 10.3.10.8, 10.3.10.9, 10.3.10.10,
104.1.1,10.4.1.2,104.1.3,10.4.1.4,10.4.1.5,10.4.1.6, 10.4.1.7, 10.4.1.8, 10.4.1.9, 10.4.1.10, 104.2.1,104.2.2,10.4.2.3,10.4.2.4, 10.4.2.5,10.4.2.6, 10.4.2.7, 10.4.2.8, 10.4.2.9, 10.4.2.10, 10.4.3.1,10.4.3.2,10.4.3.3, 10.4.3.4, 10.4.3.5, 10.4.3.6, 10.4.3.7, 10.4.3.8, 10.4.3.9, 10.4.3.10, 10.4.4.1,10.4.4.2,10.4.4.3,10.4.4.4,10.44.5,10.4.4.6,10.4.4.7, 10.4.4.8, 10.4.4.9, 10.4.4.10, 10.4.5.1,10.4.5.2,10.4.5.3, 10.4.5.4, 10.4.5.5, 10.4.5.6, 10.4.5.7, 10.4.5.8, 10.4.5.9, 10.4.5.10,
10.4.6.1,10.4.6.2,10.4.6.3, 10.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7, 10.4.6.8, 10.4.6.9, 10.4.6.10,
10.4.7.1,10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5, 10.4.7.6, 10.4.7.7, 10.4.7.8,10.4.7.9,10.4.7.10, 10.4.8.1,10.4.8.2, 10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6, 10.4.8.7, 10.4.8.8, 10.4.8.9,10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6, 10.4.9.7, 10.4.9.8, 10.4.9.9, 10.4.9.10, 10.4.10.1, 10.4.10.2, 10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8, 10.4.10.9, 10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5, 10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2, 10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9, 10.5.2.10,10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6, 10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3,10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10,10.5.5.1,10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7, 10.5.5.8, 10.5.5.9, 10.5.5.10,10.5.6.1,10.5.6.2,10.5.6.3,10.5.6.4, 10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8,10.5.6.9, 10.5.6.10,10.5.7.1,10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8, 10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5, 10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2, 10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9, 10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5, 10.5.10.6, 10.5.10.7, 10.5.10.8, 105.109, 10.5.10.10, 10.6.1.1, 10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7,10.6.1.8, 10.6.1.9,10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5, 10.6.2.6, 10.6.2.7, 10.6.2.8, re 10.6.2.9,10.6.2.10, 10.6.3.1, 10.6.3.2, 10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, : ’ 10.6.3.9,10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6, 10.6.4.7, 10.6.4.8, ! 10.6.4.9,-10.6.4.10, 10.6.5.1, 10.6.5.2, 10.6.5.3, 10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, ne 20 10.6.5.9,10.6.5.10, 10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7, 10.6.6.8, - :
PE 10.6.6.9,-10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4, 10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, : oo 10.6.7.9,.10.6.7.10, 10.6.8.1, 10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8, . 10.6.8.9,-10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5, 10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2, 10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8,10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5, 10.7.1.6, 10.7.1.7, 10.7.1.8,10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2, 10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8,10.7.2.9, 10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6, 10.7.3.7, : 10.7.3.8,10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3, 10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8,10.7.4.9, 10.74.10, 10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7, 10.7.5.8,10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4, 10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8,10.7.6.9, 10.7.6.10, 10.7.7.1, 10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8,10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5, 10.7.8.6, 10.7.8.7, 10.7.8.8,10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2, 10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8,10.7.9.9, 10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5, 10.7.10.6, 10.7.10.7,10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1, 10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6,
10.8.1.7,10.8.1.8, 10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5, 10.8.2.6, 10.8.2.7,10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2, 10.8.3.3, 10.8.3.4, 10.8 3.5, 10.8.3.6, 10.8.3.7,10.8.3.8,10.8.3.9,10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6, 10.8.4.7,10.8.4.8,10.8.4.9,10.8.4.10,10.8.5.1, 10.8.5.2, 10.8.5.3, 10.8.5.4, 10.8.5.5, 10.8.5.6,
-10.8.5.7,10.8.5.8,10.8.5.9,10.8.5.10,10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7, 10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4, 10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9,10.8.7.10,10.8.8.1,10.8.8.2,10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7,10.8.8.8,10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5, 10.8.9.6, 10.8.9.7,10.8.9.8,10.8.9.9, 10.8.9.10,10.8.10.1, 10.8.10.2, 10.8.10.3, 10.8.10.4, 10.8.10.5,
10.8.10.6, 10.8.10.7, 10.8.10.8, 10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1 4, 10.9.1.5,109.1.6,10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2, 10.9.2.3, 10.9.2.4, 109.2.5,10.9.2.6, 10.9.2.7,10.9.2.8, 10.9.2.9, 10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3 4, 10.9.3.5,10.9.3.6, 10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3, 10.9.4.4, 10.9.4.5,10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10, 10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4,
10.9.5.5,10.9.5.6,10.9.5.7, 10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4, 10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1, 10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8, 10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5, 10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2, 10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9, 10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4,
10.9.10.5, 10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1, 10.10.1.2, 10.10.1.3, : 10.10.14, 10.10.1.5, 10.10.1.6, 10.10.1.7, 10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3, 10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9, 10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5, 10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1, 10.10.42, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7, 10.10.4.8, 10.10.4.9,
10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3, 10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9, 10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5, 10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1, 10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7, 10.10.7.8, 10.10.7.9, 10.10.7.10, 10.108 1,10.108 2, 10.10.83, 10.1084, 10 10.8 5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9, 10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4,
10.10.95, 10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1, 10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7, 10.10.10.8, 10.10.10.9, 10.10.10.10 a SJ
Additional exemplary formula 1 compound groups include the following groups as disclosed below.
Group 2. Group 2 compounds are as named in Table B, i.e., R3, RjA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 5, which is the same as the formula 4 steroid nucleus, except that the 5-6 double bond is absent and hydrogen is present at the 5-position in the a-configuration : x
Qg Ry
H
Q, .
Qq4
Roa RA
N B h
H H s.
Thus, the group 2 compound named 1.2.1.1 has the structure
CH; 2
HH .
CHj, / 2, “Br
HO J ’ OH when $ EY “Wy, H 5, H H group 2, compound 1.2.1.1.
Group 3. Group 3 compounds are as named in Table B, i.e., Ry, RjA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 6, which is the same as the formula 4 steroid nucleus, except that the 5-6 double bond is absent and hydrogen is present at the 5-position in the B-configuration
Qs gd
H
Qa “2, v
Q4
Ra 3 5 7 RiA }
N KC
H H 6.
Thus, the group 3 compound named 1.2.1.1 has the structure t » a
CH; ©
H
CH, on 7, “Br
HOM] C1 § “In
H H group 3, compound 1.2.1.1.
Group 4. Group 4 compounds are as named in Table B, i.e., Ry, RJA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 7, which is the same as the formula 4 steroid nucleus, except that Qj is -CH,0H
Qs x
CH,OH CID H
Q Y
R, 3 5 ’ RiA
SN “yy,
Ny H a 7.
Thus, the group 4 compound named 1.2.1.1 has the structure -
CH, 2
CH,0H ) H . “Br $ “thy
H group 4, compound 1.2.1.1.
Group 5. Group 5 compounds are as named in Table B, i.e., Rp, R1A, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucleus shown in formula 8, which is the same as the formula 4 steroid nucleus, except that the 5-6 double hond is ahsent and hydrogen is present at the S-position in the a-configuration and Q3 is -CH)OH
Qg Xx Jd :
CH,OH ® gt Ho “2 ‘
Q4 Y
Rol s RA § i “iy
H H 8.
jis >
Thus, the group 5 compound named 1.2.1.1 has the structure
CH; ©
CH,OH CI H , “Br
HO @ OH $ A KY 3 = H
H Ct
Group 6. Group 6 compounds are as named in groups 1-5, except that Qg in formulas 4-8 is -CH20H instead of methyl. In group 6, there are 5 subgroups of group 6 compounds. The first subgroup, subgroup 6-1, has the same steroid nucleus with the substituents as defined for group 1 compounds while the second, subgroup 6-2, has the same steroid nucleus with the substituents as defined for group 2 compounds. Subgroups 6-3 through 6-5 have the same steroid nucleus with the substituents as defined for group 3 through 5 respectively. Thus, for example, the subgroup 6-1 compound named 1.2.1.1 has the structure
CH,OH © : H (0s / “Br : HO ’ OH $ K// 3 H
H : and the subgroup 6-2 compound named 1.2.1.1 has the structure
HOH,C 0
H
CH, 4 % “Br $ z KK
S = H
H A
Group 7. Group 7 compounds are as named in groups 1-5, except that the Y moiety in formulas 4-8 is in the B-configuration instead of in the a-configuration. Group 7 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the Y group is in the B-configuration.
< Ca
Group 8. Group 8 compounds are as named in groups 1-5, except that the X moiety in formulas 4-8 is in the a-configuration instead of in the B-configuration. Group 8 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the X group is in the a-configuration.
Group 9. Group 9 compounds are as named in groups 1-5, except that the Ry moiety in formulas 4-8 is in the a-configuration instead of in the B-configuration. Group 9 comprises 5 subgroups, wherein the compounds are named essentially as described for group 6 compounds, except that the Ry group is in the a-configuration.
Group 10. Group 10 compounds are as named in groups 1-9, except that R3 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0O)-CH3 2 -S-C(0)-CH»-CgHs 3 -0O-S(0)-O-CH3 4 -0-S(0)-0-CHy-C¢Hs 5 -O-S(0)(0)-0-CHj3 6 -0O-S(0)(0)-0O-CHy-CgHs 7 -O-C(0O)-NH-CH3 8 -0-C(0)-NH-CgHjs 9 -O-C(S)-CHj3 10 -O-C(S)-CHp-CgHs .
Group 10 comprises 25 subgroups of compounds. The first, subgroup 10-1, has the same steroid nucleus with substituents as defined for group 1, except that the Ry moieties or groups listed replace those in Table A above. The subgroup 10-1 compound named 1.2.1.1 has the structure
CH; 2 “Br
EARS
0 , the subgroup 10-2 compound named 1.2.1.1 has the structure
CH; ©
H
CHj 2 % “Br
HaCo Sim] Pa hd 5 A “Wy 0 H the subgroup 10-6-1 compound named 1.2.1.1 has the structure
O85 3 ‘0, “Br
HeC S OH s K// hg S “In 0 k 4 and the subgroup 10-6-2 compound named 1.2.1.1 has the structure
CH,OH ©
H
2, o “Br
HaCul Sim] AH hi § A “Uy o) H
Group 11. Group 11 compounds are as named in groups 1-9, except that Ry» moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(O)-CHpCH3-O-CHyCH3 2 -S-C(0)-CHy-CgH4OCH3 3 -0-5(0)-O-CH»CH3-O-CH7CH3 4 -0-S(0)-O-CH2-CcH4OCH3 : 5 -0-5(0)(0)-0-CHpCH2-0-CHCH3 6 -O-5(0)(0)-O-CHy-CgH40CH3 7 -0O-C(0)-NH-CH2CH2-0-CH2CH3 8 -0-C(O)-NH-CgH40CH3 9 -0O-C(S)-CHyCH-O-CH2CH3
«+ 10 -O-C(S)-CH;-C¢H40CH3
Group 12. Group 12 compounds are as named in groups 1-9, except that Ry moieties 1 through 10 in Table A are replaced with the following moieties. 1 -8-C(0)-CH;CH3-0-CH,C(O)OH 2 -8-C(0)-CHy-CgH4F 3 -0-5(0)-0-CH,CH;-0-CHC(O)OH 4 -O-S(0)-O-CH-CgHyF 5 ~0-5(0)(0)-0-CHCH2-0-CHC(0)OH 6 -0O-5(0)(0)-O-CHp-CgHyF 7 -O-C(0)-NH-CHpCH3-0-CH>C(O)OH 8 -O0-C(0)-NH-CgH4F 9 -0-C(8)-CH»CH)-O-CH>C(0O)OH 10 -O-C(S)-CHy-CgH4F
Group 13. Group 13 compounds are as named in groups 1-9, except that Ry moieties 1 through 10 in Table A are replaced with the following moieties. 1 -8-C(0)-CH7CH2-0O-CH2CH2OH 2 -S-C(0)-CHy-CgH4CH3 3 -0-S(0)-0-CH7CH»,-0-CHyCH,OH 4 -0-5(0)-0-CH3-CgH4CH3 5 -0-8(0)(0)-0-CHaCH3-0-CH2CHoOH ’ 6 -O-S(0)(0)-0-CH-CgHyCH3 7 -0O-C(0)-NH-CH7CH2-0O-CHCH0H 8 -O-C(0)-NH-CgH4CH3 9 -0O-C(S)-CHpCH3-0-CHCH2OH 10 -O-C(S)-CHy-CgH4CHj3
Group 14. Group 14 compounds are as named in groups 1-9, except that Ry moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0)-CHpCHp-0-CHyCHyORPR 2 -S-C(0)-CHp-CgH4ORPR 3 -0-S(0)-0-CHyCH3-O-CH,CHHORFPR : 4 -0-5(0)-0-CHp-CgH4ORFR : 5 -0-S(0)(0)-0-CHyCH,-0-CHpCHORPR 6 -0-S(0)(0)-O-CHy-CgH4ORPR 7 -0O-C(O)-NH-CHyCH3-O-CH7CHyORPR 8 -0-C(0)-NH-CgH4ORPR
9 -0-C(S)-CH7CH3-0-CH2CH,ORPR 10 -O-C(S)-CH-CgH4ORPR
Group 15. Group 15 compounds are as named in groups 1-9, except that Ry moieties 1 through 10 in Table A are replaced with the following moieties. 1 -8-C(0)-CH3CH3-O-CH,CH;NHRFR 2 -$-C(0)-CH,-CgH3(ORPR), 3 -0-§(0)-0-CHCH;-0-CH2CHNHRPR 4 -0-§(0)-0-CH,-CgH3(ORPR), 5 -0-S(0)(0)-0-CHyCH3-0-CHpCHyNHRFPR 6 -O-S(0)(0)-0O-CHy-CgH3(ORPR)y 7 -O-C(O)-NH-CH7CH5-0-CH>CH)NHRPR 8 -0-C(0)-NH-CgH3(ORFPR), 9 -0-C(S)-CHCH»-O-CHyCHpNHRPR 10 -O-C(S)-CH3-CgH3(ORPR)y
Group 16. Group i6 compounds are as named in groups 1-9, except that Ry moieties 1 through 10 in Table are replaced with the following moieties. : 1 -8-C(0)-(CH2)p-6-CH3 2 -S-C(0)-CHy-CgHs 3 -0-5(0)-O-(CH2)0-6-CH3 \ 20 4 -O-S(0)-O-CHp-CgHs 5 -0-S(0)0)-0-(CH2)0-6-CH3 6 -0-5(0)(0)-0-CH»-CgHs 7 -0-C(0)-NH-(CHj)g.6-CH3 : 8 -0-C(0)-NH-(CH3)g.6-C6Hs 9 -O-C(S)-(CH3)p.¢-CH3 10 -O-C(S)-CH3-CgHjs :
Group 17. Group 17 compounds are as named in groups 1-9, except that R7 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(0)-CHpCH3-(0-CH2CH2)1.50-H 2 -S-C(O)-CHy-CgH40CH;3 : 3 -0-S(0)-0-CH7CH3-(0-CH2CH))1.50-H 4 -0-8(0)-0O-CH3-CgH40OCH3 5 -0-S(0)(0)-0-CH,CHy-(0-CH2CH3)1.50-H : 6 -0-S(0)(0)-0-CH3-CgH4OCHj3 7 -0-C(0)-NH-CH3CH»-(0-CH2CH3)1.50-H

Claims (37)

CLAIMS What is claimed is:
1. Use of a compound of formula 1 for the preparation of a medicament for the treatment or prevention of a Toxoplasma or Cryptosporidium infection in a subject, or to ameliorate or reduce one or more symptoms of a Toxoplasma or Cryptosporidium infection, wherein formula 1 is Ry Ru X R Q R4 ' Ri N Ri ol is Q, > Fe 15 a, IE IRN Ry i R, 3 . 2 . § 78, Ry R4 Ri < “or” Ry Ri R, wherein : Q: is -C(Ry),- or -C(0)-; Qz is -C(Ry), -CR1)(Y)-, -C(Y)- or -CHy-CHy-; Q; and Qg independently are -H or -C(R,)3-; Qs 1s -C(Ry)2-, -C(O)-, hydroxyvinylidine or methyl methylene; Qs 1s —C(Ry)2- or -C(0)~; 'X and Y independently are -OH, -H, lower alkyl, -O-C(O)-Rs, -C(0O)-ORs, a halogen or =O; each R, independently is -H, a halogen, -OH, C,.¢ alkoxy, or C,_ alkyl; R; is -H, -OH, a halogen, C;¢ alkyl, C,. alkoxy, -ORa3, an ester, a thioester, a thioacetal, a sulfate ester, a sulfonate ester or a carbamate or R;, together with the R; that 1s bonded to the same carbon atom is =O; Rs is -S(0)(0)-OM, -S(0)(0)-0-CH,-CH(O-C(O)-Ry)-CH,-0-C(O)-Rs, -P(0)(0)-O-CH,-CH(O-C(0)-R7)-CH,-0-C(0)-R7, a glucuronide group of structure (A) 79 Amended Sheet 10/05/2002
COOH HC 0 os oom, or R3 is Cy.15 alkyl, C,.15 alkenyl, Cy.15 alkynyl, a C.;3 ester or a Cy.ig thioester, where any of the foregoing C;.15 or C,.13 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selected -OR™®, -NHR™®, or -SR**, groups, or Rj 1s a Cy fatty acid, Cs. alkynyl, (J),-phenyl-C,_s-alkyl, (T),-phenyl-C;.s- alkenyl; each Rs independently is straight or branched C,_,4 alkyl; each Rg independently is C14 straight or branched alkyl; and each Ry independently is Cy.14 straight or branched alkyl or a glucuronide group of structure (A); each R™ independently is -H or an independently selected protecting group; nis 0, 1,2 or 3; each J independently is a halogen, C,.4 alkyl, C,4 alkenyl, C,.4 alkoxy, carboxy, : nitro, sulfate, sulfonyl, a C;_¢ carboxyl ester or a C,.¢ sulfate ester; M is hydrogen, sodium, -S(O)(0)-O-CH,-CH(O-C(0)-R)-CH,-0-C(0O)-Rg, - P(0O)(0)-0-CH;-CH(O-C(0)-R7)-CH,-0-C(0O)-R; or a glucuronide group of structure (A); and the dotted lines represent an optional double bond, provided that there are not double bonds at both the 4-5 and 5-6 positions and provided that when a double bond is present, zero or 1 R; group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17- positions so that these carbon atoms are tetravalent; and : the salts, stereoisomers, positional isomers, metabolites, hydrates, tautomers, ionized forms and solvates thereof, provided that the formula 1 compound is not dehydroepinadrosterone-3-sulfate, dehydroepinadrosterone or a 3-ester or 3-ether of : dehydroepinadrosterone or a salt of any of these.
2. Use according to claim 1 wherein the formula 1 compound has the formula 9 80 Amended Sheet 10/05/2002
Qg y Qs CD Sonny SP 3 Ry RA 9 wherein the dotted line represents a double bond or a single bond with a hydrogen atom at the 5-position in the a-configuration or the B-configuration;
Qs and Qs independently are -CH; or -CH,OH, provided that if Qs is -CH,OH and no double bond is present at the 5-6 position, then the hydrogen atom at the 5-position is in the a-configuration;
Qq 1s -CH;-;
R; is -OH, =0, -0-P(0)(0)-OH, -O-P(0)(0)-0-CH,-CH(0-C(0)-CH;)-CH,-O- C(O)CHs, -O-S(0)(0)-OH, -0-S(0)(0)-O' Na", -0-8(0)(0)-OC,Hs, -O-S(0)(0)-0O-CH,- CH(O-C(0)-CH;)-CH,-0-C(0O)CH3, -0-S(0)(0)-OCH,CH,CH,CHj;, -O-S(0)(0)- OC(CHyz)s, -S-C(0)-CH3s, -S-C(0)-CH;-CgHs, -O-S(0)-0O-CHj, -O-S(0)-0-CH,-CgHs, - 0-S(0)(0)-0-CHs;, -O-S(0)(0)-O-CH;-C¢Hs, -O-C(0O)-NH-CH3, -O-C(0O)-NH-C¢Hs, -O- C(S)-CHj3, -O-C(S)-CH,-CgHs, -S-C(0)-CH,CH,-O-CH,CHj;, -S-C(0O)-CH,-CsH,OCH;, -0-S(0)-0-CH,CH,-0-CH,CH3, -O-S(0)-O-CH,-CsH4OCH3, -O-S(0)(0)-O-CH,CH,- 0O-CH,CH3, -O-S(0)(0)-0-CH,-C¢H4OCH3, -O-C(0)-NH-CH,CH,-O-CH,CHj;, -O- C(0)-NH-CsH,OCH3;, -O-C(S)-CH,CH,-O-CH,CH3, -O-C(S)-CH,-CsH,OCH3, -S-C(0)- CH,CH,-0O-CH,C(O)OH, -S-C(0)-CH,-CcH4F, -O-5(0)-O-CH,CH,-O-CH,C(O)OH, -O- S(0)-0-CH,-CcH4F, -O-S(0)(0)-0-CH,CH,-O-CH,C(O)OH, -O-S(0)(0)-O-CH;- C¢H4F, -O-C(0)-NH-CH,CH,-O-CH,C(O)OH, -O-C(O)-NH-CcH4F, -O-C(S)-CH,CH,- 0O-CH,C(O)OH, -O-C(S)-CH,-CsH,4F, -S-C(0)-CH,CH,-O-CH,CH,0OH, -S-C(O)-CH,- CsH,4CHj, -O-5(0)-0-CH,CH,-O-CH,CH,OH, -O-S(0)-O-CH,-CsH4CHj3, -O-S(0)(O)- 0-CH,CH,-O-CH,;CH,OH, -O-S(0)(0)-0O-CH,-CsH4CHj3, -O-C(O)-NH-CH,CH,-O- CH,CH,OH, -0O-C(0)-NH-C¢H4CH3;, -O-C(S)-CH,CH,-O-CH,CH, OH, -O-C(S)-CH,- CsH4CH;, -S-C(0)-CH,CH,-0-CH,CH,0R®, -S-C(0)-CH,-CsH,OR™®, -0-S(0)-O-
81 Amended Sheet 10/05/2002
CH,CH,-O-CH,CH,0R"®, -0-S(0)-0-CH,-C¢H,OR’R, -0-S(0)(0)-0-CH,CH,-0- CH,CH,OR"™®, -0-S(0)(0)-0-CH,-C¢H4ORR, -0-C(0)-NH-CH,CH,-O-CH,CH,OR"®, - 0-C(0)-NH-C¢H,0R™®, -0-C(S)-CH,CH,-O-CH,CH,0R"®, -0-C(S)-CH,-CsH,ORR, - S-C(0)-CH,CH,-O-CH,CH,NHR"®, -8-C(0)-CH,-C¢H3(OR"™),, -O-S(0)-0O-CH,CH,-O- CH,CH,NHR"®, -0-5(0)-0-CH;-C¢H3(OR"®),, -0-S(0)(0)-0-CH,CH,-O- CH,CH,NHR'®, -0-5(0)(0)-0-CH,-CsH3(OR"}),, -0-C(0)-NH-CH,CH,-O- CH,CH,NHR®, -0-C(0)-NH-C¢H;3(OR"®),, -0-C(S)-CH,CH,-O-CH,CH,NHR™®, -O- C(S)-CH,-CsH3(OR™R),, -S-C(0)-(CHa)o.6-CHs, -S-C(0)-CH,-CgHs, -O-S(0)-O~(CHa)o. 6-CHs, -0O-S(0)-0-CH,-CHs, -O-S(0)(0)-O-(CH,)o.6-CHs, -0O-S(0)(0)-O-CH,-CeHs, - O-C(0)-NH-(CH2)o.6-CH3, -O-C(O)-NH-(CHy)o.6-CsHs, -O-C(S)-(CHz)o-6-CHs, -O-C(S)- CH,-C¢Hs, -S-C(0)-CH,CH,-(O-CH,CH,);.50-H, -S-C(0)-CH,-C¢H4OCHj3, -O-S(0)-O- CH,CH,-(O-CH,CHy,),.50-H, -O-S(0)-0-CH,-CsH,OCH3, -O-S(0)(0)-0-CH,CH,-(O- CH,CH,);.50-H, -0-S(0)(0)-0-CH,-CsH,OCHj3, -0-C(0)-NH-CH,CH,-(0-CH,CH>)1.50- H, -O-C(0)-NH-C¢H;OCH3, -O-C(S)-CH,CH,-(0-CH,CHy)so-H, -O-C(S)-CH,- CsH4OCHj3, -O-C(0)-CH,CH,-(0-CH,CH,),.50-H, -0-C(0)-CH,-CsH4OCHs, -O-C(O)- (CH3)0.6-CHs, -O-C(0)-CH,-C¢H4NO,, -O-C(0)-CH,-CgHs, -O-C(0)-CH,CH,-O- CH,CHj, -O-C(0)-CgHs, -O-C(0)-CH,CH,-S-CH,CH3, -O-C(0)-CH,-CgH,F, -O- CH,CH,-(0-CH,CHy),.50-H, -O-CH,-C¢H4OCH3, -O-(CHa)o.6-CHs, -O-CH,-C6HsNO,, - 0-CH,CH,-(0-CH,CH,);.50-H, -O-CH,-C¢Hs, -O-CH,CH,-0O-CH,CHj, -O-CgHs, -O- CH,CH,-S-CH,CH3, -O-CH,-CgH,F, -C(0)-0-CH,CH,-(0-CH,CH,),.50-H, -C(0)-O- CH,-C¢H,OCH;, -C(0)-0O-(CHy)o.6-CHj, -C(0)-O-CH,-CsH4NO,, -C(0)-O-CH,-CHs, - C(0)-0-CH,CH,-0-CH,CHj3, -C(0)-0-C4Hs, -C(0)-0-CH,CH,-S-CH,CHj, -C(0)-O- CH,-CgH,F, -C(0)-0-G12, -0-C(0)-G12, -C(0)-S-G12, -S-C(0)-G12, -C(S)-0-G12, - 0-C(S)-G12, -0-C(0)-NH-G12, -NH-C(0)-0-G12, -C(0)-0-CH,-G12 or -O-C(0)-CH,- G12; R,A is -H, -OH, =0, -CHj, -OCHj, -OC,Hs, -OCH,CH,CHj, - OCH(CH3)CHs, -OCH,CH,CH,CHj or -OC(CHa)s; Y is -Br, -Cl, -1, -F, -H, -OH, =O, -OC(O)CHj3, -OC(0)CH,CHj or -
OC(O)CH,CH,CHj3;; and
82 Amended Sheet 10/05/2002
X is =0, -OH, -H, -F, -Cl, -Br, -I, -OC(O)CH3, -OC(O)CH,CHj3 or - OC(O)CH,CH,CH3; R"™is-Hora protecting group; and G12 is an organic moiety comprising 1,2, 3,4,5,6,7,8,9 10, 11 or 12 carbon atoms and 0, 1, 2, 3, 4, 5, 6, 7 or 8 independently selected O, S, N, P, or Si atoms, but, if a Si or P atom is present, only one Si or P is present, wherein the organic moiety is Cy.1; alkyl, C,.1; alkenyl, C,.12 alkynyl, aryl, a C,.¢ heterocycle or a substituted derivative of any of these comprising 1, 2, 3, 4 or more substituents, wherein each substituent is independently chosen and is selected from -O-, -S-, - NR"%-, -C(0)-, =0, =S, -N(R"®),, -C(O)OR'}, -OC(O)R™®, -OR"® | -OH, -SR*® -SH, -NO,, -CN, -NHC(O)-, -C(O)NH-, -OC(0)-, -C(0)0O-, -0O-AS, -S-A8, -C(0)-AS, - OC(0)-A8, -C(0)0-AS, =N-, -N=, =N-OH, -OPO3(R"}),, -OSO;H,, -F, -Cl, -Br or -I moieties or atoms, where each R™® is -H, an independently selected protecting group or both R™® together comprise a protecting group, and A8 is Cys alkyl, C,.s alkenyl, Css alkynyl, C4 alkyl-aryl, aryl or C4 alkyl-C;_ heterocycle.
3. Use according to claim 2 wherein the formula 9 compound has the structure 4 Qs gd \ H Qq
4. Use according to claim 2 wherein the formula 9 compound has the structure 5 Qs Ns \ H Q4 Ry RA ~ B RZ) 83 Amended Sheet 10/05/2002
: 5. Use according to claim 2 wherein the formula 9 compound has the structure 6 Qs yg Lx Q, v Ra x 3 5 CL Rik DI :
6. Use according to any of claims 2-5 wherein Y at the 16-position is in the B-configuration.
7. Use according to any of claims 2-5 wherein X at the 17-position is in the a-configuration.
8. Use according to any of claims 2-5 wherein R; at the 3-position is in the a-configuration.
0. Use according to any of claims 2-8 wherein Rj A at the 7-position is in the a-configuration. :
10. Use according to any of claims 2-5 wherein R; at the 3-position is in the a-configuration and Y at the 16-position is in the B-configuration.
11. Use according to any of claims 2-5 wherein R; at the 3-position is in the a-configuration and X at the 17-position is in the a-configuration.
12. Use according to any of claims 2-5 wherein Y at the 16-position is in the B-configuration and X at the 17-position is in the o-configuration.
13. Use according to any of claims 1 through 12 wherein the formula 1 compound is 16-fluoroepiandrosterone, 16-chloroepiandrosterone, 16- bromoepiandrosterone, 16-iodoepiandrosterone, 16-hydroxyepiandrosterone, 3,170- dihydroxyandrost-5-ene, 3p,160.,17p-trihydroxyandrost-5-ene, 33,7p,17f- trihydroxyandrost-5-ene, 38,7,16a,1783-tetrahydroxyandrost-5-ene, 3p,73,165,1753- tetrahydroxyandrost-5-ene, 16-fluoroandrost-5-ene-17-one, 7-hydroxy-16-fluoroandrost- 5-ene-17-one, 7,17-dihydroxy-16-fluoroandrost-5-ene, or 3-hydroxyandrost-5-ene-7,17- dione. 84 Amended Sheet 10/05/2002
14. Use according to claim 11 wherein the formula 1 compound is 16a.- fluoroepiandrosterone, 16a-hydroxyepiandrosterone, 16a-bromoepiandrosterone, 3B,7B,17B-trihydroxyandrost-5-ene or 3B,17B-dihydroxyandrost-5-ene.
15. Use according to any of claims 1 through 14 wherein the medicament is administered to a subject using an intermittent dosing protocol.
16. Use according to claim 15, wherein the intermittent dosing protocol comprises (a) administering the medicament 1, 2, 3, 4 or 5 times per week for about 1 or more weeks, (b) not administering the medicament for 2 or more days, (c) administering the medicament 1, 2, 3, 4 or 5 times per week for about 1 or more weeks, and (d) optionally repeating steps (a), (b) and (¢) one or more times.
17. Use according to any of claims 1 through 16 wherein the medicament is suitable for buccal or sublingual administration of the formula 1 compound to a subject.
18. Use according to any of claims 1 through 16 wherein the medicament is suitable for oral or parentaral administration of the formula 1 compound to a subject.
19. Use according to any of claims 1 through 18 wherein the formula 1 compound that is used to prepare the medicament comprises particles having an average particle size of 0.01 pm to 200 pm.
20. Use according to any of claims 1 through 19 wherein , and wherein the medicament comprises (1) a dosage comprising about 10-750 mg of a formula 1 compound or (2) a dosage comprising about 5-500 mg of a formula 1 compound.
21. Use according to any of claims 1 through 20 wherein the subject is a human or a mammal.
22. Use of a compound of formula 45 for the preparation of a medicament for the treatment or prevention of a Toxoplasma or Cryptosporidium infection in a subject, or to ameliorate or reduce one or more symptoms of a Toxoplasma or Cryptosporidium infection, wherein formula 45 is 85 Amended Sheet 10/05/2002
CH Rs2 y Rs POSE wherein, Rs is -H, -OH or =0; - Rs; is -Br, -Cl, -F, -I or -OH; Rs; is -OH or, Rs, together with the -H bonded to the same position, is =O; } Ruy is -H, -OH, or -ORs3; Rsi is Cy.5 alkyl, Cys alkenyl, Cy.i5 alkynyl, a Cy.i5 ester, a Cig thioester, wherein any of the foregoing Ci.;3 or C,.15 groups is substituted at one or more hydrogen or carbon atoms with one or more independently selected -O-, -S-, -OH, -NH,, -SH or =O groups or Rs; is a thioacetal, a sulfate ester, a sulfonate ester, a carbamate or a thioester; and the dotted line is an optional double bond, provided that the compound is not dehydroepinadrosterone-3-sulfate, dehydroepinadrosterone or a 3-ester or 3-ether of dehydroepinadrosterone or a salt of any of these.
23. Use according to claim 22 wherein Ryg is -H.
24. Use according to claim 22 or 23 wherein Rs is -OH or =O.
25. Use according to claim 22, 23 or 24 wherein Rs, is -OH, -F or -Br.
26. = Use according to claim 22, 23, 24 or 25 wherein Rs; is =O.
27. Use according to claim 22, 23, 24 or 25 wherein Rs; is -OH.
28. Use according to any of claims 20-27 wherein a double bond is present at - the 5-6 position.
29. Use according to any of claims 20-27 wherein a double bond is not present at the 5-6 position. )
30. Use of a compound of formula 1B or 1C for the preparation of a medicament for the treatment or prevention of a To oxoplasma or Cryptosporidium infection, or for the amelioration of one or more symptoms associated with a Toxoplasma or Cryptosporidium infection, wherein formula 1B and 1C are 86 | Amended Sheet 13/12/2002
X Qs 1 N % Ro Ry and Re R; 1B 1C wherein,
each R; independently is -H, -OH, a halogen, -CHCH,, -CHCHCHj3;, -CCH, - CCCHys, or, the other moiety that is bonded to the same carbon atom is absent and R; is =0;
R; is -O-C(0)-Ry, -S-C(0)-R4, -O-5(0)(0)-R4, -O-5(0)(0)-ORy, -O-C(0)-NHRy, or -O-C(S)-Ry;
R4 1s -H, a protecting group, optionally substituted C;_5 alkyl, optionally substituted C;.15 alkenyl, optionally substituted C;.;3 alkynyl, optionally substituted aryl, optionally substituted aryl-C,.¢ alkyl, optionally substituted aryl-C,.¢ alkenyl, optionally substituted aryl-C,.¢ alkynyl, optionally substituted heterocycle-C,.¢ alkyl, optionally substituted C,.¢ alkenyl-heterocycle, optionally substituted C,.¢ alkynyl-heterocycle or an optionally substituted heterocycle, where any of the foregoing moieties are optionally substituted at one, two, three, four, five or more carbon or hydrogen atoms with one or more independently selected -O-, -S-, NRR., -OR™® -NHR"®, SRR =Q, =§, -CN, - NO,, -F, -Cl, -Br or -I groups or atoms; and
Rs is straight or branched C,.;4 alkyl,
each R"™® independently is -H or an independently selected protecting group;
X is -OH, -H, lower alkyl, -O-C(0)-Rs, -C(O)-ORs or a halogen;
Q; is -C(Ry)2-, -C(0O)- or -CH,-CH,-
Q; and Qg independently are -H, -CHj; or -CH,OH; and
1,2, 3, 4,5 or 6 hydrogen atoms that are bonded to the steroid nucleus are optionally substituted with independently selected -OH, -Br, -Cl, -F, -I, -OCHj3; or -OC,H;s atoms or groups.
87 Amended Sheet 10/05/2002
31. Use according to claim 30 wherein Q3 and Qg are both -CHj in the 3- configuration; and
Q. is -CH;-, -C(O)-, -CH(Br)-, -CH(I)-, or -CH(OH)- with the Br, I or OH moieties in the a-configuration; and R; at the 7-position is -H, -OH or, when taken with the hydrogen atom that is bonded to the same carbon atom, R; at the 7-position is =O.
32. Use of a compound of formula 44 for the preparation of a medicament for the treatment or prevention of a Toxoplasma or Cryptosporidium infection in a subject, or to ameliorate or reduce one or more symptoms of a Toxoplasma or Cryptosporidium infection, wherein formula 44 is CH; 7 BOSE wherein YisH,F,Cl,Brorl; Rus is -H, -S(O)(0)-OH, -S(0)(0)-ONa, -S(0)(0)-O-CH;-CH(O-C(0)-Rs)-CH;- 0-C(0)-Re, -P(0)(0)-O-CH,-CH(O-C(0)-R7)-CH;,-O-C(0)-R7, hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl sulfate, O-dihexadecylglycerol sulfate, hexadecane sulfonate, dioctadecanoylglycerol phosphate or O-hexadecylglycerol phosphate or a glucuronide group of structure (A) COOH HC 0) os oH (ay and 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are optionally substituted with independently selected -OH, -Br, -Cl, -F, -I, -OCH; or -OC,Hj5 atoms or groups. 88 Amended Sheet 10/05/2002
33. Use according to claim 32 wherein 2 hydrogen atoms that are bonded to the steroid nucleus are substituted with independently selected -OH, -Br, -Cl, -F, -1, - OCHj3; or -OC;Hs atoms or groups.
34. Use according to any of claims 1-33 wherein the medicament is suitable for oral, topical, buccal or sublingual administration of the formula 1 compound to a human.
35. Use according to any of claims 1-33 wherein the medicament is suitable for parenteral administration of the formula 1 compound to a human.
36. Use according to any of claims 1-35 wherein the medicament comprises a nonaqueous formulation comprising less than 0.5% v/v water and two or more excipients selected from propylene glycol, a polyethylene glycol optionally selected from PEG 300 and PEG 400, ethanol, benzyl benzoate and benzyl alcohol
37. Use according to any of claims 1-35 wherein (1) the medicament comprises two or more excipients selected from a polyethylene glycol optionally selected from PEG 300 and PEG 400, ethanol, benzyl benzoate, benzyl alcohol and propylene glycol or (2) the medicament comprises a filler, a binder, a disintegrant and a lubricant, an o.-cyclodextrin, a B-cyclodextrin optionally selected from hydroxypropyl-p- cyclodextrin, or a y-cyclodextrin or (3) the medicament comprises a formula 1, 1B, 1C, 4, 5,6, 9, 44 or 45 compound that has an average particle size of 0.01 pm to 200 pm. 89 Amended Sheet 10/05/2002
ZA200103845A 1998-11-27 2001-05-11 Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in treatment of toxoplasmosis and in the treatment of cryptosporidiosis. ZA200103845B (en)

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