You are on page 1of 18

vto its dilating action on pupils of the eyes, atropine it Ssed in opthalmology.

For such use one pat of atropine in 1,30,000 parts of water is suicient to cause the dilation of the pupils of the eyes of cats. When taken internally, atropine first stimulates and then depresses tincentral nervous system. solation,! "tropine is isolated from the #uice or the powdered drug. $dseywnus muticus is the preferred source for the manufacture of atropine %ecause of its high alkaloidal content, with &. stramonium ne't in order. (he powdered drug material is thoroughly moistened with m a)ueous solution of sodium car%onate and then e'tracted with ether or %en*ene. (he alkaloidal free %ases are e'tracted from the solvent with water acidified with acetic acid. (he acid solution is then shaken with solvent ether to remove coloring matter. (he alkaloids are precipitated with sodium car%onate, filtered off, washed and dried. (he dried mtSl is dissolved in solvent ether or acetone and dehydrated with anhydrous sodium sulphate %efore filtration. (he filtrate after concentration and cooling yields crude crystals of hyoscyamine and atropine from the solution. (he crude crystalline mass is seperated from the solution. (he crude crystalline mass o%tained after filtration is dissolved in alcohol and sodium hydro'ide solution is added and the mi'ture allowed to stand until hyoscyamine is completely racemi*ed to atropine which is indicated %y the a%sence of optical activity. (he crude atropine is purified %y crystalli*ation from acetone, "tropine sulphate is the most important salt of atropine. t occurs in the form of colourless crystalline powder. t is solu%le in water and alcohol %ut insolu%le in ether and chloroform. pts+ 1, solution of atropine dissolved in - . acetic acid is spotted ovef/siica gel 0 plate and eluted in the solvent system of strong ammonia solution-methanol 11.2!1003. (45 plate is spread with im acidified iodoplatinate solution. "tropine gives the 6f value 7 8 9:"6;570<7S= ".& 9:i(75:>;lS(6= t also acts as a skeletal muscle rela'ant. ?uinidine is used to treat various cardiac arrhythmias, ventricular contractions, atrial and vent'ic@ular tachycardia and atrial fi%rillation. solatiorr +5inchona %ark is dried to 1--12, moisture and then ground o finepowder of a%out A0 mesh in disintegrator. t is mi'ed with slaked lime containing over A0, calcium hydro'ide and water. &uring mi'ing, lime fi'es the organic acids as calcium salt. (he mi'ture is left for -B hrs. and then charged and e'tracted with %en*ene at a temperature of 1C0Df using steam. (he hot e'tracted mineral solvent containing alkaloid is shaken up with dilute sulphuric acid to transfer the alkaloid to the acid. (he a)ueous acidic e'tract containing alkaloid is %oiled and filtered through filter press while the solvent freed from alkaloid is recycled further for e'traction. (he filtered hot clear acidic e'tract is neutrali*ed with hot sodium car%onate solution at p: A.2 and cooled. 5rude )uinine sulphate seperates on cooling. t is centrifuged and refined %y %oiling with water and activated car%on to yield pure, white )uinine sulphate. (he li)uor containing other cinchona alkaloidstill is treated withmother sodium car%onate and sodium hydro'ide it precipitates completely as the free %ases. t is then e'tracted with ether to separate )uinidine and cinchonidine. (he

dried ether e'tract is dissolved in dilute hydrochloric acid. (he resulting mi'ture is neutrali*ed with ammonia solution. Sodium potassium tartarate 16ochelle salt3 is added which precipitates cinchonidine as a tartarate salt. (heEfiltrate containing solu%le )uinidine tartarate is treated with potassium iodide solution where )uinidine hydrogen iodide is precipitated. t is collected and decomposed with ammonia to yield free )uinidine is washed with water, dried, powdered and used for production of )uinidine sulphate. Schematic diagram for the isolation of ma#or cinchona alkaloids is presented in scheme 9owdered 5inchona %ark F 5a7 F .a7: F with Water i reflu' :ot %en*ene e'tract i e'tract with dilute :-S0B isulphate add .a-503 to p: A.2 "lkaloid sulphat% %oil with charcoal 5ool iltrate Filtrate sulpr.iiG ?uinidine, cinchonine, cinchonidine ")ueos e'tract 1cinchonine3 %en*ene


/ 9recipitate of )uinine ?uinine

e'tract withldiiute :51 .eutrali*ed acidic e'tract add Sod. 9ol tartarate

>ther e'tract 1?unidine, cinchonidiiie3

Filtiate 1?uinidineltartarate3 H I 8, ?uinidine hydrogen iodide 1ppt3 ?u in dine Scheme C.- ! Scematic diagram for the isolation of 5inchona alkaloid (esi! &issolve pure cinchona alkaloids or the e'tract in methanol. "pph the spots over silica gel -0 plate and elute in the given solvent system Spray the dried plate with &ragendorffs reagent. Some of (45 solveir. systems and 6f values of )uinine and )uinidine are given %elow 31A S74"( 7. ".& 9: =(79:"6 "1" 5>I( 5" 4S &>.( F 5"( 7. 7F S7;>

9recipitate 15inchonidine tartarate3 #add :51 "lkaloid :5 1add .:.7: 5inchonidine

S+k 5++;hu<%+

?uinine ?uinidine 13 5hloroform-diethyl amine 1C!13 -3 5hloroform-acetone-diethyl amine 12!B!13 0.1J 0.-K 0.1J 0.-A

+ dentiication+ (he solution of cinchona alkaloid when treated with %romine and ammonia produces emrald green colour. t is known ai (halleio)uin test. +;orphine and 5odeine+ ;orp(iirieLanarcodeine are the two most important iso)uinolinc alkaloids present in the air-dried milky e'udate o%tained %y incising the unripe capsules of 9apaver somniferum 4inne. Family 9apaveraceae. 7ther important alkaloids of opium includes the%a#ll and papaverine. h. '!

67 76. mp 1D53 9ercent ;orphine -2B C-1B, 5odeine 5: 2B-12A 0.J--.2, (he%aine 5: -5: C3 0.3-1.2, 9roperties ! ;orphine and its related alkaloids occurs as white crystalline powder. ;orphine is laevorotatory, %itter alkaloid. t ff sparingly solu%le in water, ether and chloroform %ut solu%le in alcohol and alkali solution. ;orphine has %een named after $;orpheusM the 0reek god of dreams. solation of morphine was irst attempted %y &erasne in 1K03 and named it has salt of opium. n 1C02 Seturner isolated morphine in pure form and referred to it as morphine acid meconate. ;ore than twenty structures were proposed for morphine and other related alkaloids. (he currently accepted structure is that proposed in 1C-2 %y 0ulland and 6o%inson. ;orphine in the prototype 9:"6;"570.7S= ".& 9 &(70:>I S(6= 31J i

1 N N

ol opiate analgesic drugs which act at several sites in the central nervous system to produce analgesia. 5odeine and its salts are narcotic ntlgesics and antitussive agents. (hey are used as sedatives Socially in allaying cough. $#7tatif#F! Several methods have %een used for the isolation of morphine and codeine from opium. 7ne of these methods commonly used. 9owdered opium is e'tracted with warm water till e'haustion. (he a)ueous e'tract is concentrated under vacuum and treated with a solution of caicium chloride 11!13. t is kept for BK hours and then filtered. (he filtrate containing the hydrochlorides of the alkaloids is concentrated when hydrochloride salt of morphine and codeine deposit in the form of dou%le compound known as $0regory salt$. (his salt is dissolved in warm water and neutrali*ed with dilute ammonia 1p: C3. ;oiphinc precipitates while codeine remains in solution as ammonium 1udeiuc chloride. 9recipitated morphine is iltered through charcoal. (in$ filtrate is neutrali*ed with ammonia and some amount of alcohol is added to precipitate morphine. ;orphine is HO dissolved in dilute hydrochloric acid to a saturated solution which on cooling crystalli*es 7ut as morphine hydrochloride. For purification of codeine, the solution of ammonium codeine chloride is concentrated, treated with 30, sodium hydro'ide and codeine is e'tracted with chloroform. 5hloroform layer is e'tracted further with dilute sulphuic acid and the a)ueous layer is decolori*ed with carcoal and su%#ected to iltration. (he iltrate is rendered alkaline with sodium hydro'ide solution and e'tracted with %en*ene. Pen*ene e'tract after evaporation to dryness afford codeine. 5odeine phosphate i !G formed %y neutrali*ing codeine with phosphoric acid and 6#i5ipitating the salt from a)ueous solution with alcohol. 1iS+=H (he 6f value of morphine and codeine in different solvent systems are listed %elow. S74"( 7. ".& &>.( F 5"( 7. 7F S7;> 9:=(79:"6;"5>I(15"4S


solation ! (he powdered ipecacuanha is e'tracted with a%out J0, ethano(or methanol. (he e'tract o%tained is concentrated and dissolved in water and the solution is made strongly %asic with ammonia and e'tracted with di-isopropyl ether. &i-isopropyl ether e'tract is then treated with 10-12, a)ueous potassium hydro'ide to remove cephaeline. (he e'tract is further evaporated to yield emetine. t is purified via dihydro%romide or dihydroiodide salt. (hese halide salts are converted to the hydrochloride %y neutrali*ing the regenerated ree %ase. n the another process, ipecac powder is treated with ammonia and ether. (he ether e'tracts is su%#ected to dilute sulphuric acid treatment to yield alkaloids. &ilute acid e'tract is then nearly neutrali*ed and washed with ether and then made strongly alkaline and treated with ether. >metine goes into ether while cephaeline remains in the a)eous phase. (he ether e'tract is concentrated and redissolved in methanol and converted to emetine hydro%romide with a methanolic solution of hydro%romic acid. (egt+ >metine hydrochloride is dissolved in methanol or water and spotted on silica gel-0 plates. (45 is eluted n the following solvent systems and the spot is visuali*ed under IQ light or %y spraying with %romocresol green or modiied &ragendorff s reagent. Solvent system 6f 13 5hloroform-methanol1K2!123 0.3-0.2 -3 Pen*ene-(oulene-ethyl acetate diethyl amine-methanol 132!32!10!-3 0.2B 33@H+Rthy4slh+4kei?n+ethanol-ammoma12!B!l3 0.J0 strychnine and Pruc#ns Strychnine and %rucine are o%tained from the dried seeds of Strychnous nu'-vomica, family 4oganiaceae. t contains 1.2 to 2, of total alkaloid. Strychnine and %rucine are modified corynane-type monoterpenoid indole alkaloid. Strychnine was irst discovered in 1K1A in Saint gnatius %ean S. ignatii and later on 9alletier isolated it in 1K1C from nu'-vomica seeds. 3-0 S74" ( 7. ".& &>.( F15" 9: =(79:" 6;" 5> I(15" 4S ( 7. 7F S7;>

6, Strychnine Prucine

+mp -: -: -AKD5 -756 -75:, JKD5

9roperties ! Strychnine occurs as %rilliant, colourless cu%es or crystalline powder. t is very slightly solu%le in water and forms water solu%le salt in nitric and sulphuric acid. t is freely solu%le in chloroform and dissolves in alcohol, %en*ene and pyridine. Prucine i occurs as crystalline powder solu%le in chloroform and alcohol. Poth alkaloids are very %itter in taste. Prucine isreadily distinguished from strychnine %y %eing readily o'idi*ed %y dilule nitric acid with the formation of an intense red colour. Strychnine and %rucine %oth are laevorotatory and %oth are generally used in resolution of dl acids. Strychnine is e'tremely to'ic and functions as a central stimulant. Prucine is less to'ic than strychinine. t is used as an alcohol denaIirant due to its e'tremely %itter taste. solation J Strychnine and %rucine occurs together in several species of Strychnous especially in S. nu'-vomica and S. ignatii. (he dried ripe 5 seeds of nu'-vomica are treated with hot water or steam to soften and then grinded and made into a paste with slaked lime. (he pasty mass is r su%se)uently e'tracted with chloroform till e'haustion. (he chloroform e'tract is concentrated to 1EA of its volume and then successively e'tracted in seperating funnel with dilule sulphuric acid. (otal a)ueous acidic e'tract consists of strychnine and %rucine in the form of their sulphate salts. (he com%ined acid e'tract is concentrated. Strychnine and %rucine can %e separated from this acid e'tract %y one of the following procedure. 9:"6"i"500.7S= ".& 9:=(75:>SIS-(6= L1

1 3 5oncentrated acid e'tract is made alkaline with e'cess of ammonia solution, where %oth alkaloids precipitates together. (he piri tpitatc is further e'tracted with -2, alcohol which dissolves nm trie and leaves strychnine as insolu%le mass. (his residue of fiiiyehnine is iltered off, dried and recrystalli*ed from ethanol. SM


c c

N$ 3 R



U Pun-:ie %isulphate is less solu%le in concentrated acid e'tract and therefoe it comes out from the solution which is removed %y filtration. ;$iihei I)nor is neutrali*ed to yield crystalli*ed material of strychnine Titilplutle. t is then converted to its free %ase %y precipitation with ammonia solution. 1pst##%issolvc strychnine and %rucine alkaloids in methanol and spot 7Qff silica gel 0 plates. >lute the plates with %en*ene-chloroformdirtliyl#uuinc 1C!B!13 solvent system and spray the dried plate with dwgendorffs reagent. Strychnine and %rucine corresponds to 6f ogpeci#.vely.+ +tlvirt#tit!nl on#H2trychnine when treated with potassium dicromate rnd ulpliiiuc.ucid #Giyes violet colour which turns to red and finally yellow. Qili%liistine and Qincristine Qin%lastine and vincristine are the two important indol iilkiiloids o%tained from the plant 5hatharanthus roseus family "pt icyanaocac which is %etter known as ;adagaskar periwinkle. (hese tlklloids are composed %y an indole and dihydroindole unit, i.iilhiii.iiitliine and vindoline, respectively. (he former is a i%ogane type while the later %elongs to aspidospermane type monoterpenoid - indole $.l.iilitoii, 5anadian group of researchers .o%el, Peer and 5utts reported tin- isolation of these alkaloids and Svo%oda and coworkers at >li 4ily .v S $nnipany esta%lished its anticancer activity. (he active alkaloid is iVu-G,i-iii in a relatively small amount in the crude drug. "%out 200 kg of1 $ roseus leaves gives a%out 1 g of vincristine. S74"( 7. ".& &>.( F 5"( 7. 7F S7;> O,$$ 6;" 5> I( 5" 4S M2W

9: =(79:"

5M 4 5705:

:,57 5:-7: Qin%lastine Qincristine

c:-ai3 <, ocX5:3 :7 575:, 7 7 6 mp 5:, -KB--K2D5 5:7 -J3--K1D5 9roperties ! Qin%lastine and vincristine %oth are solu%le in alcohol and %en*ene. ts sulphate salt is freely solu%le in water %ut slightly solu%le ethanol. Poth the alkaloids are white to slightly yellow crystalline or amorphous, odourless powder. (hese alkaloids in their pure form are unsta%le, very hydroscopic and highly to'ic compounds. Qin%lastine sulphate is used for the treatment of wide variety of neoplasms and in :odkin$s disease. Qincristine sulphate is recommended for the treatment of acute haemocytic leukemia and in other types of sarcomas. solation-+! Qinca leaves and her% irst minced and e'tracted with a)ueous-alcoholic acetic acid solution. ")ueous e'tract is concentrated and the residue further e'tracted with -, hydrochloric acid. (his acid e'tract is ad#usted to p: B with sodium hydro'ide solution and then e'tracted with %en*ene. "gain the p: of a)ueous solution is raised to J and again e'tracted with %en*ene to separate alkaloids. (he p: J %eiv*ene e'tracts were mi'ed together, concentrated, dried and dissolved in %cn*ene-methyiene chloride 1A2!323 and further su%#ected to chromatographic fractionation on neutral alumina column with %cn*ene-methylene chloride as an eluent using gradient elution techni)ue. Qin%lastine rich fractions are evaporated to dryness to yield vin%lastine sulphate which is su%se)uently crystalli*ed from alcohol. $ll 6;"570.7S=".& 9:=(751E>; S 63 303 S

c i c

rN M-Ni

Further elution of the column at p: levels B.C to 2.C affords the fractions containing vincristine which are com%ined dried and crystalli*ed from methanol. Qincristine is converted to its sulphate salt %y addition of a)ueous or ethanolic sulphuric acid to alcoholic solution. Further evaporation of solution and crystalli*ation from ethanol yield vincastine sulphate. 5#ggtQ(hin layer chromatography is an efficient means in identifying and monitoring the separation of vinca alkaloids. (he sample alkaloid is dissolved 1 mg in 0.1 ml of -2, water in methanol and spotted on the silica get 0 plate and eluted with the solvent system acetonitril-%en*ene 13&!J03. >luted plates are dried and sprayed with 1, solution of eerie ammonium sulphate in K2, phosphoric acid. Qincristine free %ase gives the 6r value 0.3C with the a%ove spraying agent. 6eserpine 6eserpine is an indole alkaloid o%tained from the roots of 6auwolia serpentina, family "pocyanaeae and also from other different species of 6auwolfia such as 6. micrantha, 6. vomitoria and 6. tetraphylla. (he material o%tained from natural sources may contain closely related alkaloids, which includes a#maline, a#malicine, a#malinine, rescinnamine, reserpinine, serpentine and yohim%ine. n 6. serpentina, reserpine and rescinnamine %oth respond to the e'traction procedures and e'tracted as a mi'ture of %oth while in 6. tetraphylla, reserpine and deserpidine are e'tracted together. 9roperties ! 6eserpine occurs as a white or pale %uff to slightly yellow, odourless, crystalline powder. t darkens slowly on e'posure to light %ut more rapidly when in solution. t is practically insolu%le in water and solvent ether %ut solu%le in alcohol, acetone and chloroform. t is freely solu%le in acetic acid. 6eserpine must %e protected !rom light during manufacture and storage. 6eserpine is an antihypertensive and antipsychotic agent. S74"( 7. ".& F&>.( Fi5" ( 7. 7F S7;> 3-B 5>4( 5" 4S 9: =(79:" 6;"


:,57 75:, 0Y5 och/ och3 75:3 75: 6eserpine 1mp - -J0D53 solution ! 6auwolfta root powder is e'haustively e'tracted with C0, Z.-.G-! a(cli:ol %y suita%le method of e'traction such as percolation. (he alcoholic e'tract is concentrated and dried under reduced pressure %elow A0D5 to yield 6auwolia dry e'tract containing a%out B, of total alkaloids. 6auwolfia dry e'tract is e'tracted further with proportions of ether-chloroform-C0, alcohol, 1-0!K!-.23. (o the e'tract o%tained add little dilute ammonia with intermittent shaking. "lkaloid is converted to water insolu%le %ase. "dd water and allow the drug to settle after lew vigorous shakings. Fitter off the solution and e'tract the residue with B volumes of 0.2 .: S0B in seperating funnel. 5om%ine the- total acid e'tract which contains the alkaloidal salt. (he e'tract is filtered, made alkaline with dilute ammonia to li%erate alkaloid. Finally it is e'tracted with chloroform. (he total chloroform e'tract is iltered, chloroform is removed %y distillation and the total alkaloidal e'tract is dried under vacuum to yield total rauwolfia alkaloids.(otal rauwolfia alkaloid consists of the mi'ture of over 30 different components . t is su%#ected to column chromatographic fractionation for the seperation of rese#+pine. (ested3 9aper chromatography ! &issolve a%out 1 mg of the sample of rauwolfia e'tractEstandard reserpine in methanol. mmerse a -0 ' -0 sheet of whatman .o.l ilter paper in the immo%ile solvent formamids 9:"6;"570.7S= ".& 9:=(75:>; S(6= NN. [t i tW ,. c c c c. 1 V -,

r tNA iNN

cX5 i3


;X5: :5-577: :5-577: \. >rgometrine 1mp 1K2-1C0D53 1A-D53 >rgometrine maleate 9roperties ! >rgometrine maleate is a white to greyish white or faintly yellow, odourless, crystalline powder. t darkens with age and on e'posure to light. t is slightly hygroscopic in nature. >rgometrine maleate is readily solu%le in water and alcohol %ut insolu%le in chloroform and ether. ts solu%le in water 1, solution in water has a p: of 3 >rgometrine %ase is more than the other principal to 2. alkaloids of ergot. >rgometerine maleate is an o'ytocic and produces much faster stimulation of the uterine muscles than do other alkaloids . :owever it shows a much less vasoconstrictor action. solation !Hn the la%oratory scale isolation techni)ue ergot powder is completely defatted with petroleum ether 1A0-K0D3 in so'hlet e'tractor. (he petroleum ether e'tract removes a%out 30, fat and colouring matter. (he residual marc dried %elow B0D5 is$transferred to a ether and dish, dilutemade ammonia with stirring. (he is stirred to dryporcelain to semisolid mass %y mateial adding sufficient solvent ncss and then packed in a so'hlet and e'tracted with solvent ether for a%out 2 hrs. (he ether e'tract filtered and to it little acetone added and shaken in seperating funnel with three volumes of 1, of tartaric acid. (he total acidic e'tract is com%ined and died under reduced pressure to yield total ergot alkaloid. (he total alkaloid is further dissolved in dilute ammonia and e' li Gh ted with four volumes of ether. (he com%ined total ether e'tract 9:"6;"570.7S= ".& 9:7(75:>; S(6= 3-J

cis washed thoroughly with 2 successive )uantities- of water. Water insolu%le ergotamine and ergoto'ine alkaloids stay with ether while the water solu%le ergometrine tartarte remains with a)ueous e'tract. (he a)ueous e'tract is made faintly alkaline with dilute ammonia and further saturated with ether. >rgometrine ree %ase is shifted to ethereal solution. t is again washed with water to remove impurities of other alkaloids. (he ether e'tract is again treated with three volumes of 1 , wEw tartaric acid in water. (he com%ined acid e'tract is concentrated under reduced pressure to yield water solu%le alkaloid. t is further puriied %y the column chromatographic ractionation. (est ! &issolve a%out 1 mgEml of alkaloid in methanol and apply on silica gel-0 plates. >lute the plates in solvent system toluene-%utanol .:B51 1saturated3 1A!B3 and spray the dried (45 plates with &ragendorfFs reagent. >rgometrine maleate shows the 6f 0.30. (he elution of the silica gel-0 (45 plate in other solvent system chloroform-ethanol-acetone 1A!B!B3, shows the 6 value 0.-3. Easicine+ Qasicine is a pyrrola*o)uina*oline alkaloid o%tained rom the leaves of "dhatoda vasica, family "canthaceae. ".vasica known as vasaka is a highly reputed ayurvedic medicinal plant used for the treatment of respiratory ailments, particularly for the treatment of cough, %ronchitis, asthma and tu%erculosis. Qasicine is present in vasaka upto a%out 1.3,. (he other alkaloids present includes vasicinone, vasicinol, vasicinolone, vasicol and adhatonine.

7: Qasicine 1mp -10D53 3-K S74"( 7. ".& &>.( F 5"( 7. 9:=(79:"6;"5>I(15"4S 7F S7;>

Ri]a.u"^i+ SouV

$yvy& --/0 5 +/k#ltV QiF --- lie m , 3_ <S 9roperties ! Qasicine is a white, crystallin$L powder with %etter tastl. t su%limates in high vaccum. Qasicine is solu%le in alcohol, acetone and chloroform %ut slightly solu%le in water. t is responsi%le for the %ronchodilatory and e'pectorant properties. t also shows a%ortifacient and antimicro%ial activity against gingival inflammation and pyrrhoea. solation ! Qasaka leaves are dried, coarsely powdered and %asiied to p: C with ammonia solution. t is further e'tracted with chloroform, (he total chloroform e'tract is com%ined and washed with water and dried over anhydrous sodium sulphate. (he solvent evapored to get the total alkaloid e'tract containing vasicine as a ma#or alkaloid. Qasieif# can %e further purified from the dry e'tract %y crystalli*ation. $es#VG &issolve 1 mg of vasicine in 1 ml of methanol with little warming. "pply the spots of test solution on the silica gel-0 plate and elute with toluene-methanol-dio'ane-ammonia 11!1!-.2!0.23. Spray the dried (45 plate with &ragendorff$s reagent. Qasicine gives orlhge cr#loufed@spot. .k)t#ne@+ .icotine is a pyridine alkaloid o%tained from the dried leave! of to%acco plant .icotiana ta%acum, family Solanaceae. (o%acco leaveG contains - to K, of nicotine com%ined as maleate or citrate.

5:, 1-3.icotine 1%p -BJD53 9roperties ! .icotine is a colourless or pale yellow, very hygroscopic oily li)uid with an unpleasent pungent odour and a sharp %urning persistant taste. t gradually %ecomes %rownish on e'posure to air or light. Weight per ml. is a%out 1 01 g. .icotine is solu%le in watei, alcohol, chloroform, ether, kerosene, petroleum ether and i'ed oils. 9:"6;"570.7S= ".& 9:7(75:>; S(6= WWW..-`.lll i e t. BN t ^ tt t a - S-. : i t ;1+$ 3JC