Determinación de la actividad antifúngica contra Candida Albicans y Aspergillus Niger de 10 plantas medicinales de 3 departamentos del Perú

Transcripción

1 UNIVERSIDAD NACIONAL MAYOR DE SAN MARCOS FACULTAD DE FARMACIA Y BIO QUÍMICA E.A.P. DE FARMACIA Y BIOQUÍMICA Determinación de la actividad antifúngica contra Candida Albicans y Aspergillus Niger de 10 plantas medicinales de 3 departamentos del Perú TESIS para optar el Título Profesional de Químico Farmacéutico AUTOR María Elena Huamaní Achata Julio Reynaldo Ruiz Quiroz ASESOR Mirtha Roque Alcarraz Lima Perú 2005

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5 A Dios nuestro más importante guia, por habernos dado la vida y el valor necesario para afrontarla. A la Dra Mirtha Roque Alcarraz, por su amistad, sus valiosos consejos y el tiempo dedicado, muchas gracias. A los miembros del jurado calificador: Presidente : Q.F. Jose Irey Namijira Miembros : Q. F. Rosario Carreño Quispe Mg. Luis Miguel Felix Veliz Q. F. Maria Elena Salazar Salvatierra Por sus valiosas sugerencias y consejos. 1

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7 El presente trabajo investigo la actividad antifúngica in vitro de doce extractos etanolicos correspondientes a diez plantas medicinales peruanas; Annona cherimolia Mill.(hojas), Annona muricata L.(corteza y hojas), Bidens pilosa L.(partes aéreas), Hypericum laricifolium L.(partes aéreas), Juglans neotropica Diels(corteza), Piper spp. (hojas), Plantago major L.(hojas), Psidium guajava L.(hojas), Schinus molle L.(corteza y hojas) y Spartium junceum L. (planta entera). Las especies fueron recolectadas en el departamento de Amazonas, excepto Schinus molle L. (Apurímac) y Annona muricata L. (Lima). La actividad antifúngica se evaluo mediante los métodos de difusión en agar y dilución en agar para la determinación de la concentración mínima inhibitoria (CMI). Los microorganismos de prueba utilizados fueron las levaduras Candida albicans ATCC y Candida albicans cepa clínica, así como, el hongo filamentoso Aspergillus niger ATCC 16404; las cepas fueron proporcionadas por la Cátedra de Microbiología de la Facultad de Farmacia y Bioquímica de la Universidad Nacional Mayor de San Marcos. De doce extractos investigados, seis presentaron actividad antifúngica consistente con un diámetro de halos de inhibición #18mm (Prueba de Difusión en agar) frente a Candida albicans ATCC Ningún extracto mostró actividad consistente frente a la cepa clínica de Candida albicans y Aspergillus niger ATCC La CMI de los extractos que presentaron actividad consistente frente a Candida albicans ATCC 10231, fue de 250 µg/ml para Hypericum laricifolium L., Juglans neotropica Diels, Psidium guajava L. y Schinus molle L. (un extracto de corteza y uno de hojas) y de 500µg/mL para Piper spp. No se determino la CMI de los extractos (Juglans neotropica Diels y Psidium guajava L.) que presentaron halos frente al Aspergillus niger ATCC por considerarlos sin actividad significante (<18mm.). Los antifúngicos Nistatina y Fluconazol fueron incluidos en el estudio como controles positivos. Palabras clave: Actividad antifúngica, plantas medicinales, plantas del Perú, Amazonas, concentración mínima inhibitoria, Candida albicans, Aspergillus niger. 3

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9 The present work investigated the antifungal activities in vitro of twelve ethanolic extracts corresponding to ten peruvian medicinal plants; Annona cherimolia Mill. (leaves), Annona muricata L. (bark and leaves), Bidens pilosa L. (aerial parts), Hypericum laricifolium L. (aerial parts), Juglans neotropica Diels (bark), Piper spp. (leaves), Plantago major L. (leaves), Psidium guajava L. (leaves), Schinus molle L. (bark and leaves) and Spartium junceum L. (whole plant). The plants were collected in the department of Amazonas, except Schinus molle L (Apurímac) and Annona muricata L. (Lima). The antifungal activities were determinated by the methods of agar diffusion and agar dilution for the determination of the Minimal Inhibitory Concentration (MIC). The used microorganisms of test were the yeasts Candida albicans ATCC and Candida albicans clinical isolate, as well as, the filamentous fungus Aspergillus niger ATCC 16404; the microorganism were provided by the Chair of Microbiology of Faculty of Pharmacy and Biochemistry of the Universidad Nacional Mayor de San Marcos. Of twelve investigated extracts, six presented significant antifungal activity with a diameter of inhibition haloes #18mm (Agar Diffusion) against Candida albicans ATCC No extract showed significant activity against to Candida albicans clinical isolate and Aspergillus niger ATCC The MIC of the extracts that presented significant activity against Candida albicans ATCC 10231, were of 250µg/mLfor Hypericum laricifolium L., Juglans neotropica Diels, Psidium guajava L. and Schinus molle L.(bark and leaf extracts) and of 500µg/mL for Piper spp. We do not determine the MIC of the extracts (Juglans neotropica Diels and Psidium guajava L.) that presented haloes against Aspergillus niger ATCC for considering them without significant activity (<18mm.). The antifungal agents Nistatin and Fluconazole were included in the study as positive controls. Key words: Antifungal activity, medicinal plants, Peruvian plants, Amazonas, minimal inhibitory concentration, Candida albicans, Aspergillus niger. 5

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

27 7 8 P 9A P 9A A ' H9 ' H9. A 9A A H 9 A A 1 3 # / *" " + / : *" " * + K #! * $ & # #<* $ #! J!! 7 8 # $!$ *! 0! & #$! =,! *" " / *! $ $ $ 12F &D#! / # / / $ 3 FFF! /"! "&"# "! #! "/! +!, "/! $! " "#/" * # :!" + *D "/ *" " " # & # "* #/" / #;*"/ #/ #! # #! $ & # "# D! + " "$ $!!! / *! ",!:, #/";# $! /"!: / "!: * $!: / & * # # *!!! /"! " # # & # "* #/" / * #! # * #! *!! /"! $! &D#! 1 $ $ >12? &D# / * #$ L =,! +,!!!" * 8 $! $ 0 E!!!:!"*!: #!!! " "! # /"*! K"! *"#! /"! = "@ / $ / #, #& $ #/"* $ 8 " : / # 4.5 ;,!:!"! # / # 4.5 D!, #/!L #$ / / # # *!!! *,! $"!!! # 8 "!! "! #, + &,! " " * : 8 /! / *! ", * #$ #! 1FF! /"! # "8! $ *D "/ "/ >12? % & ' % '? H +, : & +, > "8" : *," : / $ : <: P /0 =./ / > "8"?L & ", : & ", " : / & ", >!"?L! 0 "# > <A /0? >4?: & +," : R"* >/ / *?: R"* #!R": ;*+ > *!0?: *!:! /0 :! " : & + 8 : 0 +, >13? ' )?, 7 J $ 0! 5 * $ L! *" "/ $!L 0 E!!!:! #/"!: / "=/!: #!: 8 $!L!, #/!: 7 J!: $"!!! #! K"! $! 0 E!L! #, + / *! ", 7 * # / * " / #$ * $ : $ #! 5 /* $ $"=* : &,! : "! : / # #! $ + # *!!! *"! >4? ' & $ %$ C" A # <: / / # / "*! "/! +!, "/!A # "#: : ' =# / : Y #"#: "* : >13? + #! / * #! K " #$ $!$ DK"/ + # *D "/ : 0! $ *D "/ : #! / "/!" + <: #! # "! +! $ "$ = / ;&"/! #/ # # #E / $ : / # *"! 7 # 8 # *=! = $! 3F[ $ / $ 0 *"! " "&! =! 8 $ Q "/ :!" + #$" + / * #! #/ # # *=! $ 5F!! / # / "* "/ # ' S ": & +, / / # #E! $!D "/! / # /" " /" #! * #! 25F ** >-6? 23

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` / "8 7 : # $ & # " <#&"/ >5F?, / / / 4 8 # /! $ 8 /";#: & #! 0 #&! 0 # $ "# / / "8 * # / #! #! 8"8! * + $!! "# //" #!! # 8 # E!!! #!:! :! / /"*" # + $! : / * # /! $ *+/ 0"@ + #$ "! 9 : ; < = > 5? "# *, & # * + $, /" #! $! #! 0 + "#$"8"$! 7! #!"! #! "# //";# <#&"/ "# //";# # #! +!! ;& #!! / * E + $! * +! / "/ # / *,"# /";# $ $ $ # +! 0 #&!!! &"! $ $ #! $! #! / #!! ;& #!! # *< "! "#/ + #! $ 7 *"/! # " <#&"/! 2I

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a a a *" #! / $ $ /!! 0"! #!" "8! $!"! #/"!"! D*"/ $7 " "$ / * /";# $ # 8! # " <#&"/! 7 *"/!! /!! # * $! " K"#! ) D *"# b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a H"*#! *! a #&"! * >* # / + $ # + $"/ + $ #?

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

36 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # "#0","/";# $!/ # K"$! : *" " #$ / * /";# $!/ # >7! ;K"/! /D!? >B4: B6?! =! # $,"# "# >B5? # " "# + # :! # " /, *! $! ; "/ >11? % "% '? #0", * "# >11?! $ /! "! *!!: + C %$%' ' %?! # $ >5. /"!"#?: /! #! $ 0 /" *! + &! $! *"# /";#! * $ *"#! : / "#0",! #!"! * / / $! =! # $ " "*"$"# /"!"# 0 #&!!/ ", # /"!"# / "8 >5. /"? /"!"# >B4: B6: BG? K % 'A #0", #! #!"! $ c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d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

38 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # 34

39 57, 57, / :, / / :, / 57 7 / 2, ' a "! a #! a /, / $! a /! " a,! $, a "/ "! a "! $ 1FF _ a P"! K )%' a / 8 a #@ # "/! #!"," "$ $ F:1 *& #8 $ b.3ff 35

40 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # a 7 " $ a! a "# $ / /0"! W' a E ** "& $ a / 9 68 a #$"$,"/ #! 1F231 a! &"! #"& 164F4 a #$"$,"/ #! / / #"/ 16B4243 > "! $ $ /" # / # / #$"$"!"! a 8 &"# $ '! " 9 /" # N2 $ 57+7,, + O? 6 / /! #! >8, 9e 1? # / / $! # $ * # $ #!: * / + "* # *! $ E #" $ 2 FF4 / 9 N?, / / 1 / ') % & % # $ % ) %7 O, %!7P ' %Q "! ( "! $ " "* + H #=, # $" 0"#/0 #& 9 & "/ # D# H +, * #! > + M "#&? "* > "* M # # $!? #! > + M "#&? #! > + M "#&? #! > + M "#&? #! > 0 /0 +!M 0 /0 +!? #! > 0 /0 +!M 0 /0 +!? #! > + M "#&? * / > +*!M +? #! > 0 /0 +!M 0 /0 +!? / 9 1 6, / * " / / $ / #$"/" # $ +!," "@ $ # / $ $ * /" + " 7 *"/ $ #"8!"$ $ 9 /" # + $ # /! 32 e $ * 36

41 57, / :, / K"* $ * #! / $!!! 7!! # # 0 E!: :! D! + # # $ #$" #$ $ # >8, 9[ 2? # "@ $ *!!! * "; # /! $ $ //";# $ * J $ /! # # * "# $ / /0"! f 21!$ CE0D F G4 F $ 4 $ C 4 HCI 4 H@ F 4 H Y H Y P 9-9H g9 3G

42 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # 57;7 :/ / 6 / / / 6 / 4 8,, E; / # 8 $ &"$ $ / $! /" K //";#! "@; * / /";# >1F& $ 8 "@ $! # IF * $ # I5 C? * *," #! 8 # $ # 8 # # 8 / $ : / # "# #$ * / /";# 0! / * #! * # & * / $ " $ + * "# " 4F e >/.0? 8 $! 7 $ $ 57;7 7 / 6 8 # 8 # O *5Q #$ * # A!,!,! # "#0","/";# $ / /"*" # <#&"/ : * $" # $"!";# $!!! #/"! / "8! # # * $"!; "$ 7! 8"$ #/" / # * /";# $ 0! $ "#0","/";# %% $ ' %' a #$"$,"/ #! 1F231 a! &"! #"& 164F4 a #$"$,"/ #! / / #"/ 9[ 16B42I3, ) ') ' %A! / "8! $ / $ # $ *"/ & #"!*! $, # / "8 $! # / $ $ K!, $ 3B!

43 57, / :, /, * / A * #! $ $ / #"! / $ # $ / "8!/ >24 0? $ #$"$ $ # & $ K!, $ >? +!!! #$ # 5 * $! /";#! "# "!" ;&"/! D " + / # + $ $ #! / ;* > #&" $ $ #$ A 53F #*?:! E! # $ #!"$ $ ; "/ 0! / $, 9e B 3 $!/ $ / #$ 7 "8 # # / #/ # /";# K"* $ $ I K 1F /D! $ *"/ & #"!* M*,? * #! $ $ / #"! / $ # $ /! $ G $"! $ # "&h $ $ +!!! #$ # 5 * $! /";#! "# "!" ;&"/! D " 0! B / #@ # / #/ # /";# 7 "8 # I K 1F!!M* : "@ $ /=* / # $ $ /D! +M / *, $ / # $ $" /" #!! " $! # / : "@ $ 7 $ $ F:F1 * $ # $" /";# 1A1FF 8 #" #! $ 8 "! $" /" #! $ "#;/ E! $!, /! $! /! # "#/, $! 2B.3F e + # K *"# $! $" " * #! #/" $ / #"! <#&"/!! / #"! # / # $! / * M* / #$ / /"*" #! 0"@ 8"!",, ) ', '? /";# $! /!! " "@; * $" & $ K!, $L 8" * # / #! " "$ :! " "@ $ : # " $ + * # #"$ 45 e :! " * #! & &; 1 * $!! #!";# $ "#;/ / $ 1FF * $ * $" $ / "8 : $!!D "/ * # :! &" ;! 8 * # +! "; # /! $ 2F * / :! $ E! "$" "/ +! ; / # # *, $ *"/ & #"!*! "& &! / # + $ $ #! /, / $ $ / $ 1F ** $ $"=* : # / # $ / $ /, ) ' ' '? # " $ K /! / :! $" +; / # # I6C: 0!, # # / #/ # /";# $ 25 *&M* % & ' ' 'A / $ / / F:1 * $! K /! #; "/! >25 *&M*?: $! $" #! *!!, E! $" #!! / 0 /0! 8" * # & # * + $"!";# $! *!!! $ E! 1 0 * *," # + &! 8 # * $ "#/, /";# $ 3F e B 0! % % $!%? " "@; # I6 C % % ',%'!%'? $"* "! ;K"$ ^? " "@; / + 9"! "# >F:2 *&M* #!,!! "@ # " "/ $ ) %' ' %'? & $ #!/ "$ " * $ "#/, /";#! / $"; "@ / /! #$" # / #,! 8 /";# #! /! $ "#0","/";# $ / /"*" # : * $" # &"! $! $"=*! # ** #!! //" # #! *!!!" "8! >0 * + 1B ** $ $"=*?:! *, $ $" /";# # & + $ *"# #/ # /";# #"* #0"," " >? 57;757 E/ 6 8 OFQ %?!,!,! # "#0","/";# $ / /"*" # <#&"/ : * $" # 3I

44 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # $" /";# $! K /! #; "/! >!! #/"! / "8!? # & : +! " * #! 8"$ #/"! #/" $ / /"*" # #! /! %% $ ' %' a #$"$,"/ #! 1F231 a! &"! #"& 164F4 % % ',%'!%' O $ ' "# $ %'Q a / F: _&M* a 9"! "# _&M* >G? % % ' $!%' a a > "* "! ;K"$? # I6 C ' ' " /" #!! " $! $,! $ 62:5.2 FFF _&M*! /!! # " $ K /! / $! *!! &"$! "*! #! /";#! /R $ 1FF *&M* + &!!"&!7 * $ $" /";# $, 9e 3 $" /";# "# 1A5F! " "@ * $" $ / "8 / * $" + # :, #" #$ /! " / #! / #/ # /" #! $! $! $ *! %!% & K!, $ >?, ) ', 'A /";# $! /!! " "@; * $" & $ K!, $L 8" * # / #! " "$ :! " "@ $ : # " $ + * # #"$ 45 e :! " * #! & &; F:25 * $! $" /" #! $! K /! #; "/! # / * #$ 12:5 * #! /! " / # * $" $ / "8 : "/ * # L $ E! "$" "/ +! / # $" /";#: *! + # *, $ *"/ & #"!*! "&!$ CE)D FH$9 HJC F $ ^ "* "! ;K"$! 4 ia #/ # * $" $ 125FF &M*, ) ') ' %, * /? / &" #$ / #! $ / "8 5 / #"! 1 ** + $ 24 0 $ / /"*" # # / $ 7!!! #$ # # #, $! /";#! "# > 9 F:B5C? &"," # +: / # + $ $ #! / ;* > #&" $ $ #$ A 53F #*?:! E! # $ #!"$ $ ; "/ F:5 / #$: J $" #$ / # "$ $ 4F

45 57, / :, / # /! " $! /";#! "#!! /";# " # # / #/ # /";# K"* $ $ 1K1F 6. 5K1F M* ^ #"$ $ * $ $ #"! 6,? # &D# >1F3? "#;/! " $ # / "8 $ G $! $ / /"*" # 3F e # & & /! $ $ >?: * $" 7 "#$ / * /";# $ / #"$"!! #&"!! /" " / &"$ $ / #"$"!: "# $ /"! $ / "8 # S! #/"* $! / #"$"!L $! D!!! #$ #! /";#! "# E! $"* #! /! $ # 3.5 *"# : #! ", + &" 8"&! * # $ # 15! & #$!!, # $ # # 2F + # + $ $ #! / ;* > #&" $ $ #$ A 53F #*?:! E! # $ #!"$ $ ; "/ >? $ F:FI.F:1G >BF.B2C!*" #/"?A F:41.F:56 / #$: 6, # # / #/ # /";# $ 1.5K1F M* / # " "/ /";# $ "#;/ "@ $ 7 $ $ F:F1 * $ # $" /";# 1A1FF $ "#;/ E! $!, /! $! /! # "#/, $! 2B.3F e + # K *"# $! $" " * #! #/" $ / #"! <#&"/!! / #"! # / # $! / * M* / #$ / /"*" #! 0"@ 8"!", % & ' ' ' OFQ? #! "/" $ &! 8" F:F1 * >1F j? $!! #!";# $!! / "8! "#;/!: /!! / $! "/" $ / / # + $ $ #! = $ "&!R+! /! # "#/, $! 2I [ / /"*" # <#&"/ /0 7 $ : "* # / # $ /! $!"# & # *! $, : $! D!! 24: + 4B 0 $ #$" #$ $ ";$ $ "#/, /";# 7 "$ # / /"*" # 8"!", L 24 0! : + 4B 0 $? < H % H& $ "#"$ / * *=!, E / #/ # /";# $ K / 7 "#0", / /"*" # 8"!", # & 57;7+7 / / 2 -, # "# "$ $ $ "$ # " "/ *, "! / "8! #!! /"! *=! / "8! $!,! # "!:! "@; #! $" "*"# # $" #! * $"! $ K //";# / #!"& " # / $"*" # A > %' J $"; # 1F& $ # 8 :! & &; IF * $ & $! " $ :! / $"; / # # 0 GF [ &" #$ : &! " ; + / #/ # ; 0! # 8 * # $ 5F * > J $"; # 1F& $ # 8 :! & &; IF * $ # :! / $"; / # # 0 E, J $ 8 65 [ + / # &" /";# &! " ; +! 8 ; / 0 # 8 &% %' "@; * $" #,! "!"/ 7 *"/!: $ / / "@ /";# >32? #! *, "!,!/ $! # *! /, 0"$!: #"#!: / *!! #; "/!: 41

46 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # / "$!:! "$!: 8 # "$!:! #"#! 42

47 +7 / +7 / +7 7 E/ 6 8!, #! "#$"/; //";# "#0"," " $! $" #! K /! #; "/! $! #! 25 *&M 8 $! #! 8 $! 1F231: / / #"/ L + 0 #& " * #! < 164F4 >8, 4 + "&! 1 G? +757 E/ 6 8!, #! "#$"/ #/ # /";# #"* #0"," " $! K /! #; "/! $! #!! //" #! / # *D $ # " # 8 $ 1F231: + 0 #& " * #! 164F4 >8, 5+ "&! B 13? +7+7 / / 2 -,!! $! $!! $"! *! # #!, 6 43

48 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # CK-D HIHF F 4 C H LC@H 4 F $G4 M 7 G4 CG$H G4 79FG4 $ # A : L ': 0 E!L :! D! >0 E!:!: +?L : # # A #$"$,"/ #! 1F231L >?A #$"$,"/ #! / / #"/ L #A! &"! #"& 9 A 9! $ : A "* "! ;K"$!$ CE2D HIHF F 4 C H 9C@H 4 F $G4 M 7 G4 CG$H G4!! $" $!A : L ': 0 E!L :! D!L : # # 9 A #! $!$ CE6D 4 9FHG H GN9H H G F $ M 7 G CG$H G F $ 4 $ C 4 4 HI 4!! $" $!A : L ': 0 E!L :! D!L : # # 9 A #! $ L >.?A! #/" L >km.?a "&! #/" L >k?a! #/" 44

49 +7 / H@97 CE/D 3 = A? " 02 O $ /.0)/? A ( "! ># &?. A >/0"#/0 #&? X! D! A # A 4 1 > *? X # # 45

50 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # H@97 CE0D 3 = A? " 02 O $ /.0)/ A >* "/?. 0 E! A 1 3 >& +,? X 0 E! A 4 >*?. A 4 >*?. 0 E! 46?

51 +7 / H@97 CE)D 3 = A?. 0 O $ /.0)/ 3 A / 9A 9"! "# H@97 CE-D 3 = A? "? 4G

52 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # 02 O $ < A 1 3 >& +,? X 0 E! A 4 >*?. 0 E! A 4 >*?. A ( "! ># &?. A A >/0"#/0 #&? X! D! >* "/?. 0 E! H@97 CE2D 3 = A? 5 ( F % & 02 O $ /6-4B "?

53 +7 / H@97 CE6D 3 = A? " 02 O $ /6-? A ( "! ># &?. A >/0"#/0 #&? X! D! H@97 CE*D 3 = A? 3 4I

54 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', #. 0 O $ /6- A / 9A 9"! "# H@97 CE+D 3 = A? "? /.0)/ D % A & HD 02. P O $ 1A 2 FFF j&m* 2A 1 FFF j&m* 3A 5FF j&m* 4A 25F j&m* 5A 125 j&m* 6A 62:5 j&m* 5F

55 +7 / H@97 CE,D 3 = A? " /.0)/! A? >0 E!? A 5FF j&m* >.?A # # & "8 1A 2 FFF j&m* 2A 1 FFF j&m* 3A 5FF j&m* 4A 25F j&m* 5A 125 j&m* 6A 62:5 j&m* 51

56 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # H@97 CE/.D 3 = A? 5 /.0)/ A l32 j&m* >.?A # # & "8 1A 32 j&m* 2A 16 j&m* 3A B j&m* 4A 4 j&m* 5A 2 j&m* 52

57 +7 / H@97 CE//D 3 = A? /.0)/ A B _&M* >.?A # # & "8 1A 64 j&m* 2A 32 j&m* 3A 16 j&m* 4A B j&m* 5A 4 j&m* 6A 2 j&m* GA 1 j&m* 53

58 ! "# $ % & ' ( ') $ ' $ * ) ' ' + ) %', # H@97 CE/0D 3 = A? 5 /6 A l 64 _&M* >.?A # # & "8 1A 64 j&m* 2A 32 j&m* 3A 16 j&m* 4A B j&m* 5A 4 j&m* 54

59 +7 / H@97 CE/)D 3 = A? /6- HD - Q O $ >.?A # # & "8 1A 64 j&m* 2A 32 j&m* 3A 16 j&m* 4A B j&m. 5A 4 j&m* 6A 2 j&m* GA 1 j&m* 55

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