|
1 khoom (10Vials)
| Ntim: | |
|---|---|
▎ Epi Structure
Source: PubChem |
Ib ntus: Ala-Glu-Asp-Gly Molecular Formula: C 14H 22N 4O9 Molecular Luj: 390.35 g / mol CAS Nr .: 307297-39-8 PubChem CID: 219042 Synonyms: Epita |
▎ Epi Kev Tshawb Fawb
Dab tsi yog qhov kev tshawb fawb keeb kwm ntawm Epi?
Nyob rau xyoo 1980, ib pab pawg kws tshawb fawb Lavxias coj los ntawm Vladimir Khavinson thawj zaug pom Epi1 [1] . Epi yog ib qho hluavtaws luv peptide uas muaj plaub amino acids: alanine, glutamic acid, aspartic acid, thiab glycine. Nws synthesis yog raws li lub ntuj peptide epithalamion muab rho tawm los ntawm lub caj pas pineal. Epi ntseeg tias muaj cov teebmeem antioxidant piv rau cov melatonin thiab tej zaum yuav muaj txiaj ntsig ntawm kev ua neej ntev [2] . Cov kws tshawb fawb tau pom tias Epi tuaj yeem txhawb kev ua haujlwm ntawm telomerase. Telomerase yog ib qho enzyme uas tuaj yeem tiv thaiv thiab txuas ntxiv telomeres ntawm qhov kawg ntawm chromosomes. Raws li cov neeg muaj hnub nyoog, telomeres luv, uas cuam tshuam nrog cov kab mob uas muaj hnub nyoog thiab lub neej luv. Los ntawm kev txhawb nqa kev ua haujlwm telomerase, Epi tuaj yeem pab txuas ntxiv telomeres, yog li qeeb cov txheej txheem kev laus thiab tiv thaiv kev laus ntawm cov kab mob [1] . Qee qhov kev tshawb fawb tau pom tias Epi tuaj yeem koom nrog hauv kev tswj hwm kev qhia ntawm CCL11 thiab HMGB1 cov noob thiab ua raws li tus neeg ua haujlwm ntawm kev qhia ntawm cov noob no. Tib lub sijhawm, dipeptide vilon (Lys-Glu) thiab tetrapeptide Epi (Ala-Glu-Asp-Gly) tuaj yeem ua rau lawv cov teebmeem tiv thaiv kev laus los ntawm inhibiting cov noob no. Ua ke, Epi thiab vilon paub los tswj cov noob qhia thiab cov protein synthesis, txhawb kev txo qis hauv kev tuag thiab kev qeeb hauv kev loj hlob ntawm cov neeg laus [3] . Tam sim no, kev tshawb fawb ntawm Epi feem ntau tsom mus rau theem kev sim tsiaj, thiab nws cov txiaj ntsig ntev thiab kev nyab xeeb hauv tib neeg tsis tau txiav txim siab tag nrho. Txawm hais tias qee qhov kev tshawb fawb tsiaj tau ua tiav cov txiaj ntsig txhawb nqa, xws li hauv nas, Epi cuam tshuam nrog lub neej ntev thiab kev noj qab haus huv zoo dua, kev siv tau ntawm cov txiaj ntsig no hauv tib neeg tseem xav tau kev tshawb fawb ntxiv [1].
Yuav ua li cas yog lub mechanism ntawm kev txiav txim ntawm Epi nyob rau hauv lub teb ntawm anti-aging?
Txo cov qib ntawm reactive oxygen hom:
Reactive oxygen hom (ROS) ua lub luag haujlwm tseem ceeb hauv kev laus ntawm oocytes. ROS ntau dhau yuav ua rau oxidative puas tsuaj rau oocytes, cuam tshuam rau lawv qhov zoo thiab kev loj hlob muaj peev xwm. Cov kev tshawb fawb tau pom tias Epi tuaj yeem txo tus nqi ntawm cytoplasmic fragmentation ntawm oocytes los ntawm kev laus thiab cov ntsiab lus ntawm intracellular reactive oxygen hom [2] . Raws li cov tshuaj antioxidant, Epi tuaj yeem ua rau lub cev tsis muaj zog ROS thiab txo nws txoj kev puas tsuaj rau oocytes. Tshwj xeeb, nws yuav ua tiav nyob rau hauv ob txoj kev hauv qab no: Ua ntej, ncaj qha scavenging ROS. Epi tej zaum yuav muaj peev xwm los cuam tshuam ncaj qha nrog ROS thiab hloov nws mus rau hauv cov khoom tsis zoo. Thib ob, txhim kho kev ua haujlwm ntawm cov enzymes antioxidant. Epi tuaj yeem txhawb kev ua haujlwm ntawm intracellular antioxidant enzymes, xws li superoxide dismutase (SOD), catalase (CAT), thiab lwm yam. Cov enzymes no tuaj yeem pab txhawm rau txhawm rau ROS thiab tswj kom muaj qhov sib npaug ntawm intracellular redox.
Txhim kho mitochondrial muaj nuj nqi:
Mitochondria ua lub luag haujlwm tseem ceeb hauv lub zog metabolism thiab kev muaj sia nyob ntawm tes ntawm oocytes. Raws li oocytes hnub nyoog, mitochondrial muaj nuj nqi yuav maj mam poob, tshwm sim raws li ib tug txo nyob rau hauv mitochondrial daim nyias nyias muaj peev xwm thiab ib tug txo nyob rau hauv daim ntawv tus naj npawb ntawm mitochondrial DNA. Epi tuaj yeem ua kom cov mitochondrial membrane muaj peev xwm thiab cov ntawv luam ntawm mitochondrial DNA [2] . Qhov no yuav pab txhim kho lub zog ntawm oocytes thiab tswj cov kev ua haujlwm ntawm lub cev ntawm cov hlwb. Cov txheej txheem tshwj xeeb ntawm kev ua haujlwm yuav suav nrog: Ua ntej, ua kom cov mitochondrial membrane muaj peev xwm. Kev tuav lub mitochondrial membrane muaj peev xwm yog qhov tseem ceeb rau kev ua haujlwm ntawm mitochondria. Epi tuaj yeem ua kom cov mitochondrial membrane muaj peev xwm los ntawm kev tswj cov ion raws lossis thauj cov proteins ntawm mitochondrial membrane, txhim kho lub zog tsim muaj peev xwm ntawm mitochondria. Qhov thib ob, nce cov ntawv luam ntawm mitochondrial DNA. Ua kom cov ntawv luam ntawm mitochondrial DNA tuaj yeem txhim kho lub peev xwm synthesis ntawm mitochondria thiab muab lub zog ntau rau cov hlwb. Epi tuaj yeem nce tus lej luam ntawm mitochondrial DNA los ntawm kev txhawb nqa kev rov ua dua ntawm mitochondrial DNA lossis txo nws txoj kev degradation.
Txo qhov txawv txav spindle morphology thiab txawv txav exocytosis ntawm cortical granules:
Thaum lub sij hawm laus txheej txheem ntawm oocytes, qhov sib piv ntawm txawv txav spindle morphology thiab txawv txav exocytosis ntawm cortical granules yuav nce, uas yuav cuam tshuam rau fertilization thiab embryonic kev loj hlob muaj peev xwm ntawm oocytes. Epi tuaj yeem txo qhov sib txawv ntawm qhov txawv txav ntxaiv morphology thiab txawv txav exocytosis ntawm cortical granules [2] . Qhov no tej zaum yuav yog vim muaj kev tswj hwm ntawm Epi ntawm kev ruaj ntseg ntawm cytoskeleton thiab cell membrane: Ua ntej, stabilizing cov qauv spindle. Lub spindle yog ib qho tseem ceeb ntawm cov txheej txheem ntawm kev faib cell, thiab nws cov morphology txawv txav yuav ua rau txawv txav chromosome segregation thiab cuam tshuam rau kev loj hlob ntawm oocytes. Epi tuaj yeem txhim kho cov qauv spindle los ntawm kev tswj cov polymerization thiab depolymerization ntawm tubulin, txo qhov tshwm sim ntawm qhov txawv txav ntawm morphology. Thib ob, tswj kev ruaj ntseg ntawm cortical granules. Cortical granules ua lub luag haujlwm tseem ceeb hauv cov txheej txheem fertilization ntawm oocytes. Epi tuaj yeem tswj kev ruaj ntseg ntawm cortical granules los ntawm kev tswj cov permeability ntawm cell membrane los yog calcium ion signaling, txo qhov tshwm sim ntawm txawv txav exocytosis.
Txo cov cim apoptosis:
Thaum lub sij hawm kev laus ntawm oocytes, apoptosis signals yuav nce, ua rau cell tuag. Epi tuaj yeem txo qhov zoo ntawm Annexin V staining thiab fluorescence siv ntawm γH2AX hauv vitro laus oocytes [2] . Qhov no qhia tias Epi tuaj yeem txo qhov apoptosis ntawm oocytes. Cov txheej txheem tshwj xeeb yuav suav nrog: Ua ntej, inhibiting apoptosis signaling pathway. Epi tuaj yeem cuam tshuam kev sib kis ntawm apoptosis cov cim los ntawm kev tswj hwm cov proteins tseem ceeb hauv txoj kev taw qhia apoptosis, xws li Bcl-2 tsev neeg cov proteins thiab caspase tsev neeg cov proteins, thiab txo cov cell tuag. Thib ob, tswj genomic stability. γH2AX yog ib qho ntawm cov cim ntawm DNA puas. Epi tuaj yeem tswj hwm kev ruaj ntseg genomic los ntawm kev txo cov DNA puas thiab txo cov cim apoptosis.
Epi khaws cia ib txwm spindle kev ncaj ncees thiab CGs faib.
Source: PubMed [2]
Dab tsi yog hom tshwj xeeb ntawm kev ua ntawm Epi hauv kev kho cov kab mob neurodegenerative?
Kev tswj kev tiv thaiv kab mob:
Cov kev tshawb fawb tau pom tias Epi tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob ntawm cov nas nyob rau hauv ntau yam kev ntxhov siab. Nyob rau hauv lub ntsej muag ntawm kev tiv thaiv kev tiv thaiv kev sib hloov kev ntxhov siab thiab kev tiv thaiv kab mob sib xyaw ua ke, Epi tuaj yeem ua rau muaj kev loj hlob ntawm thymocytes [4] . Qhov no txhais tau hais tias Epi tuaj yeem txhim kho lub cev tiv thaiv kab mob neurodegenerative los ntawm kev tswj lub cev tiv thaiv kab mob. Kev loj hlob ntawm thymocytes yog ze ze rau kev ua haujlwm ntawm lub cev tiv thaiv kab mob, thiab lub cev tiv thaiv kab mob ua lub luag haujlwm tseem ceeb hauv kev tshwm sim thiab kev loj hlob ntawm cov kab mob neurodegenerative. Piv txwv li, qee cov kab mob neurodegenerative tej zaum yuav cuam tshuam nrog kev ua kom tsis zoo lossis ua tsis taus ntawm lub cev tiv thaiv kab mob. Kev txhawb nqa ntawm Epi ntawm kev loj hlob ntawm thymocytes tuaj yeem pab tswj kev sib npaug ntawm lub cev tiv thaiv kab mob, yog li txo cov tsos mob ntawm cov kab mob neurodegenerative.
Influence ntawm lub teeb liab transduction txoj kev:
Epi muaj kev tswj xyuas cov txiaj ntsig ntawm interleukin-1β (IL-1β) teeb liab hloov txoj hauv kev. Tshwj xeeb, Epi tuaj yeem ua rau muaj kev sib koom ua ke ntawm IL-1β thiab cuam tshuam rau kev ua haujlwm ntawm cov enzyme tseem ceeb hauv ceramide teeb liab hloov txoj hauv kev hauv cerebral cortex membrane, uas yog daim nyias nyias nruab nrab sphingomyelinase (nSMase) [4] . IL-1β yog ib qho tseem ceeb cytokine koom nrog ntau yam txheej txheem physiological thiab pathological. Hauv cov kab mob neurodegenerative, qhov txawv txav ntawm IL-1β tuaj yeem ua rau cov kab mob neuroinflammation thiab neuronal puas. Los ntawm kev tswj hwm IL-1β teeb liab kev hloov pauv txoj hauv kev, Epi tuaj yeem txo qis neuroinflammation thiab tiv thaiv cov neurons los ntawm kev puas tsuaj. Tsis tas li ntawd, kev hloov pauv hauv kev ua ntawm nSMase kuj muaj feem xyuam rau cov kab mob neurodegenerative. Cov kev cai ntawm kev ua ntawm nSMase los ntawm Epi tuaj yeem pab tswj kev ua haujlwm ntawm cov paj hlwb. Txawm li cas los xij, kev tshawb fawb tam sim no ntawm Epi hauv kev kho cov kab mob neurodegenerative tseem nyob rau theem ua ntej, thiab xav tau kev tshawb fawb ntxiv kom paub meej tias nws cov txiaj ntsig thiab kev nyab xeeb.
Kev tshawb nrhiav kev vam meej ntawm Epi
Qhov cuam tshuam rau qhov zoo ntawm oocytes
Kev ncua kev laus ntawm oocytes:
Cov kev tshawb fawb hauv vitro tau pom tias Epi tuaj yeem txo cov qib ntawm intracellular reactive oxygen hom (ROS) hauv cov laus nas oocytes tom qab ovulation. Nyob rau tib lub sijhawm, kev loj hlob ntawm oocytes yuav maj mam txo qis tom qab ovulation hauv vivo lossis hauv vitro. Raws li ib qho hluavtaws luv peptide, Epi ua zoo ib yam li melatonin thiab yog ib qho antioxidant zoo, uas yuav muaj txiaj ntsig ntawm kev ua neej ntev. Kev kho mob nrog Epi txo qhov zaus ntawm spindle defects thiab txawv txav ntawm cortical granules thaum lub sij hawm 12 teev thiab 24 teev ntawm kev laus, thiab nyob rau tib lub sij hawm nce lub mitochondrial membrane muaj peev xwm thiab cov ntawv luam ntawm mitochondrial DNA, yog li txo cov apoptosis ntawm oocytes thaum 24 teev nyob rau hauv vitro. Cov txiaj ntsig no qhia tau tias Epi tuaj yeem ncua kev laus ntawm oocytes hauv vitro los ntawm kev tswj hwm kev ua haujlwm mitochondrial thiab ROS qib [2].
Txhim kho qhov zoo ntawm oocytes:
Ntxiv 0.1 mM ntawm Epi rau hauv vitro kab lis kev cai nruab nrab tuaj yeem txo tus nqi ntawm cytoplasmic fragmentation hauv parthenogenetic ua kom oocytes tshwm sim los ntawm kev laus hauv vitro tom qab ovulation, txo qhov sib txawv ntawm qhov txawv txav spindle morphology thiab txawv txav exocytosis ntawm daim ntawv cortical granules, nce mitochon lub peev xwm thiab cov DNA. Qhov zoo ntawm Annexin V staining thiab fluorescence siv ntawm γH2AX hauv vitro laus oocytes. Qhov no qhia tau hais tias Epi tuaj yeem txhim kho qhov teeb meem ntawm organelles thaum lub sij hawm hauv vitro aging txheej txheem ntawm oocytes thiab txhim kho qhov zoo ntawm oocytes (Xue Yue).
Qhov cuam tshuam rau qhov sib txawv ntawm cov paj hlwb
Cov kev tshawb fawb tau pom tias AEDG peptide (Epi) tuaj yeem ua kom cov synthesis ntawm neurogenic sib txawv cov cim hauv tib neeg gingival mesenchymal qia hlwb, xws li Nestin, GAP43, β Tubulin III, thiab Doublecortin. Molecular qauv qauv qhia tau hais tias Epi nyiam khi rau H1 / 6 thiab H1 / 3 histones, uas tej zaum yuav yog ib qho ntawm cov txheej txheem rau nce kev hloov pauv ntawm cov noob caj noob ces sib txawv [5].
Kev tswj cov nyhuv ntawm lub paj hlwb
Tswj kev ua haujlwm neuronal:
Los ntawm kev tshawb fawb ntawm nas, nws tau pom tias intranasal infusion ntawm Epi (2 ng) tuaj yeem ua kom muaj kev ua haujlwm ntawm lub paj hlwb ntawm nas nyob rau hauv ob peb feeb, thiab qhov hluav taws xob ntau zaus ntawm cov neurons tau nce los ntawm 2 - 2.5 zaug [6] . Hauv qee cov ntaub ntawv kaw, cov lus teb nyuaj uas muaj ntau theem kuj tau pom. Qhov nce hauv qhov kev ua haujlwm ntawm cov neurons los ntawm Epi yog tshwm sim los ntawm ntau zaus ntawm cov haujlwm uas twb muaj lawm thiab kev koom tes ntawm cov hlwb uas ntsiag to yav dhau los. Yam tsawg kawg yog thawj theem ntawm qhov kev txiav txim ntawm Epi tuaj yeem piav qhia los ntawm qhov ncaj qha cuam tshuam ntawm peptide no ntawm cov hlwb ntawm lub cev muaj zog cortex.
Kev tiv thaiv kev ntxhov siab:
Epi muaj kev tiv thaiv kev ntxhov siab rau cov nas uas muaj kev ntxhov siab sib txawv. Kev sim tau pom tias Epi nce qhov kev loj hlob ntawm thymocytes. Txawm hais tias nws tau txhim kho nyob rau hauv kev tiv thaiv kev tiv thaiv kev ntxhov siab lossis kev cuam tshuam hauv kev tiv thaiv kev tiv thaiv kev ntxhov siab, Epi tuaj yeem ua lub luag haujlwm tswj hwm (Vladimir Kh Khavinson, 2002). Nyob rau tib lub sijhawm, Epi tuaj yeem ua rau muaj kev sib koom ua ke ntawm interleukin-1β (IL-1β) thiab muaj kev cuam tshuam rau cov kev hloov hauv kev ua ntawm sphingomyelinase (nSMase) hauv cerebral cortex membrane vim kev ntxhov siab. Qhov no qhia tau hais tias Epi muaj kev tiv thaiv kev ntxhov siab nyob rau theem ntawm IL-1β teeb liab hloov mus rau hauv txoj kev sphingomyelin thiab nyob rau theem ntawm lub hom phiaj thymocyte proliferation hauv paj hlwb.
Qhov cuam tshuam rau kev ua haujlwm ntawm endocrine ntawm cov tsis yog tib neeg primates:
Hauv cov laus rhesus liab, Epi tuaj yeem txo qis cov piam thaj thiab insulin thiab nce qib melatonin hmo ntuj. Nyob rau tib lub sijhawm, Epi tuaj yeem txo qhov chaw hauv qab plasma qabzib cov lus teb nkhaus, nce qhov ' ploj lawm' tus nqi ntawm cov piam thaj, thiab normalize cov ntshav plasma insulin kinetics teb rau kev tswj hwm cov piam thaj. Qhov no qhia tau hais tias Epi yog qhov muaj txiaj ntsig zoo rau kev kho lub hnub nyoog ntsig txog endocrine tsis ua haujlwm hauv cov tsiaj txhu [7].
Lub peev xwm siv Epi hauv kev kho cov kab mob paj hlwb
Alzheimer's disease: Alzheimer's disease yog ib hom kab mob neurodegenerative, feem ntau tshwm sim los ntawm kev poob ntawm kev txawj ntse thiab kev nco. Cov kev tshawb fawb tam sim no qhia tau hais tias Alzheimer's kab mob cuam tshuam nrog kev cuam tshuam ntawm neurogenic sib txawv. Tus naj npawb ntawm neural qia hlwb nyob rau hauv lub hlwb ntawm Alzheimer's tus neeg mob txo qis, thiab lawv cov peev xwm sib txawv kuj tseem inhibited. Epi tuaj yeem txhawb kev loj hlob thiab kev sib txawv ntawm cov kab mob neural, ua kom cov neurons, thiab txhim kho kev paub txog kev ua haujlwm ntawm cov neeg mob Alzheimer's disease. Tsis tas li ntawd, Epi kuj tseem tuaj yeem tswj hwm kev tso tawm ntawm cov neurotransmitters, txhim kho kev nco thiab kev kawm muaj peev xwm ntawm cov neeg mob Alzheimer's disease [8].
Parkinson's disease: Parkinson's disease yog kab mob neurodegenerative feem ntau tshwm sim los ntawm lub cev muaj zog. Nws lub ntsiab pathological feature yog qhov poob ntawm dopaminergic neurons hauv substantia nigra. Txoj kev kho tam sim no tsuas yog txo cov tsos mob los ntawm kev ntxiv dopamine lossis inhibiting degradation ntawm dopamine, tab sis cov txheej txheem no tsis tuaj yeem nres qhov kev loj hlob ntawm tus kab mob. Kev hloov pauv ntawm neural qia cell yog ib txoj kev kho mob uas muaj peev xwm, tab sis qhov muaj peev xwm thiab kev sib txawv ntawm cov qia hlwb tseem muaj teeb meem. Epi tuaj yeem txhawb nqa kev loj hlob thiab kev sib txawv ntawm cov kab mob neural, nce cov dopaminergic neurons, thiab txhim kho lub cev muaj zog ntawm cov neeg mob Parkinson [8].
Mob stroke thiab hlwb raug mob: Stroke yog ib yam kab mob cerebrovascular, thiab nws lub ntsiab tshwm sim yog kev tuag ntawm neurons thiab neurological dysfunction. Kev raug mob hauv hlwb kuj tuaj yeem ua rau poob ntawm cov neurons thiab ua haujlwm tsis zoo. Neural qia hlwb ua lub luag haujlwm tseem ceeb hauv kev kho thiab rov tsim dua tshiab tom qab mob stroke thiab hlwb raug mob. Epi tuaj yeem txhawb nqa kev loj hlob thiab kev sib txawv ntawm cov kab mob neural qia hlwb, nce cov neurons, thiab txhim kho kev ua haujlwm ntawm lub paj hlwb ntawm cov neeg mob stroke thiab mob hlwb [8].
Nyob rau hauv xaus, raws li ib tug hluavtaws tetrapeptide, lub tseem ceeb los tiv thaiv kev laus mechanism ntawm Epi nyob rau hauv activating cov kev qhia ntawm lub telomerase reverse transcriptase subunit (TERT) noob, ncua qhov ntev ntawm telomeres thiab tswj telomerase kev ua, yog li cuam tshuam rau hauv cov txheej txheem tseem ceeb ntawm cellular aging. Nws qhov tseem ceeb yog nyob rau hauv thawj qhov kev paub txog kev tiv thaiv kev laus los ntawm kev xav ntawm telomere biology, tawg los ntawm kev txwv ntawm cov tshuaj antioxidants uas tsuas yog tsom rau cov dawb radicals, thiab muab lub hom phiaj tshiab rau ncua hnub nyoog cov kab mob xws li Alzheimer's kab mob thiab kab mob plawv. Txawm hais tias nws txoj kev nyab xeeb mus sij hawm ntev (tshwj xeeb tshaj yog kev pheej hmoo ntawm mob qog noj ntshav) tseem yuav tsum tau kuaj xyuas hauv theem III kev sim tshuaj ntsuam xyuas, raws li kev tshawb fawb thiab kev loj hlob paradigm ntawm thawj telomerase activator-hom tshuaj tiv thaiv kev laus, nws yog ib qho kev hloov pauv ntawm kev laus kev cuam tshuam los ntawm cov tsos mob kev txhim kho rau molecular mechanism tswj kev ncua ntawm tib neeg lub neej.
Hais Txog Tus Sau
Cov ntaub ntawv hais saum toj no yog txhua yam tshawb fawb, kho thiab sau los ntawm Cocer Peptides.
Kev Tshawb Fawb Phau Ntawv Sau Ntawv Vladimir Khavinson yog tus kws tshaj lij Lavxias teb sab biogerontologist thiab tus kws tshawb fawb peptide bioregulator. Nws yog tus thawj coj ntawm St. Petersburg lub koom haum ntawm Bioregulation thiab Gerontology thiab ib tug tswv cuab ntawm Lavxias teb sab Academy of Medical Sciences. Khavinson tau ua haujlwm tseem ceeb hauv kev tshawb fawb txog kev laus thiab tau sau ntau cov ntawv tshaj tawm hauv cov ntawv xov xwm muaj npe xws li 'Molecular Biology of Aging' thiab 'Journal of Anti-Aging Medicine'. Nws txoj haujlwm feem ntau tsom rau kev txhim kho thiab siv cov peptide bioregulators los tawm tsam cov kab mob uas muaj hnub nyoog thiab txhim kho kev noj qab haus huv. Khavinson txoj kev tshawb fawb tau muaj kev cuam tshuam hauv kev ua haujlwm ntawm gerontology, muab cov kev nkag siab tshiab thiab cov kev kho mob rau kev laus noj qab haus huv. Vladimir Khavinson tau teev nyob rau hauv qhov kev siv ntawm cov ntaub ntawv [5].
