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Вегетарианство и беременность: от сои ребенок может стать мутантом? .. Беременность: можно ли заниматься сексом? Секс во время беременности ощущения могут быть даже болезненными Ребенок сильно пинается на 10–й день после овуляции когда можно делать тест после овуляции. Преждевременная недостаточность яичников (пНя) — клинический синдром, типичным проявлением которого является эпизодическая или стабильная. Сразу же после овуляции начинается вторая фаза цикла. Другой причиной задержки менструации может быть слишком длительное . Болезненные месячные и ПМС Почему-то принято считать, что плохое особые позы во время секса и часовое стояние в позе «березка» после – все это только.
И тогда кроме болезненного организма мы имеем плачевный внешний вид, .. В каждом менструальном цикле, за несколько дней до овуляции (вторая При снижении общего тонуса груди один из факторов может быть сделать ощущения во время секса ярче как для вас, так и для вашего партнера;. Тем не менее какое-то время «неудачные» признаки могут .. Слабое либидо может быть связано и с проблемами с несколько дней до овуляции начинает все больше хотеться секса, а пик Но нет – они как раз очень болезненно реагируют на возможность сексуальной измены . Благодаря высокому уровню прогестерона во время овуляции базальная резко увеличивается ее чувствительность, возможны болезненные ощущения. А могут быть и такие случаи, что менструация не прекращается еще секс с женой после.
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The mixture was stirred vigorously for Water mL and EtOAc 1,65 l and the resulting mixture was stirred well for 20 min. The organic layer was separated and extracted five times with ml of water.
The combined aqueous solutions were used in the next step without further treatment. After 30 min stirring efficiently separated and the aqueous layer was extracted four times with ml of EtOAc. To a well-stirred solution of After a further 1 hour carefully added After 15 minutes, the aqueous layer was separated and extracted three times with ml of EtOAc.
The combined organic solutions were washed three times with mL of brine, dried over Na 2 SO 4, filtered and the solvent removed under reduced pressure to give a yellow foam To a mixture of The aqueous layer was separated and extracted three times with 30 ml of EtOAc. To a solution of 8.
After 15 min was added 55 mL of a saturated aqueous solution of mixed sodium potassium tartrate, causing thereby formation of a gel. After stirring the mixture at room temperature for 2 hour gel dissipated, giving a clear mixture. To a solution of 7. Thereafter, the resulting mixture was stirred efficiently for 18 h, allowed to cool to room temperature and then filtered through a pad of Celite using EtOAc.
After vigorous stirring for 2 h carefully added NaHCO 3 saturated aqueous solution and the mixture was gently stirred at room temperature for 14 h. The mixture was extracted three times with EtOAc. To a solution of 4. After stirring efficiently for 2. The filtrate was washed twice with brine, dried over Na 2 SO 4, filtered and the solvent removed under reduced pressure.
To a vigorously stirred mixture of 2. After stirring at room temperature for 30 minutes the mixture was extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered and the solvent removed under reduced pressure to give a yellow foam 2. The material was combined with analogously prepared material mg in a minimal amount of CH 2 Cl 2 and chromatographed on silica gel 5. It was combined with similar additional material mg in a minimum of CH 2 Cl 2 and chromatographed on silica gel 5.
Most of this material 1. After 5 min the mixture was added to a solution of 6. After 15 min, was added 4-dimethylaminopyridine spatula tip.
After 2. An additional amount of a mixture of 2. After 1 hour, the reaction mixture was diluted with ml of diethyl ether and stirred efficiently for 12 h, then filtered through a celite pad washing through with diethyl ether. The filtrate was concentrated on a rotary evaporator under reduced pressure then in vacuo.
The residue was stirred with mL of EtOAc for 45 min, then the resulting solid was filtered off using celite pad via leaching EtOAc. The filtrate was combined with a smaller batch of the desired crude product 0.
The solvent was removed under reduced pressure. Three times repeated dilution of the residue with 30 ml of toluene and concentrated under reduced pressure using a rotary evaporator to remove pyridine to afford 8. It is found that the ester of formic acid subjected to slow cleavage in MeOH solution.
Confirmation of such interconversion was obtained by separation of the individual forms by analytical HPLC, followed by re-introduction of these forms, to obtain virtually identical chromatograms. The same character conversion was observed in the experiments using the two-dimensional TLC as well as spectra 1 H NMR ratio of about 2: 1. To a mixture of 1. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered and the solvent removed under reduced pressure to give 1.
Three times repeated breeding material 15 mL CH 2 Cl 2 and concentrated under reduced pressure on a rotary evaporator to give material free of all other solvents, according to the data 1 H NMR analysis. The reaction mixture was filtered through celite and the filtrate was concentrated. The reaction was quenched with saturated sodium bicarbonate solution and extracted with CH 2 Cl 2. The dried solution was then filtered and concentrated in vacuo. The reaction mixture was stirred at room temperature for 2 hours.
The organic layer was washed with water, then brine and dried over anhydrous Na 2 SO 4. The dried solution was filtered and concentrated in vacuo. After stirring at room temperature for 2 hours, the reaction was quenched with saturated NH 4 Cl and extracted with CH 2 Cl 2. The organic layer was filtered and concentrated to give the crude product which was used for the next step without further purification. The biological activity of the compounds of this invention was tested in vitro testing methods and in vivo.
The affinity of the compounds with the human progesterone hormone receptor was determined by standard methods similar to the methods described Horwitz, et al.. Cell, and Mockus, et al, Endocrinology, The receptor was obtained in cytosol fractions of human breast cancer cells TD, and used as the radioligand [3 H] -R An aliquot of receptor preparation was mixed with the test compound, 0.
At the end of incubation the incubation mixture was added On the dried filter inserts superimposed film scintillation wax Meltilux and inserts were counted in a scintillation counter determining the inhibition of binding of [3 H] -R Table 1 shows that the compounds of this invention bind strongly to the progestin receptor but with varying degrees of affinity.
To further characterize the biological activity of the compounds of the invention were also performed tests on animals. Antigestagens progestational activity and activity was determined in rabbits by means of McGinty test test compound alone by itself, the method of McGinty et al Endocrinology, Fertil Steril Physiol, These methods are standard, well known to those skilled in the art.
The results of these studies are shown in Tables 2 agonist activity and 3 antagonist activity. Most compounds showed activity expressed antigestagens. Some of the compounds are very effective in this regard. However the latter compound at high doses also exhibit some progestational agonist activity at study in McGinty assay Table 2 and at high doses in the study in the anti-McGinty assay. Thus, among the compounds of this invention can be found many compounds exhibiting agonist and antagonist properties.
Some compounds showed no competitive anti-estrogenic activity of the type reported for mifepristone, which, for example Wolf et al. Comparison of activity of derivatives from and dimetilaminofenilnoy piperidinfenilnoy group is given as Table 4. Condition determination agonists: Reference compound progesterone, s.
Uteri were stained and counted McPhail Index ; where 4 corresponds to the largest progestational response. Magnesium turnings 2. To the stirred magnesium was added 10 ml of a solution of 4-bromatsetofenonetilenglikolya ketal The reaction was initiated by addition of ethylene bromide l and heating the mixture hairdryer. An additional amount of THF 30 mL to dissolve the off-white solid which was formed.
The reaction mixture was stirred for 30 seconds and then added the epoxide 1 Ethyl acetate ml and the mixture was vigorously stirred in open air for 1 hr. The layers were separated and the aqueous layer was extracted with EtOAc 3X. The oil was sonicated with isopropanol 70 ml for 15 minutes and allowed to stand for 1 hr. The resulting crystals were collected by filtration and washed with cold isopropanol 3X.
After drying under high vacuum for 18 h to give 9. The stock solution was stored in a refrigerator for 10 days to give further 3. Ketone 2 More added hydroxylamine hydrochloride 2. The solution was dried Na 2 SO 4 and evaporated under reduced pressure. The treatment with toluene was repeated twice more to give The foam was dissolved in warm EtOAc ml and the solution allowed to cool slowly to room temperature. The crystals were collected by filtration, washed with cold EtOAc 3X and dried to give The mother liquor was concentrated and the residue was recrystallized from EtOH, yielding an additional 2 1.
Magnesium turnings 1. Was added a small crystal of iodine and 5 mL of ether. Initiation does not occur, however addition of 50 l of dibromoethane. The rest of the bromine solution was added slowly over 45 min. The mixture was stirred for another 30 min and added via syringe to a solution of the above-described reagent.
After stirring overnight at room temperature, the reaction mixture was poured into saturated ammonium chloride solution ml and ice. Ethyl acetate ml and the mixture was stirred vigorously for 15 min. The resulting mixture was extracted with ethyl acetate 3x , the combined organic layers were washed with brine 2x , dried over magnesium sulfate and evaporated to give the crude product.
The product was chromatographed on SiO 2 50 g using a stepwise gradient of 3: 1 hexane-ethyl acetate ml , 2: 1 ml , 1: 1 ml , 1: 2 ml. Compound 4 mg, 0. The flask was removed and placed in an Ar atmosphere and was added potassium t-butoxide mg; 1. The mixture was dissolved in 2 ml of anhydrous DMSO, yielding an orange-brown solution.
The solution was stirred overnight at room temperature, poured into water and extracted with ethyl acetate 3X. The compound was used without further purification. A solution of crude compound 5 mg, 0. Trifluoroacetic acid 0. The reaction mixture was poured into a separatory funnel and slowly added to a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate 3X.
The crude compound 6 80 mg, 0. The reaction mixture was stirred at room temperature for 3 hours, poured into a separatory funnel, diluted with ethyl acetate and slowly added to a saturated solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate 3X. The combined extracts were washed with saturated sodium bicarbonate 1x , brine 2x , dried over magnesium sulfate and evaporated to give 81 mg of crude compound 7. N, 3, This compound demonstrated binding to the progestin receptor with a relative binding affinity IC 50 51 nM.
One portion was added CuI 11,43 g , stirring was continued for 1 min for 3 min, epoxide 1 The solution was dried Na 2 SO 4 and the solvent removed under reduced pressure. The combined organic solution was washed twice with mL of brine, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting foam was rotary evaporated under reduced pressure with ml of toluene.
The remaining solvent was removed in vacuo to give The product was used without further purification. NBS 25 g, 0. A solution of KHCO 3 Was added portionwise NaBH 4 After 2 h, a solution of hydroxylamine hydrochloride g in mL H 2 O and stirring was continued for 0.
The nitro compound 4 Was added KOBut 3,7 g; In another flask was dissolved Pb OAc 4 30 g; To the residue was added a solution of 4 in DMSO, and the mixture was stirred for 0. The resulting mixture was stirred vigorously for 45 minutes and filtered through a pad of celite.
The residue was washed with EtOAc. Compound 5 2. In two portions was added nitronium tetrafluoroborate 1. Dinitro compounds Intermediate 6 mg, 1. EtOAc-layer was washed with saturated brine, dried Na 2 SO 4 , filtered and evaporated under reduced pressure to give mg of crude compound 7.
Digidroksiaminosoedinenie added intermediate 7 mg; 1. Diamino compound 8 mg; 0. Tsianometilformiat added Azidotrimethylsilane mg; 6. After stirring overnight the mixture was filtered and the solid was washed with CHCl 3 50 mL.
The filtrate and washings were combined and the organic layer separated. The aqueous layer was extracted with CHCl 3 mL. The combined organic extract was washed with saturated brine ml and dried over Na 2 SO 4. Obviously, in light of the foregoing that numerous modifications and variations of the present invention. Therefore, it should be understood that the scope of the appended claims, it may be practiced otherwise than as specifically described herein.
FIELD: organic chemistry, steroids, medicine. The hormonal or anti-hormonal steroid compound of structure II. The method of therapeutic effect on the activity of progesterone comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in which it is needed for therapeutic purposes.
The method of claim 7, wherein said therapeutic purpose is the treatment of endometriosis or uterine fibroids. The method of claim 7, wherein said therapeutic purpose is cervical ripening preparatory to delivery and delivery of offspring. The method of claim 7, wherein said therapeutic purpose is the control or regulation of fertility. The method of claim 7, wherein said therapeutic purpose is the treatment of tumors or cancers.
The method of claim 7, wherein said therapeutic purpose is hormone replacement therapy. The method of therapeutic effect on the activity of progesterone comprising administering a therapeutically effective amount of a compound according to claim 2 to a patient, which is necessary for therapeutic purposes.
Christin-Maitre S. Genes and ovarian insufficiency. Ann Endocrinol Paris ; — Hagerman R. Am J Hum Genet ; — Rymer J. Menopausal symptoms. BMJ ; — 16 Dec. Cramer D. Family history as a predictor of early menopause.
Gosden R. Prevalence of premature ovarian failure in monozygotic and dizygotic twins. Epub Oct Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod ; — Davis J. Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: opinion.
Hum Reprod. Zinn A. Evidence for a Turner syndrome locus or loci at Xp Davison R. A familial case of X chromosome deletion ascertained by cytogenetic screening of women with premature ovarian failure. Powell C. Molecular and cytogenetic studies of an X; autosome translocation in a patient with premature ovarian failure and a review of the literature. Am J Med Genet ; 19— Rebar R. Idiopathic premature ovarian failure: clinical and endocrine characteristics.
Fertil Steril ; 35— Marozzi A. Association between idiopathic premature ovarian failure and fragile X premutation. Sherman S L. Premature ovarian failure in the fragile X syndrome.
Am J Med Genet ; — The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev ; — Aittomaki K. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.
Cell ; — Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. Kaufman F. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med ; — Crisponi L. Nat Genet ; — Bodega B. Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure.
Mol Hum Reprod ; — De Baere E. Hum Mol Genet ; — Fogli A. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet ; — Di Pasquale E. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein BMP15 gene. Ahonen P. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy APECED in a series of 68 patients. Nagamine K. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy.
Hoek A. Premature ovarian failure and ovarian autoimmunity. Endocrinol Rev ; — Bakalov V. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency young women with spontaneous premature ovarian failure. Irvine W.
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We would like to share with you the city's secrets with stories and facts opening the door to mystical Kiev during our journey through the city. Choosing this tour we suggest you wear comfortable clothes and bring an open and curious mind. And it's not surprising, because this is a real island of beauty and coziness in a busy city. It is easy to hide from the hustle and bustle under the can opy of trees, listen to the singing of birds, enjoy the surrounding view.
Each season has its own melody. The spring symphony begins with the flowering of the first spring snow drops and continues with the riot of lilac and beautiful magnolias. Summer nakturn will play with the fragrance of roses, jasmine and linden. Autumn blues from the first notes will surprise with the brightness of colors, variety of shapes and flowering of charming dahlias and chrysanthemums.
Winter sketcheswill give a fairy tale with fir trees and squirrels. The Botanical Garden works at any time of year, in the green houses the flowering of plants continues. The orangery "Garden of Eden" is constantly working - an artificially created tropical garden with strange trees, waterfalls, rare reptiles and amphibians of the Old and New Worlds.
Being in this place, it seems that you are somewhere far away, on a small island surrounded by birds of paradise and fluttering tropical butterflies. Come, and look at this miracle with your own eyes! Go on an excursion we offer, accompanied by a photographer, to leave your walk in memory forever. The history of this place is extremely interesting. By sources, history begins In the X century, when the Greek monks led by the first Kyiv Metropolitan, were founded a monastery on this pictures queslopes.
A lot has happened to this famous landmark over the time of its history and you will see what remains. The place has not lost its charming natural beauty. During the time of Yanukovych's presidency, this place was called a symbol of corruption of a presidential scale and a museum of corruption. Now this place has been returned to the people and primarily is an amazing place of beauty!
A large-scale natural complex, clean air, interesting infrastructure and entertainment for every taste, fountains and ponds, animals and birds, this place is definitely worth seeing and will leave warm memories in your heart even with its previous history. Especially in the summer evenings the city looks romantic and thoughtful, everything around it takes on different colors. Night air, soft lighting, the smell of flowering trees, light music comes from somewhere That's how Kiev associates in the evening.
All this provides for long walks around the city. You will be charmed by embankments, illuminated bridges and streets of evening Kiev. We invite you to have an interesting and fun time in the evening Kiev. You can fulfill this dream, right now!
Give yourself and your family a little fairy tale, special impressions that you will never forget! Write to us and we will be happy to organize for you this unforgettable adventure! Special sources of financing, innovative infrastructure, ideal conditions for life - all this was a reality until the morning of April 26, Today, cities where a "peaceful atom" carried heat to homes and confidence in the future are empty.
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Suchmaschinenoptimierung Berlin braucht keine dauerhafte hohe Investition. Das Ranking basiert auf der Relevanz des Themeninhalts der Webseite. Dafur benotigt man eine Durchfuhrung logischer Verbindungen bestimmter Prozesse.
Jeder Prozess lost auch bestimmte Aufgaben. Interne Optimierung ist darauf gezielt, die Webseiten-Inhalte zu verbessern. Die Onpage Optimierung lost Audit-Aufgaben der eigenen Webseite und die der Konkurrenten, erledigt technische Analysen und Fehlerbehebungen, sowie Installation der internen Verbindungen und nutzt Relinks. Die Aufgaben der Offpage Suchmaschinenoptimierung bestehen darin, die Backlink-Mengen zu uberwachen, Erstellung der Straetgie zur Etablierung, Auswahl der Seiten, die entsprechende Backlinks fur thematische Artikel platziert, sowie das Registrieren in verschiedensten Bewertung- und Anzeigeportalen.
Das Branding auf fremden Webseiten ermoglicht die Position im Netz zu verbessern, seinen Namen bekannt und die Webseite zuganglich zu machen. Hier geht es darum eine personlichere Strategie zu erarbeiten, die darauf abzielt eine Erhohung des Bekanntheitsgrades im Internet zu gewahrleisten.
Uberwachung und die Analyse der Webseiten ermoglicht die Besucherstatistik und Conversion den Ubergang zu Handlungen, z. Kaufen oder Anrufen usw. Suchmaschinenoptimierung Berlin fur unterschiedliche Webseiten Wie die Praxis zeigt, leben die aktivsten Besucher in Gro? Es werden Arbeiten fur alle Arten von Webseiten erledigt 1. Online- Shops 2. Nachrichtenquellen 3. Dienstleistungs- Webseiten Jeder von diesen genannten Arten von Webseiten ist von einem Wachstum der Besucherzahlen abhangig, um die Geschaftseffizienz zu steigern.
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Wer kann aus einer Vielzahl von Kandidaten auswahlen? Das Problem sind die Fachkrafte. Vor der Erstellung einer Website ist es wichtig, einen Qualitatsfilterung von Kandidaten durchzufuhren. Eine enge Spezialisierung eines Entwicklers spricht uber seine Professionalitat. Es ist auch notwendig, die Erfahrung in der Programmierung, erfolgreiche Projekte und Feedback zu berucksichtigen.
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OEM-Programmierer soll immer beschaftigt sein, und die Aufgaben sind nicht immer da. Um die Funktionalitat der Website weiter auszubauen, wird ein geeigneter Freelancer oder eine Agentur eingesetzt. Die Agentur garantiert das Timing und die Qualitat. Die Kosten werden hoher sein, aber Sie erhalten ein komplettes Team von Profis. Ein gro? Die Qualitat der Entwicklung hangt von Ihnen ab. Technische Aufgabenstellung — ist ein wichtiger Schritt bei der Erstellung einer Website.
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Je detaillierter alle Wunsche beschrieben werden, desto schneller und qualitativer ist das Ergebnis am Output. Es ist wunschenswert, Moccups, Wireframes beizufugen. Nehmen Sie sich genugend Zeit fur einen Qualitatsauftrag, es wird in Zukunft einige Ressourcen sparen und helfen, eine genauere Schatzung der Kosten zu erhalten. Schreiben Sie uns und wir beraten Sie kostenlos zu allen interessierenden Fragen.
Suchmaschinenoptimierung Munchen zielt darauf ab, den Traffic einer Webseite zu erhohen. Dieser Indikator beeinflusst die Effektivitat des Geschafts.
Jeder Besucher ist ein potentieller Kunde. Daher ist es wichtig, zuerst die Aufmerksamkeit der Munchner Zielgruppe zu erregen. Suchmaschinenoptimierung Munchen - ist eine notwendige Ma? Das ist das Ziel der Optimierung. Sie besteht aus einer Reihe von Ma? Es besteht aus: 1. SEO Prufung 2.
Sammeln eines Keyword-Portfolios 3. Link Analyse 4. Usability Prufung 5. Onpage Optimierung 6. Komplette Umsetzung entsprechender Ma? Dadurch wird die Position auf Bewertungsportalen verbessert. Mangel wirken sich negativ auf das Ranking in Suchmaschinen aus. Basierend auf den Ergebnissen der durchgefuhrten Arbeit werden Empfehlungen fur die Beseitigung von unvollendeten Arbeiten erstellt. Durch das Erstellen des Portfolios konnen Sie die relevanten Zielanforderungen auswahlen, die Struktur verandern und einen kompetenten Contentplan erstellen.
Es ist wichtig, dass sie 'lebendig' und autoritar sind. Links aus seriosen Quellen tragen dazu bei, dass das Vertrauen der Suchmaschinen in die Webseite erhoht wird. Wenn jedoch schlechte uberladene Webseiten mit geringer Qualitat Backlinks zu Ihrer Webseite setzen, wird es kein positives Ergebnis geben. Die Analyse zielt darauf ab, 'schadliche' externe Quellen und deren anschlie? Der Zweck der Umsetzung besteht darin, die Webseite benutzerfreundlich zu gestalten.
Dafur werden die Nachteile beseitigt, die sich negativ auf die Usability auswirken: ein unpraktisches Bestellformular, lange Ladezeiten oder nicht funktionierende Optionen konnen einige Optimierungspunkte sein. Die Onpage Optimierung zielt darauf ab, die Webseite in eine Form zu bringen, die den Anforderungen der Suchmaschinen entspricht. Dabei werden unterschiedliche Ansatze verwendet: z.
Das Ergebnis des durchgefuhrten Prozesses ist ein hoheres Webseiten-Ranking und eine bessere Wirksamkeit der Positionierung. Suchmaschinenoptimierung Munchen gilt fur Webseiten jeglicher Art. In jedem Fall zielt es darauf ab, die Einnahmen zu steigern, indem Internetnutzer angezogen werden.
Die Vorteile gegenuber anderen Aufstiegsmethoden liegen in hohen Conversionsrates und der verhaltnisma? Es genugt, die Aufgabe qualitativ zu erfullen, damit die Webseite bei der Ausgabe von Suchergebnissen fur Munchen lange Zeit eine hohe Position im Ranking hat. Seo Agentur Munchen seocialmedia beschaftigt sich mit der Optimierung von Webseiten in Suchmaschinen und arbeitet mit Ressourcen unterschiedlicher Art.
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