Background: Opioid dependence is a chronic disease. Substitution treatment for opioid addiction involves a lot of rules and control that can lead to stigmatization. Purpose: To describe the experience of control and stigma in people with substitution treatment during opioid dependence. Method: A literature review with qualitative content analysis inspired by Graneheim & Lundman (2004). The study is based on 14 scientific articles that were applied mainly through the databases Cinahl and Pubmed. Result: Two main themes with eight sub-themes emerged. The most prominent in the result was that people with substitution treatment feel stamped as a drug addict. They can also feel suspicious and less credible. Having substitution treatment is associated with shame. One does not always dare to tell the surroundings that one has treatment. Within the framework of treatment, they feel controlled and supervised. Conclusion: People with substitution treatment experience stigma in terms of discrimination, preconceived opinions and reduced credibility. Stigma arises in several different contexts, such as work, friends and family, but also in health care and even in substitution treatment. This is because this form of treatment includes a number of rules and controls that make you feel controlled and supervised. This risks contributing to further stigmatization.

Background: To assess the long-term course of the feasibility and safety of orally administered heroin [diacetylmorphine (DAM)] tablets in substitution treatment of severely addicted opioid users. Design: Open-label, prospective cohort study with 2 non-randomly assigned treatment arms: DAM tablets only (n = 128) or DAM tablets combined with injected DAM and/or other opioids (n = 237). The average duration of the observation period was 62 months. Study endpoints were the time to discharge from treatment and the number of serious adverse events. Results: Both patient groups had a higher than 70% retention rate after the first 48 months of treatment, with similar long-term retention rates (after 8 years both groups had retention over 50%). The physician-verified rate of serious adverse events was 0.01 events per application year among the exclusively oral substitution group (intention-to-treat analysis) during the last year of observation, and 0.005 events per application year in the other group. Conclusions: Because of their feasibility and safety over years, DAM tablets may be a valuable long-term therapeutic alternative. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Abstract The study mapped various aspects of buprenorfine (Subutex \regm{}, herein S) abuse among opiate-dependent community. It analyses three sources of data, questionnaires distributed in general problem drug-users community ({\clq}non-substitution sample{\crq}, n = 64), questionnaires distributed among patients of buprenorphine substitution treatment ({\clq}substitution sample{\crq}, n = 42), and semi-structured moderated interviews conducted with S users attending low-threshold contact centre in Ceske Budejovice (n = 15). Prevalence of non-commissioned S abuse was 57% of the non-substitution sample and 21% of the sample claimed S as their primary drug. Illicit market prices range from prescription price to its multiple of eight, are higher in small towns and during weekends, and lower in case of close relationships between the seller and buyer. There are no regular big dealers in the community, and the contracts are rather based on close acquaintance among baseline users. The user view S price and availability as worse/higher than in case of marihuana, comparable with hallucinogens and ecstasy, and better/cheaper than metamphetamine and heroin. The main driver for buying was occasional abuse over the prescription dose, the main incentive to sell was to help a friend. Illicit S users view substitution treatment as a chance how to reduce their drugrelated expenses and stabilise their life, but some are repelled by strict treatment rules. Both licit and illicit users displayed comparably high (over 90%) prevalence of injection use; they typically understand the risks, but explain the injection use by their psychological attachment to the injection ritual. An indisputably positive aspect of substitution treatment is lower total number of drugs abused by individual patients, compared to general drug-abusing population. Illicit S market bears only marginal societal risks and its existence is rather positive with respect to harm reduction philosophy, as it supplies the community of illicit drug users with cheaper and safer alternative to street opiates.

Durant les années 1990, en France, en Suisse et au Québec, de nouveaux médicaments ont reçu une autorisation de mise sur le marché, dans le cadre de la prise en charge de la dépendance aux opiacés. Vingt cinq ans plus tard, notre thèse interroge les usages qu’en font les personnes en traitement. A partir de la méthode biographique, nous étudions la substitution en terme d’« ajustements ». Les détournements de l’usage prescrit des TSO, étiquetés comme « mésusages » par les pouvoirs publics et un certain nombre de praticiens, apparaissent dès lors comme une modalité d’adaptation et de réappropriation du traitement. En évaluant les convergences et les divergences dans les pratiques et leurs effets, la comparaison de nos trois terrains d’enquête nous permet d’analyser les différents sens associés à la substitution, selon les contextes et les structures de soin au sein desquels l’usager est accueilli. / For a long time, ending drug addiction meant completely stopping any consumption. In the context of harm reduction policies, the introduction of substitution treatments has drastically changed the abstinence paradigm. Ending an addiction has taken a plural meaning, adding complexity to the delimitation already porous between “normal and pathological”. Nowadays stabilizing Methadone maintenance treatment or taking drugs on an irregular basis are perceived as an alternative to abstinence or other forms of recovery. In this thesis, wiitch deals with polysemic uses of substitution treatment, we analyze the attempts and strategies of the adjustment process in entering an addiction centre. The aim of this study is to show the different competencies that people can display in situations of vulnerability. Our interest is to find out how valuable expertise can emerge from the layperson point of view.

Studien syftar till att undersöka hur det går till att sluta använda heroin utan att byta till användning av andra opioidpreparat och utan att erhålla substitutionsbehandling med opioidpreparaten metadon eller buprenorfin. Forskningsgenomgången visar att det är möjligt att sluta med heroin utan substitutionsbehandling, men att det är svårt att leda i bevis att vissa specifika behandlingsmetoder skapar detta resultat. Det empiriska materialet består av djupintervjuer med tio personer som delar erfarenheten av att ha varit heroinberoende och av att ha slutat använda heroin utan att erhålla substitutionsbehandling. Som teoretisk utgångspunkt används en syntes av flera sociologiska och socialpsykologiska teorier och analysbegrepp som syftar till att förklara relationen mellan mänskliga betenden och de sociala sammanhang som människan ingår i och relaterar till. Studien visar att en framgångsrik återhämtning från heroinberoende innebär en sekundär socialisering in i sociala gemenskaper organiserade kring andra företeelser än heroinanvändning, vilket möjliggör för den före detta heroinanvändaren att avhålla sig från heroin- och annan opioidanvändning. Studien visar även att en viktig komponent i återhämtningen är att, framförallt under den första tiden i återhämtningsprocessen, utveckla ett överväldigande engagemang i någon typ av sysselsättning, samt att personer som under tiden de använde heroin saknade ett överbryggande socialt kapital, har möjlighet att skapa ett sådant efter att de slutat använda heroin. / The study aims to investigate how to stop using heroin without replacing heroin with use of other opioid preparations and without receiving substitution treatment with the opioid preparations methadone or buprenorphine. The research review shows that it is possible to quit heroin addiction without substitution treatment, but it is difficult to prove that certain specific treatment methods create this result. The empirical material consists of in-depth interviews with ten people who share the experience of being addicted to heroin and having stopped using heroin without receiving substitution therapy. As a theoretical point of view, a synthesis of several sociological and social psychological theories and concepts of analysis is used to explain the relationship between human behavior and the social context in which human beings belong and relate. The study shows that a successful recovery from heroin addiction involves secondary socialization into social communities organized around phenomenas other than heroin use, which enables the former heroin user to refrain from heroin and other opioid use. The study also shows that an important component of the recovery process is, especially during the first phase of the recovery process, developing an overwhelming involvement to some type of pursuit, and that people who when they used heroin lacked any sort of bridging social capital, are able to create such after they stopped using heroin.

<p>Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najče&scaron;će koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najče&scaron;će prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodi&scaron;njeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiolo&scaron;ka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistolo&scaron;ki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim o&scaron;tećenjem. &Scaron;to se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (&lt;1 &mu;g/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih &scaron;irom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23&plusmn;17,11 mg, 47,11&plusmn;16,79 mg, 50,00&plusmn;17,55 mg i 78,63&plusmn;18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92&plusmn;10,47 mg, 33,89&plusmn;9,23 mg, 28,33&plusmn;11,55 mg i 28,12&plusmn;11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44&plusmn;111,51 ng/ml, 157,43&plusmn;112,39 ng/ml, 176,77&plusmn;118,56 ng/ml i 342,86&plusmn;181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00&plusmn;537,89 ng/ml, 923,76&plusmn;739,96 ng/ml, 560,74&plusmn;436,72 ng/ml i 1045,32&plusmn;932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87&plusmn;27,22 ms, tj. 414,64&plusmn;29,38 ms 8. dana STM, 416,97&plusmn;26,39 15. dana, i 425,20&plusmn;17,71 ms nakon 1. meseca tj. 423,50&plusmn;14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori &ndash; koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi mu&scaron;kog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi mu&scaron;kog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog o&scaron;tećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije do&scaron;lo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razja&scaron;njenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.</p> / <p>Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias &ndash; torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals&rsquo; control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (&lt;1 &mu;g/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23&plusmn;17.11 mg, 47.11&plusmn;16.79 mg, 50.00&plusmn;17.55 mg and 78.63&plusmn;18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92&plusmn;10.47 mg, 33.89&plusmn;9.23 mg, 28.33&plusmn;11.55 mg and 28.12&plusmn;11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44&plusmn;111.51 ng/ml, 157.43&plusmn;112.39 ng/ml, 176.77&plusmn;118.56 ng/ml and 342.86&plusmn;181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00&plusmn;537.89 ng/ml, 923.76&plusmn;739.96 ng/ml, 560.74&plusmn;436.72 ng/ml and 1045.32&plusmn;932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87&plusmn;27.22 ms, 414.64&plusmn;29.38 ms on the 8th day of MMT, 416.97&plusmn;26.39 on the 15th day of MMT, after 1 month of MMT 425.20&plusmn;17.71 ms and after 6 months of MMT 423.50&plusmn;14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.</p>

The thesis is devoted to the issue of addiction services with a focus on substitution treatment. Theoretical part focuses on presenting of susbstitution treatment, its history and description of the substitution substances and their effects on the human body. Describes the abuse of substitution treatment by problem drug users and tries to map out the various addiction treatment services with a focus on substitution treatment in Prague. The research section defines the attitude of society towards the establishment and functioning of Prague substitution centers. The thesis concludes with an overview of addiction services and substitution programs in the capital city of Prague. Powered by TCPDF (www.tcpdf.org)

<p>Uvod: Temperament predstavlja skup psiholo&scaron;kih osobina, to jest način, brzinu i jačinu umnog i emotivnog reagovanja svojstven pojedincu, odnosno njegovu narav, ćud, prirodu. Savremena istraživanja premorbidnog afektivnog tipa temperamenta, govore u prilog njegovog značaja u etiologiji i kliničkoj evaluaciji bolesti zavisnosti. Cilj: Utvrditi i uporediti temperament kod osoba obolelih od mentalnog poremećaja i poremećaja pona&scaron;anja zbog upotrebe opijata i zdrave populacije. Materijal i metode: Istraživanje je urađeno po tipu studije preseka, i obuhvatalo je 200 ispitanika, podeljenih u dve grupe. Ispitivanu grupu činilo je 100 stabilnih zavisnika od opijata na supstitucionoj terapiji metadonom, starosti od 18 do 40 godina, bez komorbidne bolesti iz kruga psihotičnih poremećaja. U kontrolnu grupu uvr&scaron;teno je 100 zdravih osoba &scaron;to sličnijih sociodemografskih karakteristika sa ispitivanom grupom. Njihov temperament je određivan TEMPS-A upitnikom samoprocene. Rezultati: Utvrđeno je statistički značajno če&scaron;će postojanje dominantog temperamenta kod zavisnika, kao i prisustvo depresivnog, ciklotimnog, razdražljivog i anksioznog temperamenta, koji govore u prilog osnovne razlike između zdrave populacije i populacije sa mentalnim poremećajem i poremećajem pona&scaron;anja zbog upotrebe opijata. Zaključak: Afektivni temperament, kao premorbidna karakteristika ličnosti, ima uticaja na nastanak i razvoj zavisnosti od opijata. Stoga je od značaja da se uzmu u obzir osobine hipertimnog temperamenta kao protektivnog ili depresivnog, ciklotimnog, radražljivog i anksioznog temperamenta kao rizičnih faktora u etiologiji, prevenciji i terapiji bolesti zavisnosti.</p> / <p>Introduction: Temperament is a set of psychological characteristics, ie the speed and strength of mind and emotional reactions peculiar to the individual, or his character, temperament, nature. Modern research of the premorbid affective temperament is in favor of its significance in the etiology and clinical evaluation of substance abuse. The Aim: To determine and compare the temperament of people suffering from mental and behavioral disorders due to use of opioids and healthy population. Materials and Methods: The study was cross-sectional, and 200 subjects were included and divided into two groups. The study group included stable opiate addicts on substitution therapy with methadone, aged 18 to 40 years, without co-morbid psychotic disorders. The Control group consisted of 100 healthy individuals with similar sociodemographic data as the Study group. Their temperament was determined with the TEMPS-A auto-questionnaire. Results: Statistical significance of a dominant temperament was more frequently found in the subjects with opioid dependence, as well as in depressive, cyclothymic, anxious and irritable temperament, which leads to the fundamental differences between a healthy population and a population with mental and behavioral disorders due to the use of opioids. Conclusion: Affective temperament, as a premorbid personality trait, has an impact on the occurence and development of opiate dependence. Therefore, it is essential to take into account the characteristics of a hyperthymic temperament as a protective factor or depressive, cyclothymic, irritable and anxious temperament as risk factors in etiology, prevention and treatment of addiction.</p>

Background: To assess the long-term course of the feasibility and safety of orally administered heroin [diacetylmorphine (DAM)] tablets in substitution treatment of severely addicted opioid users. Design: Open-label, prospective cohort study with 2 non-randomly assigned treatment arms: DAM tablets only (n = 128) or DAM tablets combined with injected DAM and/or other opioids (n = 237). The average duration of the observation period was 62 months. Study endpoints were the time to discharge from treatment and the number of serious adverse events. Results: Both patient groups had a higher than 70% retention rate after the first 48 months of treatment, with similar long-term retention rates (after 8 years both groups had retention over 50%). The physician-verified rate of serious adverse events was 0.01 events per application year among the exclusively oral substitution group (intention-to-treat analysis) during the last year of observation, and 0.005 events per application year in the other group. Conclusions: Because of their feasibility and safety over years, DAM tablets may be a valuable long-term therapeutic alternative. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Bakgrund: LARO i Sverige är omgärdat av strikta regler. Läkemedlen som används, däribland buprenorfin, intas dagligen övervakat av sjuksköterska de tre första månaderna och vidare till dess att patienten bedöms kunna ta läkemedlet på egen hand. Sedan 2018 finns buprenorfin som depotinjektion veckovis eller månadsvis, vilket innebär en ny omvårdnadssituation. Syfte: Att utforska sjuksköterskans perspektiv på införandet av buprenorfin som depotinjektion i LARO. Metod: Tolv semistrukturerade intervjuer av sjuksköterskor med erfarenhet av depotinjektioner buprenorfin i LARO. Resultat: Införandet av depotinjektioner innebar ett fokusskifte i behandling och omvårdnad med bland annat minskad kontroll och ökad tillit mellan sjuksköterska och patient. Behandlingen med depotinjektioner ansågs kunna öppna för ökad egenmakt för patienterna. LARO-enheternas organisatoriska förutsättningar påverkade hur de tagit sig an den nya behandlingsformen. Kunskap och samsyn efterfrågades. Slutsats: Depotinjektioner buprenorfin kan öppna upp för nya sätt att främja egenmakt i LARO. Det finns ett behov av forskning på området. / Background: Opioid substitution treatment in Sweden is strictly regulated. Medications like Buprenorphine are taken daily supervised by a nurse during the initial three months and thereafter until the patient is assessed to be trusted with self-administration. Prolonged-release injectable Buprenorphine has beenavailable since 2018 for weekly or monthly use. This has implications for nursing care and practices. Purpose: To explore the nurse’s perspective on introducing prolonged-release injectable buprenorphine in opioid substitution treatment. Method: Twelve semi-structured interviews were conducted with nurses experienced in treatment with prolonged-release injectable buprenorphine. Results: The introduction of injection treatment entailed a shift in focus regarding restrains, trust and patient empowerment. The care units’ approaches to the new treatment differed and was influenced by organisational conditions. Nurses requested more knowledge and consensus about the new treatment. Conclusion:Prolonged-release injectable formulations may enable new approaches to patientempowerment in opioid substitution treatment. Research in this field is required.