natgillin/translations-raw huggingface dataset:
The vector comprises a protein shell derived from adeno-associated virus serotype 1 (AAV1), the Cytomegalovirus (CMV) promoter, a woodchuck hepatitis virus posttranscriptional regulatory element and AAV2 derived inverted terminal repeats.
Vektor je sestavljen iz proteinske kapsule, pridobljene iz adenoasociiranega virusnega serotipa 1 (AAV1), promotorja citomegalovirusa (CMV), elementa za posttranskripcijsko regulacijo virusa hepatitisa svizca in invertiranih terminalnih zaporedij, pridobljenih iz serotipa AAV2.
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the medicinal product is on the market.
Imetnik dovoljenja za promet z zdravilom mora zagotoviti, da je sistem farmakovigilance, predložen v modulu 1.8.1 dovoljenja za promet z zdravilom, vzpostavljen in deluje, preden da zdravilo v promet in ves čas trženja zdravila.
Assessment of immune response at baseline, 6 months and 12 months in at least 12 newly treated patients.
Ocena imunskega odziva ob izhodišču, po 6 mesecih in po 12 mesecih pri vsaj 12 na novo zdravljenih bolnikih.
• Information on the treatment procedure with Glybera
• Informacije o postopku zdravljenja z zdravilom Glybera
If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using any medicine.
Nosečnost in dojenje Če ste noseči ali dojite, menite, da bi lahko bili noseči ali načrtujete zanositev, se posvetujte z zdravnikom ali farmacevtom, preden vzamete to zdravilo.
What Glybera is and what it is used for
Kaj je zdravilo Glybera in za kaj ga uporabljamo
Glybera will only be given to you if you show detectable levels of LPL protein in your blood.
Zdravilo Glybera smete prejeti samo, če pri vas ugotovijo določljive ravni proteina LPL v krvi.
Spinal anaesthesia and multiple intramuscular injections may further increase the risk of (thrombo) embolic events at and shortly after administration of Glybera.
Spinalna anestezija in večkratno intramuskularno injiciranje lahko dodatno povečata tveganje za (tromb) embolične dogodke med dajanjem zdravila Glybera in takoj po njem.
• Guidance on the need to measure immune response at baseline and at 6 and 12 months after treatment
• Smernice o potrebi po merjenju imunskega odziva ob izhodišču in 6 ter 12 mesecev po zdravljenju
What Glybera is and what it is used for What you need to know before you are given Glybera
Kaj je zdravilo Glybera in za kaj ga uporabljamo Kaj morate vedeti preden vam bodo dali zdravilo Glybera
Lipoprotein lipase is a key ‘first step' enzyme in the metabolism of lipoproteins following fat intake with diet.
Lipoproteinska lipaza je ključni encim „prvega koraka“ pri presnovi lipoproteinov po vnosu maščobe s hrano.
Muscle biopsies taken half a year post administration demonstrated long-term expression of the LPL gene and the presence of biologically active LPL protein.
Biopsije mišic, ki so jih odvzeli pol leta po injiciranju, so pokazale dolgotrajno ekspresijo gena LPL in prisotnost biološko aktivnega proteina LPL.
Animal studies do not indicate any harmful effects on pregnancy or embryonal/foetal development from Glybera (see section 5.3).
Študije na živalih niso pokazale škodljivih učinkov zdravila Glybera na nosečnost ali razvoj zarodka/ploda (glejte poglavje
• Increased blood level of the muscle enzyme creatine kinase
• zvišane ravni mišičnega encima kreatin kinaze v krvi
- Product information (summary of product characteristics, patient information leaflet and
- Informacije o zdravilu (povzetek glavnih značilnosti zdravila, navodilo za uporabo in
The dose per injection site is 1.5 x 1012 gc, or 0.5 ml of solution for injection.
Odmerek na mesto injiciranja je 1,5 x 1012 gk ali 0,5 ml raztopine za injiciranje.
Due to the large number of individual injections that you will receive during the Glybera therapy session, you will be given either a regional anaesthetic into the spine (which will numb your legs only), or a more localised anaesthetic before you are given the Glybera injections.
Zaradi velikega števila posameznih injekcij, ki jih boste prejeli med enkratnim zdravljenjem z zdravilom Glybera, boste pred injiciranjem zdravila Glybera dobili regionalni anestetik v hrbtenico (ki bo omrtvil samo noge) ali bolj lokaliziran anestetik.
Upon intramuscular injection, the patient will receive multiple injections of 0.5 ml (one injection per syringe), distributed over the muscles of both upper and lower legs, under aseptic conditions such as iodine.
Pri intramuskularnem injiciranju bo bolnik prejel večkratno injiciranje 0,5 mililitra (eno injiciranje na injekcijsko brizgo), ki se razporedi po mišicah zgornjega in spodnjega dela nog, pri čemer se uvedejo aseptični pogoji, na primer z uporabo joda.
People who are affected by this condition have a build up of very high fat levels in their blood (hyperchylomicronemia).
Pri ljudeh s to boleznijo se v krvi kopičijo zelo visoke ravni maščob (hiperhilomikronemija).
The amount of sodium and potassium that you may receive depends on the number of injections that you need; your doctor will work this out depending on your weight.
Količina natrija in kalija, ki jo prejmete, je odvisna od števila injekcij, ki jih potrebujete, kar bo izračunal zdravnik na podlagi vaše telesne mase.
Glybera is expected to be degraded by endogenous protein and DNA catabolic pathways.
Pričakuje se, da se bo zdravilo Glybera razgradilo z endogenim proteinom in katabolnimi potmi DNK.
LPL protein mass should be measured in a blood sample from the patient against a control sample from healthy volunteers.
Maso proteina LPL je treba izmeriti v bolnikovem krvnem vzorcu in jo primerjati s kontrolnim vzorcem zdravega prostovoljca.
The holder should not donate blood, organs or tissues and should use barrier contraception at least 12 months after Glybera treatment.
Imetnik te kartice ne sme darovati krvi, organov ali tkiv in mora uporabljati pregradno kontracepcijo vsaj 12 mesecev po zdravljenju z zdravilom Glybera.
Shedding was assessed in the clinical studies by collecting saliva, urine and semen.
Razsejanje so v kliničnih študijah ocenili z odvzemom sline, urina in sperme.
Anti-platelet or other anti-coagulant medicinal products must not be taken for at least one week before the leg injections or one day after the injection (see section 4.3).
Antiagregacijska sredstva in antikoagulanti se ne smejo uporabljati vsaj en teden pred injiciranjem v nogo ali en dan po injiciranju (glejte poglavje 4.3).
Glybera therapy will be overseen by a doctor who is specialised in the treatment of patients affected by your condition and will be administered to you by an appropriately qualified and trained doctor or nurse.
Zdravljenje z zdravilom Glybera bo nadzoroval zdravnik, specializiran za zdravljenje bolnikov z vašo boleznijo, ter ga bo opravil ustrezno kvalificiran in usposobljen zdravnik ali medicinska sestra.
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
• v 60 dneh po doseženem pomembnem mejniku (farmakovigilančnem ali povezanem z zmanjševanjem tveganja), • na zahtevo Evropske agencije za zdravila.
Glybera should only be administered to patients with an LPL protein mass of at least 5% of normal.
Zdravilo Glybera se sme uporabiti samo pri bolnikih z maso proteina LPL, ki je vsaj 5 % normalne vrednosti.
MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
IZDELOVALEC BIOLOŠKE ZDRAVILNE UČINKOVINE IN IZDELOVALEC , ODGOVOREN ZA SPROŠČANJE SERIJ
The lowest number of copies was found in the brain, lung, heart and non-injected groups of muscle.
Najmanjše število kopij so odkrili v možganih, pljučih, srcu in skupinah mišic, v katere niso injicirali zdravila.
• Guidelines for the safe handling, administration and disposal of Glybera
• Smernice za varno ravnanje, injiciranje in odstranjevanje zdravila Glybera
• It is important that you fully understand the benefits and risks associated with the treatment by discussing with your doctor
• Pomembno je, da se posvetujete z zdravnikom in da popolnoma razumete koristi in tveganja, povezana z zdravljenjem.
Cell and tissue donation
Darovanje celic in tkiv
Chiesi SAS Tél: + 33 1 47688899
ChiesiSAS Tél: + 33 1 47688899
Furthermore, Glybera allows expression of the LPL protein in injected muscle which is reflected by the improvement of postprandial chylomicron (CM) metabolism observed in a small subset of patients.
Poleg tega zdravilo Glybera omogoča ekspresijo proteina LPL v mišici, v katero se je injiciralo, na kar kaže izboljšanje postprandialne presnove hilomikronov, ki so ga opazili pri majhni podskupini bolnikov.
Important information about some of the ingredients of Glybera
Pomembne informacije o nekaterih sestavinah zdravila Glybera
Your doctor should give you a copy of the patient information leaflet (like this one) for the immunosuppressants you will need to take.
Zdravnik vam mora dati izvod navodila za uporabo (kot je to navodilo) za imunosupresivna sredstva, ki jih boste morali jemati.
The safety and efficacy of Glybera in children and adolescents below 18 years has not been established.
Pediatrična populacija Varnost in učinkovitost zdravila Glybera pri otrocih in mladostnikih, starih manj kot 18 let, nista bili dokazani.
What you need to know before you are given Glybera Do not receive Glybera
Kaj morate vedeti, preden boste prejeli zdravilo Glybera Zdravila Glybera ne smete prejeti
Patients are advised to continue to follow a low-fat diet and refrain from alcohol consumption.
Bolnikom je treba svetovati, da se še naprej prehranjujejo z manj maščobami in ne pijejo alkohola.
Assessment of postprandial chylomicron metabolism in at least 12 patients before 12 months and 24 months after treatment with Glybera to be chosen in addition to the patients included in study CT-AMT.011.02; and eight healthy subjects in the second study.
Ocena postprandialne presnove hilomikronov pri vsaj 12 bolnikih pred zdravljenjem z zdravilom Glybera in 12 in 24 mesecev po njem poleg bolnikov, vključenih v študijo CT-AMT.011.02, ter pri osmih zdravih preskušancih v drugi študiji.
The clinical efficacy and safety of Glybera has been evaluated in three interventional clinical studies with AAV1-LPLS447X in LPLD subjects.
Klinična učinkovitost in varnost zdravila Glybera sta se ocenili v treh intervencijskih študijah z AAV1-LPLS447X pri preskušancih z LPLD.
Pharmacokinetics in special populations e.g. elderly/renal impairment etc. Glybera is injected directly into the target organ, skeletal muscle.
Farmakokinetika pri posebnih populacijah, npr. starejših bolnikih/ledvični okvari Zdravilo Glybera se injicira neposredno v tarčni organ, skeletno mišico.
• sensation like that of insects crawling on (or under) the skin
• občutek mravljinčenja na koži ali pod njo
Limited data are available in diabetic patients.
Podatki, ki so na voljo za sladkorne bolnike, so omejeni.
- if you are allergic to alipogene tiparvovec or to any of the other ingredients of Glybera (listed in section 6 ‘Further information').
- če ste alergični na alipogentiparvovek ali katero koli sestavino zdravila Glybera (navedeno v poglavju 6 ‘);
Contents of the pack and other information What Glybera contains
Vsebina pakiranja in dodatne informacije Kaj vsebuje zdravilo Glybera
It contains genetically modified organisms.
Vsebuje gensko spremenjene organizme.
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING Pharmacovigilance system
DRUGI POGOJI IN ZAHTEVE DOVOLJENJA ZA PROMET Z ZDRAVILOM Sistem farmakovigilance
• Anti-platelet or other anti-coagulant medicinal products must not be used concomitantly with Glybera at the time of injection and for at least one week before or one day after the injection.
• Antiagregacijske učinkovine ali antikoagulanti se ne smejo uporabljati sočasno z zdravilom Glybera v času injiciranja ter vsaj en teden pred injiciranjem ali en dan po njem.
The first 2 patients enrolled received a dose of 3 x 1011 gc/kg, the next 4 patients received a dose of 3 x 1011 gc/kg with immunosuppressant regiment (oral ciclosporin and oral mycophenolate mofetil from the day after Glybera administration until Week 12) and the final 8 patients received a dose of 1 x 1012gc/kg with immunosuppressant regiment.
Prva vključena bolnika sta prejela odmerek 3 x 1011 gk/kg, naslednji 4 bolniki so prejeli odmerek 3 x 1011 gk/kg z imunosupresivnim režimom (peroralni ciklosporin in peroralni mofetilmikofenolat od dneva po injiciranju zdravila Glybera do 12. tedna), zadnjih 8 bolnikov pa je prejelo odmerek 1 x 1012 gk/kg z imunosupresivnim režimom.
The elements of the vector were chosen such that expression of the LPL S447X gene is promoted, by co-opting the expression machinery of the cell and the myocytes produce the protein product of the transgene LPL S447X without the vector being able to reproduce itself.
Elementi vektorja so se izbrali tako, da se promovira izražanje gena LPLS447X s privzemanjem ustroja ekspresije celice in da miociti proizvajajo proteinski produkt transgena LPLS447X , tako da se vektor ne more reproducirati.
Glybera has minor influence on the ability to drive and use machines¸ dizziness was commonly observed after Glybera administration (see section 4.8).
Zdravilo Glybera ima blag vpliv na sposobnost vožnje in upravljanja s stroji, saj so po uporabi zdravila Glybera pogosto opazili omotico (glejte poglavje 4.8).
Small amounts of blood will be drawn before treatment, 6 months and 12 months after treatment to measure how your body's immune (defence) system is responding to the treatment with Glybera.
Pred zdravljenjem ter 6 mesecev in 12 mesecev po zdravljenju vam bodo odvzeli majhno količino krvi, s čimer bodo izmerili, kako se vaš imunski sistem odziva na zdravljenje z zdravilom Glybera.
Instructions for preparation and handling and disposal Refer to local biosafety guidelines applicable for handling and disposal of medicinal products containing genetically-modified organisms.
Navodila za pripravo in ravnanje z zdravilom in odlaganje Glejte lokalne smernice za biološko varnost, ki veljajo za ravnanje z zdravili, ki vsebujejo gensko spremenjene organizme, in njihovo odstranjevanje.
The levels of Glybera vector DNA found in gonads were measurable but lower than in other non-target organs.
Ravni DNK vektorja iz zdravila Glybera, ki so jih odkrili v gonadah, so bile merljive, vendar nižje kot v netarčnih organih.
The MAH shall also provide a patient alert card in each medication pack, the text of which is included in Annex III.
Imetnik dovoljenja za promet z zdravilom vsakemu pakiranju priložil tudi opozorilno kartico za bolnike, katere besedilo je vključeno v Prilogo III.
Glybera with alcohol
Zdravilo Glybera skupaj z alkoholom
This is an open-label study of alipogene tiparvovec at a fixed dose of 1x1012 gc/ kg body weight administered by a single series of intramuscular injections.
To je odprta študija alipogentiparvoveka v fiksnem odmerku 1 x 1012 gk/kg telesne mase, ki se je dajal kot enkratni niz intramuskularnih injiciranj.
Upon treatment four weeks prior to mating, no maternal, foetal and developmental toxicity was seen in mice.
Med zdravljenjem štiri tedne pred parjenjem pri miših niso opazili toksičnosti za samice, plod in razvoj.
The European Medicines Agency will review any new information on the medicine every year and this leaflet will be updated as necessary.
Evropska agencija za zdravila bo vsako leto ponovno pregledala vse nove podatke o tem zdravilu.
• If you do become pregnant during treatment with Glybera, tell your doctor.
• Če med zdravljenjem z zdravilom Glybera zanosite, o tem obvestite zdravnika.
In addition, patients, who have been treated with Glybera in a clinical trial shall be enrolled in the registry at the end of the trial.
Bolniki, ki se bodo zdravili z zdravilom Glybera v kliničnem preskušanju, se bodo na koncu preskušanja prav tako vključili v register.
The aim of this open label, dose escalating study was to assess the safety profile and reduction of fasting plasma triglyceride (TG) levels after 12 weeks post Glybera administration in 14 LPLD patients.
Cilj odprte študije s povečevanjem odmerka je bil oceniti varnostni profil in znižanje ravni trigliceridov v plazmi na tešče 12 tednov po injiciranju zdravila Glybera pri 14 bolnikih z LPLD.
If you receive two doses in one injection site by mistake this might lead to more local reaction such as bruising or sensitivity.
Če pomotoma prejmete dva odmerka na istem mestu injiciranja, to lahko povzroči več lokalnih reakcij, kot sta podplutba ali občutljivost.
The other ingredients are, disodium phosphate, potassium chloride, potassium dihydrogen phosphate, sodium chloride, sucrose, and water for injections.
Druge sestavine zdravila so dinatrijev fosfat, kalijev klorid, kalijev dihidrogenfosfat, natrijev klorid, saharoza in voda za injekcije.
Each preformed transparent sealed plastic casing contains either 2 or 3 individual vials with a liquid absorbing sheet.
Vsak oblikovan, prozoren, zatesnjen plastični ovoj vsebuje 2 ali 3 posamezne viale z listom za absorpcijo tekočine.
Recipients of Glybera may display a rise in serum creatine kinase activity that becomes evident about 2 weeks after administration, peaks at around 8 weeks and then returns to baseline by week 26.
Pri prejemnikih zdravila Glybera se lahko pojavi povečanje aktivnosti serumske kreatin kinaze, ki postane očitno približno 2 tedna po dajanju, doseže vrhunec v približno 8 tednih in se nato do
Work surfaces and material which have potentially been in contact with Glybera must be decontaminated with appropriate virucidal disinfectants with activity for non-enveloped viruses (such as hypochlorite and chlorine releasers) for at least 10 minutes.
Delovne površine in material, ki so morda prišli v stik z zdravilom Glybera, je treba za vsaj 10 minut dekontaminirati z ustreznimi virucidnimi dezinfekcijskimi sredstvi, ki delujejo na viruse brez ovojnice
Number of injection sites
Število mest injiciranja
Glybera is authorised for single treatment only and should not be re-administered.
Zdravilo Glybera je odobreno samo za enkratno zdravljenje in se ne sme uporabiti ponovno.
In half of the subjects a T-cell response to the vector was seen.
Pri polovici preskušancev so opazili odziv limfocitov T proti vektorju.
One patient was diagnosed with pulmonary embolism 7 weeks after therapy.
Pri enem bolniku se je 7 tednov po zdravljenju postavila diagnoza pljučne embolije.
In case of contraindication for such procedure deep sedation is advised instead.
Če je to kontraindicirano, se pri takem injiciranju priporoča globoka sedacija.
Examples of these immunosuppressants are ciclosporin, mycophenolate mofetil.
Primera imunosupresivnih sredstev sta ciklosporin in mofetilmikofenolat.
It is not known whether Glybera passes into breast milk.
Ni znano, ali zdravilo Glybera prehaja v materino mleko.
• Glybera is a gene therapy product.
• Zdravilo Glybera je namenjeno genski terapiji.
The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.
Redno posodobljena poročila o varnosti zdravila (PSUR) Zahteve glede predložitve rednega posodobljenega poročila o varnosti zdravila za to zdravilo so določene v seznamu referenčnih datumov EU (seznamu EURD), opredeljenem v členu 107c(7)
No dose adjustment of Glybera is necessary in the elderly population.
Prilagajanje odmerka zdravila Glybera pri starejši populaciji ni potrebno.
At this time a series of injections (27 to 60 injections) into the muscles of both upper and lower legs will be given.
V tem času vam bodo v mišice zgornjega in spodnjega dela noge dali niz injekcij (od 27 do 60).
All patients were controlled on low fat diets in the 12-week main study period.
Vsi bolniki so bili v glavnem 12- tedenskem obdobju študije na nadzorovani dieti z majhnim vnosom maščob.
Muscle biopsies obtained up to 52 weeks after administration of Glybera show an infiltrate of lymphocytes and macrophages.
Biopsije mišic, pridobljene do 52. tednov po dajanju zdravila Glybera, kažejo na infiltrat limfocitov in makrofagov.
The MAH shall set up a long term surveillance programme/ disease registry to collect information on the epidemiology of the disease and the demographics, safety, and the effectiveness outcomes of patients treated with Glybera.
Imetnik dovoljenja za promet z zdravilom vzpostavi dolgotrajni program spremljanja/register bolezni, s katerim zbira podatke o epidemiologiji bolezni in izidih glede demografije, varnosti ter učinkovitosti pri bolnikih, ki so se zdravili z zdravilom Glybera.
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to
Spodaj našteti neželeni učinki so razvrščeni po organskem sistemu MedDRA in po ji pogostnosti: zelo pogosti (≥ 1/10), pogosti (≥ 1/100 do < 1/10), občasni (≥ 1/1000 do < 1/100), redki (≥ 1/10.000 do < 1/1000), zelo redki (< 1/10.000), neznana (ni mogoče oceniti iz razpoložljivih podatkov).
Glybera contains the human LPL gene variant LPL S447X in an adeno-associated virus serotype 1 (AAV1) vector intended to target the muscle.
Zdravilo Glybera vsebuje humano varianto gena LPLS447X v vektorju z adenoasociiranim virusnim serotipom 1 (AAV1), ki je usmerjen na mišico.
Male patients must use condoms for at least 12 months after injection with Glybera.
Moški bolniki morajo uporabljati kondome vsaj 12 mesecev po injiciranju zdravila Glybera.
Glybera is delivered in a patient-specific pack and will therefore contain the precise amount of vials per patient, calculated according to the patient's weight.
Zdravilo Glybera je dobavljeno v za bolnika specifičnem pakiranju, kar pomeni, da vsebuje točno število vial za enega bolnika, ki se izračuna na podlagi bolnikove telesne mase.
Glybera is a clear to slightly opalescent, colourless solution for injection, supplied in a clear glass vial with a siliconised injection stopper and flip-off seal.
Zdravilo Glybera je bistra do rahlo opalescentna, brezbarvna raztopina za injiciranje, ki se dobavlja v prozorni stekleni viali s silikoniziranim injekcijskim zamaškom in zaporko.
This medicinal product contains 47.5 mg sodium per administration at 27 injection sites to 105.6 mg sodium per administration at 60 injection sites.
To zdravilo vsebuje 47,5 mg natrija na vsako uporabo na 27 mestih injiciranja do 105,6 mg natrija na uporabo na 60 mestih injiciranja.
Glybera contains alipogene tiparvovec, a gene therapy product that works by delivering a gene into the body to correct a genetic deficiency.
Zdravilo Glybera vsebuje alipogentiparvovek, učinkovino za gensko terapijo, ki deluje tako, da dovaja gen v telo in s tem odpravi genetsko pomanjkanje.
Re-administration of Glybera after this first treatment session is not recommended.
Ponovna uporaba zdravila Glybera po prvem zdravljenju ni priporočljiva.
An appropriate CE marked test or full gene sequencing should be used to confirm the diagnosis.
Za potrditev diagnoze je treba uporabiti ustrezne teste z oznako CE ali celotno zaporedje genov.
The patients in CT-AMT-010-01 have been followed for up to 5 years (n=6) post therapy administration, those in CT-AMT-011-01 for up to 5 years (n=13), and those in CT-AMT-011-02 for up to 1 year (n=3).
Pri bolnikih v študiji CT-AMT-010-01 so sledenje opravljali do 5 let (n = 6) po zdravljenju, pri bolnikih v študiji CT-AMT011-01 do 5 let (n = 13), pri bolnikih v študiji CT-AMT-011-02 pa do 1 leta (n = 3).
Glybera is administered as a one-time series of intramuscular injections in the legs.
Zdravilo Glybera se daje kot enkratni niz intramuskularnih injiciranj v noge.
To calculate the number of injection sites and the number of syringes, the patient's weight is determined to the nearest whole kg.
Pri izračunu števila mest injiciranja in števila injekcijskih brizg se bolnikova telesna masa zaokroži na najbližji kilogram.
Other medicines and Glybera
Druga zdravila in zdravilo Glybera
The diagnosis of LPLD has to be confirmed by genetic testing.
Diagnozo LPLD je treba potrditi z genskimi preiskavami.