FrancophonIA/ELRC3.0 huggingface dataset:
English: Patients with mild (either AST >ULN and total bilirubin ≤ULN or any AST and total bilirubin >ULN but 1.5×ULN), moderate (any AST and total bilirubin >1.5×ULN and 3×ULN), or severe (any AST and total bilirubin >3×ULN) hepatic impairment or normal (AST and total bilirubin ≤ULN) hepatic function, who were matched controls for mild or moderate hepatic impairment, were enrolled in an open-label, non-randomised clinical study (Study 1012), based on NCI classification.
Danish: Patienter med let (ASAT > ULN og total bilirubin ≤ ULN eller enhver ASAT og total bilirubin > ULN men  1,5 × ULN), moderat (enhver ASAT og total bilirubin > 1.5 × ULN og  3 × ULN) eller svært (enhver ASAT og total bilirubin > 3 × ULN) nedsat leverfunktion eller normal (ASAT og total bilirubin ≤ ULN) leverfunktion, som var matchede kontroller for let eller moderat nedsat leverfunktion, indgik i et open-label, ikke-randomiseret klinisk studie (Studie 1012) baseret på NCI klassifikationen.
English: In Study 1001, patients were required to have advanced ROS1-positive advanced NSCLC prior to entering the clinical trial.
Danish: I studie 1001 var det påkrævet, at patienterne havde fremskreden ROS1-positiv NSCLC, inden de indtrådte i det kliniske forsøg.
English: Pharmacotherapeutic group: Anti-neoplastic agents, protein kinase inhibitor; ATC code: L01XE16.
Danish: Farmakoterapeutisk klassifikation: Antineoplastiske midler, protein kinase-hæmmer, ATC-kode: L01XE16
English: One hundred forty-four (84%) patients in the chemotherapy arm received subsequent crizotinib treatment.
Danish: 144 (84%) patienter i kemoterapi-armen fik efterfølgende crizotinibbehandling.
English: In ALK-positive NSCLC patients, the frequency of adverse reactions was generally similar for patients <65 years of age and patients 65 years of age with the exception of oedema and constipation, which were reported with greater frequency (≥15% difference) in Study 1014 among patients treated with crizotinib 65 years of age.
Danish: Hos ALK-positive NSCLC-patienter var hyppigheden af bivirkninger generelt sammenlignelig for patienter <65 år og 65 år med undtagelse af ødemer og obstipation, som blev rapporteret med større hyppighed (forskel på (≥15%) i studie 1014 hos patienter ≥65 år, der blev behandlet med crizotinib.
English: The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant pre-existing cardiac disease and/or electrolyte disturbances.
Danish: Fordele og mulige risici ved crizotinib skal overvejes før behandlingen indledes hos patienter med præeksisterende bradykardi, som tidligere har haft eller er disponeret for QTcforlængelse, som tager antiarytmika eller andre lægemidler, der kan forlænge QT-intervallet, og hos patienter med relevant præeksisterende hjertesygdom og/eller elektrolytforstyrrelser.
English: Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed.
Danish: Det bør overvejes midlertidigt at pausere behandlingen, nedsætte dosis eller seponere behandlingen, hvis nævnte symptomer opstår.
English: Due to the small size of the increases in crizotinib exposure (5%-15%), no starting dose adjustment is recommended for patients with mild or moderate renal impairment.
Danish: På grund af de meget små stigninger i crizotinibeksponeringen (5%-15%) er justering af startdosis til patienter med let eller moderat nedsat nyrefunktion ikke nødvendig.
English: • Swallow the capsules whole and do not crush, dissolve or open the capsules.
Danish: • Synk kapslen hel, kapslen må hverken knuses, opløses eller åbnes.
English: Carcinogenicity studies with crizotinib have not been performed.
Danish: Der er ikke foretaget karcinogenicitetstudier med crizotinib.
English: These patients received a starting oral dose of 250 mg taken twice daily continuously.
Danish: Disse patienter fik en oral startdosis på 250 mg 2 gange dagligt kontinuerligt.
English: o. Blood creatinine increased (blood creatinine increased, creatinine renal clearance decreased).
Danish: o) Forhøjet blod-kreatinin (forhøjet blod-kreatinin, nedsat kreatininclearance).
English: Crizotinib also demonstrated marked antitumour activity in mouse xenograft studies, where tumours were generated using a panel of NIH-3T3 cell lines engineered to express key ROS1 fusions identified in human tumours.
Danish: Crizotinib udviste også markant antitumoraktivitet i xenograftstudier med mus, hvor tumorer blev genereret med et panel af NIH-3T3 cellelinjer til at udtrykke vigtige ROS1-fusioner, identificeret i humane tumorer.
English: Grade 3 QTc prolongation
Danish: Grad 3 QTc forlængelse
English: 2013; OS is based on the last patient last visit date of 30 November 2016, and is based on a median follow up of approximately 46 months.
Danish: *PFS, objektiv responsrate og responsvarighed er baseret på cutoff-dato 30. november 2013; OS er baseret på dato for sidste patients sidste besøg 30. november 2016 og er baseret på en median opfølgningstid på ca. 46 måneder.
English: No starting dose adjustment is recommended for patients with mild (60≤ creatinine clearance [CLcr] <90 mL/min) or moderate (30≤ CLcr <60 mL/min) renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients.
Danish: Justering af startdosis er ikke nødvendig hos patienter med let (60 ≤ kreatininclearance [CLcr] < 90 ml/min) eller moderat (30 ≤ [CLcr] < 60 ml/min) nedsat nyrefunktion, da den farmakokinetiske populationsanalyse ikke viste nogen ændringer af klinisk betydning i steady state crizotinib-eksponeringen hos disse patienter.
English: Increases to Grade 3 or 4 ALT or AST elevations were observed in 187 (11%) and 95 (6%) of patients, respectively.
Danish: Grad 3 eller 4 ALAT- eller ASAT-stigning sås hos henholdsvis 187 (11%) og 95 (6%) af patienterne.
English: l. Gastrointestinal perforation (Gastrointestinal perforation, Intestinal perforation, Large intestine perforation).
Danish: l) Gastrointestinal perforation, (gastrointestinal perforation, tarmperforation, perforation af tyktarmen).
English: In studies in patients with ALK-positive advanced NSCLC (N=1669), the following adverse reactions were reported with an absolute difference of ≥10% in Asian patients (N=753) than in non-Asian patients (N=916): elevated transaminases, decreased appetite, neutropenia, and leukopenia.
Danish: I studier hos patienter med ALK-positiv fremskreden NSCLC (N=1669) blev følgende bivirkninger rapporteret med en absolut difference på ≥10% hos asiatiske patienter (N=753) end hos non-asiatiske patienter (N=916): forhøjede aminotransferaser, appetitløshed, neutropeni og leukopeni.
English: Based on the National Cancer Institute (NCI) classification, no starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST > Upper Limit of Normal (ULN) and total bilirubin ≤ULN or any AST and total bilirubin >ULN but 1.5 × ULN).
Danish: Baseret på National Cancer Institute (NCI) klassifikationen anbefales justering af startdosis af crizotinib ikke hos patienter med let nedsat leverfunktion (ASAT > over øvre normalgrænse (ULN) og total bilirubin ≤ ULN eller en enhver ASAT og total bilirubin > ULN men  1,5 × ULN).
English: Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in Study 1007 and Study 1014 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy.
Danish: I spørgeskemaet til vurdering af symptomer på synspåvirkning (Visual Symptom Assessment Questionnaire - VSAQ-ALK) rapporterede de patienter, der blev behandlet med crizotinib i studie 1007 og studie 1014, en højere forekomst af synsforstyrrelser sammenlignet med de patienter, der blev behandlet med kemoterapi.
English: Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.
Danish: Crizotinib var ikke mutagent in vitro i bakterielle tilbagemutationstest (Ames).
English: Less than 0.5% of patients experienced febrile neutropenia in clinical studies with crizotinib.
Danish: Færre end 0,5% af patienterne oplevede febril neutropeni i kliniske studier med crizotinib.
English: • If you are allergic to crizotinib or any of the other ingredients of this medicine (listed in Section 6, “What XALKORI contains”).
Danish: - hvis du er allergisk over for crizotinib eller et af de øvrige indholdsstoffer i XALKORI (angivet i punkt 6).
English: • If you have been told that you have an abnormality of your heart tracing after an electrocardiogram (ECG) known as prolonged QT interval.
Danish: • Hvis du har fået at vide, at du har forstyrrelser i hjerterytmen kaldet forlænget QT-interval, som kan ses på et elektrokardiogram (ekg).
English: It may help shrink tumours.
Danish: Det kan også få tumoren til at skrumpe.
English: The capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened.
Danish: Kapslerne må ikke knuses, opløses eller åbnes.
English: Grade 4 QTc prolongation
Danish: Grad 4 QTc forlængelse
English: Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or haemolysis)
Danish: Grad 2, 3 eller 4 ALAT- eller ASAT-stigning med samtidig grad 2, 3 eller 4 total bilirubinstigning (uden kolestase eller hæmolyse)
English: Seventy-seven of 106 patients (73%) continued crizotinib treatment for at least 3 weeks after objective disease progression.
Danish: 77 af 106 patienter (73%) fortsatte med crizotinibbehandlingen i mindst 3 uger efter objektiv sygdomsprogression.
English: There is insufficient information to characterize the risks of resumption of crizotinib in patients with a severe visual loss.
Danish: Der er utilstrækkelige oplysninger til at karakterisere risikoen ved at genoptage crizotinib-behandling hos patienter med alvorligt synstab.
English: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with crizotinib.
Danish: Alvorlig, livstruende eller dødelig interstitiel lungesygdom (ILD)/pneumonitis kan opstå hos patienter, der behandles med crizotinib.
English: However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam.
Danish: Der er imidlertid ikke observeret induktion in vivo, når crizotinib administreres samtidig med CYP3A-testsubstratet midazolam.
English: XALKORI is an anticancer medicine containing the active substance crizotinib used to treat adults with a type of lung cancer called non-small cell lung cancer, that presents with a specific rearrangement or defect in either a gene called anaplastic lymphoma kinase (ALK) or a gene called ROS1.
Danish: XALKORI indeholder det aktive stof crizotinib, som anvendes til behandling af voksne med en særlig form for lungekræft, som kaldes ikkesmåcellet lungekræft, hvor der er en ændring eller en fejl i enten et gen, som kaldes anaplastisk lymfomkinase (ALK), eller et gen, som kaldes ROS1.
English: Transaminase elevations generally occurred within the first 2 months of treatment.
Danish: Aminotransferasestigninger opstod generelt indenfor de første 2 behandlingsmåneder.
English: Symptomatic bradycardia (e.g., syncope, dizziness, hypotension) can occur in patients receiving crizotinib.
Danish: Symptomatisk bradykardi (fx synkope, svimmelhed eller hypotension) kan opstå hos patienter, der får crizotinib.
English: If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Danish: Hvis du er gravid eller ammer, har mistanke om, at du er gravid, eller planlægger at blive gravid, skal du spørge din læge til råds, før du tager XALKORI.
English: • Light-headedness, fainting, or chest discomfort Tell your doctor right away if you experience these symptoms which could be signs of changes in the electrical activity (seen on electrocardiogram) or abnormal rhythm of the heart.
Danish: • Uklarhed/svimmel, med besvimelse eller ubehag i brystet Kontakt straks lægen, hvis du får disse symptomer, det kan være tegn på ændringer i hjertets elektriske impulser (kan ses på elektrokardigram (ekg)) eller unormal hjerterytme.
English: i. Interstitial lung disease (Acute respiratory distress syndrome, Alveolitis, Interstitial lung disease, Pneumonitis).
Danish: i) Interstitiel lungesygdom (akut respiratorisk distress-syndrom, alveolitis, interstitiel lungesygdom, pneumonitis)
English: Final OS analysis was not adjusted for the potentially confounding effects of crossover (154 [89%] patients received subsequent crizotinib treatment).
Danish: Endelig analyse af OS var ikke justeret for den mulige konfunderende effekt ved overkrydsning (154 [89%] patienter fik efterfølgende behandling med crizotinib).
English: Your doctor may do blood tests and if the results are abnormal, your doctor may decide to reduce the dose of XALKORI.
Danish: Lægen kan tage en blodprøve, og hvis værdierne er unormale, kan det være nødvendigt, at lægen nedsætter dosis af XALKORI.
English: XALKORI 250 mg hard capsules EU/1/12/793/003
Danish: XALKORI 250 mg hårde kapsler EU/1/12/793/003
English: Fifty-two (52) patients treated with crizotinib and 57 chemotherapy-treated patients with previously treated or untreated asymptomatic brain metastases were enrolled in randomised Phase 3 Study 1007.
Danish: 52 patienter i crizotinib-armen, og 57 patienter i kemoterapi-armen, som havde tidligere behandlede eller ubehandlede asymptomatiske hjernemetastaser, indgik i det randomiserede fase 3-studie 1007.
English: XALKORI dose modification - non-haematological toxicities CTCAEa Grade
Danish: XALKORI dosisjustering - non-hæmatologisk toksicitet
English: Withhold until recovery to Grade ≤1, check and if necessary correct electrolytes, then resume at the next lower doseb,c
Danish: Hold pause indtil forbedring til grad ≤ 1, elektrolytter kontrolleres og korrigeres om nødvendigt, herefter genoptages dosering med den næste lavere dosis b,c
English: Partial responses were observed in 20 of 45 patients with non-adenocarcinoma NSCLC for an ORR of 44%, and 9 of 22 patients with SCC NSCLC for an ORR of 41%, both of which were less than the ORR reported in Study 1005 (54%) for all patients.
Danish: Der sås partielt respons hos 20 af 45 patienter med non-adenokarcinom NSCLC med en ORR på 44% og hos 9 af 22 patienter med SCC-NSCLC med en ORR på 41%, hvor begge er lavere end ORR i studie 1005 (54%) for alle patienter.
English: Ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss, should be performed.
Danish: Der skal udføres en oftalmologisk undersøgelse bestående af bedst korrigeret synsskarphed, nethindefotografier, synsfelter, optisk kohærens tomografi (OCT) og andre relevante undersøgelser for nyligt opstået alvorligt synstab.
English: Any Grade interstitial lung disease (ILD)/pneumonitis
Danish: Alle grader interstitiel lungesygdom (ILD)/pneumonitis
English: Oesophagitisk (2%) Dyspepsia (8%)
Danish: Øsofagitis k (2%) Dyspepsi (8%)
English: Thirty-eight (70.4%) of the 54 patients experienced an Eye Disorders System Organ Class treatment-emergent allcausality adverse event of which 30 patients had ophthalmic examinations.
Danish: 38 (70,4%) af de 54 patienter oplevede behandlingsrelaterede bivirkninger i systemorganklassen Øjne, og 30 af disse patienter fik foretaget oftalmologiske undersøgelser.
English: Therefore, starting dose adjustment is not required when crizotinib is coadministered with agents that increase gastric pH (such as proton-pump inhibitors, H2 blockers, or antacids).
Danish: Justering af startdosis er derfor ikke nødvendig, når crizotinib administreres sammen med lægemidler, der øger gastrisk pH (såsom syrepumpehæmmere, H2-blokkere eller antacida).
English: m. Elevated transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Liver function test abnormal, Transaminases increased).
Danish: m) Stigning i aminotransferase (forhøjet alaninaminotransferase, forhøjet aspartataminotransferase, forhøjet gamma-glutamyltransferase, forhøjet leverenzym, unormal leverfunktion, unormal leverfunktionstest,
English: Concurrent elevations in ALT and/or AST ≥3 × ULN and total bilirubin ≥2 × ULN without significant elevations of alkaline phosphatase (≤2 × ULN) have been observed in less than 1% patients treated with crizotinib.
Danish: Samtidig stigning i ALAT og/eller ASAT ≥ 3 × ULN og total-bilirubin ≥ 2 × ULN uden signifikant stigning i alkalisk fosfatase (≤ 2 x ULN) blev set hos mindre end 1% af de patienter, der blev behandlet med crizotinib.
English: A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14% when a 250 mg single dose was given to healthy volunteers.
Danish: Et fedtrigt måltid reducerer crizotinib AUCinf og Cmax med ca. 14%, når en enkelt oral dosis gives til raske frivillige.
English: Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events and selected ALK mutations).
Danish: Crizotinib er en selektiv lav-molekylær hæmmer af ALK receptortyrosinkinase (RTK) og dens onkogene variant (dvs. ALK-fusion og udvalgte ALK-mutationer).
English: c. Leukopenia (Leukopenia, White blood cell count decreased).
Danish: c) Leukopeni (leukopeni, nedsat antal hvide blodlegemer).
English: A total of 259 (16%) of 1666 patients with at least 1 postbaseline vital sign assessment had a pulse rate <50 bpm.
Danish: I alt havde 259 (16%) ud af 1.666 patienter med mindst 1 vurdering af vitale værdier efter baseline en pulsfrekvens på < 50.
English: The European Medicines Agency has waived the obligation to submit the results of studies with XALKORI in all subsets of the paediatric population in NSCLC (see section 4.2 for information on paediatric use).
Danish: Det Europæiske Lægemiddelagentur har dispenseret fra kravet om at fremlægge resultaterne af studier med XALKORI i alle undergrupper af den pædiatriske population med NSCLC.
English: • Quinidine, digoxin, disopyramide, amiodarone, sotalol, dofetilide, ibutilide, verapamil,
Danish: • Kinidin, digoxin, disopyramid, amiodaron, sotalol, dofetilid, ibutilid, verapamil, diltiazem til behandling af problemer med hjertet.
English: Patients with or without pre-existing cardiac disorders, receiving crizotinib, should be monitored for signs and symptoms of heart failure (dyspnoea, oedema, rapid weight gain from fluid retention).
Danish: Patienter med eller uden præ-eksisterende hjertesygdom, som bliver behandlet med crizotinib, skal monitoreres for symptomer på hjertesvigt (åndenød, ødemer, hurtig vægtøgning pga. væskeretention).
English: If QTc increases by greater than or equal to 60 msec from baseline but QTc is <500 msec, crizotinib should be withheld and cardiologist advice should be sought.
Danish: Hvis QTc forlænges ≥60 ms i forhold til baseline, men QTc er <500 ms, skal behandlingen med crizotinib afbrydes, og en kardiolog konsulteres.
English: d. Neuropathy (Burning sensation, Dysaesthesia, Formication, Gait disturbance, Hyperaesthesia, Hypoaesthesia, Hypotonia, Motor dysfunction, Muscle atrophy, Muscular weakness, Neuralgia, Neuritis, Neuropathy peripheral, Neurotoxicity, Paraesthesia, Peripheral motor neuropathy, Peripheral sensorimotor neuropathy, Peripheral sensory neuropathy, Peroneal nerve palsy, Polyneuropathy, Sensory disturbance, Skin burning sensation).
Danish: d) Neuropati (brændende fornemmelse, dysæstesi, ”myrekryb”, gangforstyrrelser, hyperæstesi, hypæstesi, hypotoni, motorisk dysfunktion, muskelatrofi, muskelsvaghed, neuralgi, neuritis, perifer neuropati, neurotoksicitet, paræstesi, perifer motorisk neuropati, perifer sensorisk-motorisk neuropati, perifer sensorisk neuropati, parese fra perifere nerver, polyneuropati, føleforstyrrelser, brændende fornemmelse i huden).
English: If QTc increases to greater than or equal to 500 msec, cardiologist advice must be immediately sought.
Danish: Hvis QTc forlænges til ≥500 ms, skal en kardiolog straks konsulteres.
English: No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat.
Danish: Der er ingen dyreforsøg med crizotinib til evaluering af fertilitet, men baseret på fund fra repeat-dose toksicitetsstudier i rotter vurderes crizotinib at have potentiale for at påvirke reproduktion og fertilitet hos mennesker.
English: Median times to onset for diarrhoea and constipation were 13 and 17 days, respectively.
Danish: Mediantid til forekomst af diarré og obstipation var hhv. 13 og 17 dage.
English: Withhold until recovery to Grade 1 or baseline, then resume at 250 mg once daily and escalate to 200 mg twice daily if clinically toleratedb,c
Danish: Hold pause indtil forbedring til grad ≤ 1 eller baseline, herefter genoptages dosering med 250 mg en gang dagligt med stigning til 200 mg 2 gange dagligt, hvis det tolereres klinisk b,c
English: In vitro studies in human hepatocytes indicated that crizotinib may induce pregnane X receptor (PXR)and constitutive androstane receptor (CAR)-regulated enzymes (e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).
Danish: In vitro studier med humane hepatocytter antyder at crizotinib kan inducere preganan-X-receptor (PXR)- og konstitutiv androstanreceptor (CAR)-regulerede enzymer (fx CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).
English: Supportive care for diarrhoea and constipation should include the use of standard antidiarroheal and laxative medicinal products, respectively.
Danish: Understøttende behandling af diarré og obstipation bør omfatte brug af standardbehandling med henholdsvis obstipantia og laksantia.
English: Crizotinib is extensively metabolized in the liver.
Danish: Crizotinib metaboliseres i stort omfang i leveren.
English: • Atazanavir, ritonavir, cobicistat, used to treat HIV infections/AIDS.
Danish: • Atazanavir, ritonavir, cobicistat bruges til behandling af hiv-infektioner/AIDS.
English: A total of 53 ROS1-positive advanced NSCLC patients were enrolled in the study at the time of data cutoff, including 46 patients with previously treated ROS1-positive advanced NSCLC and a limited number of patients (N=7) who had no prior systemic treatment.
Danish: I alt 53 patienter med ROS1-positiv fremskreden NSCLC var inkluderet i studiet på datacutoff, herunder 46 patienter, der tidligere var blevet behandlet for ROS1-positiv fremskreden NSCLC, og et begrænset antal patienter (N=7), der ikke tidligere havde fået systemisk behandling.
English: You can take XALKORI with or without food; however, you should avoid drinking grapefruit juice or eating grapefruit while on treatment with XALKORI as they may change the amount of XALKORI in your body.
Danish: Du bør dog ikke drikke grapefrugtjuice eller spise grapefrugt, mens du er i behandling med XALKORI, fordi grapefrugt kan ændre på mængden af XALKORI i kroppen.
English: The recommended dose schedule of XALKORI is 250 mg twice daily (500 mg daily) taken continuously.
Danish: Den anbefalede dosis af XALKORI er 250 mg 2 gange dagligt (500 mg dagligt) indtaget kontinuerligt.
English: Information is available from 45 response-evaluable patients with previously treated non-adenocarcinoma NSCLC (including 22 patients with SCC) in Study 1005.
Danish: Der er tilgængelig information fra 45 responsevaluerbare patienter med tidligere behandlet nonadenokarcinom NSCLC (herunder 22 patienter med SCC) i studie 1005.