human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Abstract . Rationale : Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning , drug craving and mood . Objective : The present study aim ed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme . Methods : Patients were r and omly allocated to one of two groups who received either 50 % or 100 % of their daily stabilisation dose , and a placebo , in a double-blind , cross-over design . Twenty patients completed the study , all were assessed pre- and post-drug on 2 separate testing days . Results : Performance on a task tapping episodic memory ( delayed recall of a prose passage ) was significantly impaired following the 100 % daily dose of methadone . Methadone treatment had no effect on craving or mood . Patients were unable to distinguish between methadone and placebo treatments . Conclusions : A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years . Such impairment can be avoided by giving methadone in divided doses This study tested whether opiate dependence , tobacco smoking , or their combination accompanied impaired performance on the  gambling task ( GT )  , which tests decision-making .  GT previously detected impairments in patients with lesions of the ventromedial prefrontal cortex and in substance abusers . Four groups were matched on demographic characteristics and intelligence : methadone-maintained smokers ( n = 9 ) and nonsmokers ( n = 9 ) , and control ( i.e. , not opiate-dependent ) smokers ( n = 9 ) and nonsmokers ( n = 10 ) . The  Wisconsin Card Sorting Task ( WCST )  was administered to test whether differences in  GT performance reflected generalized deficits in prefrontal cortical function . While there were no significant group differences on the WCST , groups differed significantly on  GT performance ( F(3,31 ) = 2.95 , P = 0.048 ) , controlling for depressive symptom ratings and childhood attention deficit hyperactivity disorder .  Methadone-maintained smokers ( but not nonsmokers ) performed more poorly than either of the two control groups ( P = 0.007 versus smokers ; P = 0.024 versus nonsmokers ) . In a planned analysis of methadone-maintained subjects , smokers scored more poorly on  GT  than nonsmokers ( F(1,18 ) = 5.64 , P = 0.032 ) and had more treatment failures ( 67 % heroin use during the last 30 days versus 20 % ) . The findings suggest that among opiate-dependent individuals , tobacco smoking may be a marker for a more severe form of substance abuse disorder , reflecting impaired decision-making , as modeled by GT Reinforcing properties of psychoactive substances are considered to be critically involved in the development and maintenance of substance dependence . While accumulating evidence suggests that the sensitivity to reinforcement values may generally be altered in chronic substance users , relatively little is known about the influence reinforcing feedback exerts on ongoing decision-making in these individuals . Decision-making was investigated using the Cambridge Risk Task , in which there is a conflict between an unlikely large reward option and a likely small reward option . Responses on a given trial were analyzed with respect to the outcome on the previous trial , providing a measure of the impact of prior feedback in modulating behavior . Five different groups were compared : ( i ) chronic amphetamine users , ( ii ) chronic opiate users in methadone maintenance treatment ( MMT ) , ( iii ) chronic users of illicit heroin , ( iv ) ex-drug users who had been long-term amphetamine / opiate users but were abstinent from all drugs of abuse for at least 1 year and ( v ) matched controls without a history of illicit substance use . Contrary to our predictions , choice preference was modified in response to feedback only in opiate users enrolled in MMT . Following a loss , the MMT opiate group chose the likely small reward option significantly less frequently than controls and heroin users . Our results suggest that different opiates are associated with distinctive behavioral responses to feedback . These findings are discussed with respect to the different mechanisms of action of heroin and methadone AIMS To assess the influence of methadone and buprenorphine maintenance treatment on the driving aptitude of opioid-dependent patients . DESIGN Prospect i ve , open label , outpatient maintenance , single-blind ( investigator ) study . PARTICIPANTS AND SETTING Thirty opioid-dependent patients maintained on either methadone or buprenorphine were recruited from the drug-addiction outpatient clinic in Vienna . MEASUREMENTS The traffic-relevant performance dimensions of the participants were assessed 22 h after receiving synthetic opioid maintenance therapy  , by a series of seven tests constituting the Act & React Test System ( ART ) 2020 St and ard test battery , developed by the Austrian Road Safety Board ( ARSB ) . To test for additional consumption of illicit substances , blood and urine sample s were taken at the beginning of the tests . FINDINGS The patient group only differed from control subjects in two of the ART 2020 St and ard tests . During a task to test the subject 's attention under monotonous circumstances ( Q1 test ) , patients had a significantly greater number of reactions ( p = 0.027 ) and a significantly higher percentage of incorrect reactions than control subjects . When driving in a dynamic environment ( DR2 test ) patients had a significantly longer mean decision time ( p = 0.029 ) and mean reaction time ( p = 0.009 ) compared with control subjects . Interestingly , when separated into treatment groups , the mean decision and reaction times of buprenorphine-maintained patients in the DR2 test did not differ from controls , whereas patients maintained on methadone showed significantly prolonged mean decision ( p = 0.009 ) and reaction times ( p = 0.004 ) . In this same test , patients who had consumed additional illicit drugs had a longer mean reaction time compared with control subjects ( p = 0.036 ) . CONCLUSION The synthetic opioid-maintained subjects investigated in the current study did not differ significantly in comparison to healthy controls in the majority of the ART 2020 St and ard tests Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared , together with age- and IQ-matched control subjects . The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory , spatial working memory , planning , sequence generation , visual discrimination learning , and attentional set-shifting . Many of these tests have previously been shown to be sensitive to cortical damage ( including selective lesions of the temporal or frontal lobes ) and to cognitive deficits in dementia , basal ganglia disease , and neuropsychiatric disorder . Qualitative differences , as well as some commonalities , were found in the profile of cognitive impairment between the two groups . The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task ( a core component of the Wisconsin Card Sort Test ) whereas in contrast , the heroin abusers were impaired in learning the normally easier intra-dimensional shift component . Both groups were impaired in some of tests of spatial working memory . However , the amphetamine group , unlike the heroin group , were not deficient in an index of strategic performance on this test . The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task . The two groups were profoundly , but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction . These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry Fifty-six heroin addicts and 60 age-matched controls were offered choices between monetary rewards ( $ 11-$80 ) available immediately and larger rewards ( $ 25-$85 ) available after delays ranging from 1 week to 6 months . Participants had a 1-in-6 chance of winning a reward that they chose on one r and omly selected trial .  Delay-discounting rates were estimated from the pattern of participants ' choices . The discounting model of impulsiveness ( Ainslie , 1975 ) implies that delay-discounting rates are positively correlated with impulsiveness . On average , heroin addicts ' discount rates were twice those of controls ( p = .004 ) , and discount rates were positively correlated with impulsivity as measured by self-report question naires ( p < .05 ) . The results lend external validity to the  delay-discounting rate  as a measure of impulsiveness , a characteristic associated with substance abuse BACKGROUND Slow-release oral morphine ( SROM ) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence . However , the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population . METHODS In 14 methadone maintenance patients reporting adequate ( holders , n=7 ) or inadequate ( non-holders , n=7 ) withdrawal suppression between doses , plasma drug concentrations and indices of opioid effect ( withdrawal severity , pupil diameter , and respiratory rate ) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM ( once-daily Kapanol ) using an open-label , crossover design . RESULTS Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations , which peaked later for morphine compared to (R)-methadone ( 6.5 + /- 2.3 h vs. 2.5 + /- 1.4 h , P<0.001 ) . For methadone non-holders , the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone ( 3.4 + /- 2.6 vs. 9.0 + /- 3.2 , P<0.01 ) ; for holders it was approximately equal ( 4.4 + /- 3.0 vs. 4.0 + /- 3.7 , P<0.76 ) . Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication . Twelve of the 14 subjects preferred SROM to methadone ( P=0.01 ) . CONCLUSIONS The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence , particularly for patients responding poorly to methadone maintenance treatment BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool , the Cochrane Collaboration Risk of Bias Tool ( CCRBT ) , for all review groups . However , the psychometric properties of this tool to date have yet to be described . Thus , the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity , in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ) . METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions  to improve the management of cancer pain . Each study assessment was completed independently by two review ers using each tool . We analysed the inter-rater reliability of each tool 's individual domains , as well as final grade assigned to each study . RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade . In contrast , the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade . Of interest , no agreement between the two tools was evident in their final grade assigned to each study . Although both tools were developed to assess ' quality of the evidence ' , they appear to measure different constructs . CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain . The newly introduced CCRBT assigned these studies a higher risk of bias . Its psychometric properties need to be more thoroughly vali date d , in a range of research fields , to underst and fully how to interpret results from its application Longitudinal data from a representative sample of 1,978 Black and White adolescents were used to examine the role of personality in multiple risk or problem behaviors . Results indicate that covariation among diverse behaviors ( educational underachievement , delinquent behavior , substance use , sexual behavior ) can be adequately modeled by a single higher order factor , and that impulsivity and avoidance coping serve as generalized risk factors for involvement in these behaviors . Whereas none of the personality variables examined explained change in problem behaviors once established , avoidance coping prospect ively predicted involvement among a subgroup of adolescents with little or no prior involvement . Results suggest that dysfunctional styles of regulating emotions and emotionally driven behaviors are core features of risky or problem behaviors during adolescence Cognitive impairment in drug-dependent patients receiving methadone ( MMP ) maintenance treatment has been reported previously . We assessed cognitive functioning after at least 14 days of stable substitution treatment with buprenorphine ( BUP ) or MMP and after 8 to 10 weeks . We performed a r and omized , nonblinded clinical trial in 59 drug-dependent patients receiving either BUP or MMP maintenance treatment and healthy normal controls ( n = 24 ) matched for sex , age , and educational level . Thirteen patients dropped out of the study before the second testing was performed  ( BUP , n = 22 ; MMP , n = 24 ) . A neuropsychological test battery was used to measure selective attention , 
    Output:
    
agent
HighlightsA broad range of domains of neuropsychological performance are significantly impaired in studies which have compared  methadone population s with the healthy controls .
However low power , poor quality and heterogenous population s limit the interpretation of these results .Short term ( less than 1 year ) abstinent groups , when compared with methadone groups , still exhibited cognitive impairments but results are inconclusive .
It is still not clear what the role of global sedative effects of opioids such as methadone have on cognitive impairment .
Only higher quality longitudinal studies using ecologically valid cognitive tests , in well‐defined population groups can address this question .Methadone population s present with a broad range of neuropsychological impairment when compared with healthy controls .
Results : Data from a total cohort of 1063 CM , 412 AP and 879 HP participants , from 23 independent studies  indicate global impairments in neurocognitive function in CM relative to HP participants .
Conclusion : Method ological issues such as small sample sizes , heterogeneity and poor quality limited the interpretation of the results and does not address whether the observed impairments reflect co‐morbid functioning , methadone‐related sedation and /or other factors .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Abstract . Rationale : Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning , drug craving and mood . Objective : The present study aim ed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme . Methods : Patients were r and omly allocated to one of two groups who received either 50 % or 100 % of their daily stabilisation dose , and a placebo , in a double-blind , cross-over design . Twenty patients completed the study , all were assessed pre- and post-drug on 2 separate testing days . Results : Performance on a task tapping episodic memory ( delayed recall of a prose passage ) was significantly impaired following the 100 % daily dose of methadone . Methadone treatment had no effect on craving or mood . Patients were unable to distinguish between methadone and placebo treatments . Conclusions : A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years . Such impairment can be avoided by giving methadone in divided doses This study tested whether opiate dependence , tobacco smoking , or their combination accompanied impaired performance on the  gambling task ( GT )  , which tests decision-making .  GT previously detected impairments in patients with lesions of the ventromedial prefrontal cortex and in substance abusers . Four groups were matched on demographic characteristics and intelligence : methadone-maintained smokers ( n = 9 ) and nonsmokers ( n = 9 ) , and control ( i.e. , not opiate-dependent ) smokers ( n = 9 ) and nonsmokers ( n = 10 ) . The  Wisconsin Card Sorting Task ( WCST )  was administered to test whether differences in  GT performance reflected generalized deficits in prefrontal cortical function . While there were no significant group differences on the WCST , groups differed significantly on  GT performance ( F(3,31 ) = 2.95 , P = 0.048 ) , controlling for depressive symptom ratings and childhood attention deficit hyperactivity disorder .  Methadone-maintained smokers ( but not nonsmokers ) performed more poorly than either of the two control groups ( P = 0.007 versus smokers ; P = 0.024 versus nonsmokers ) . In a planned analysis of methadone-maintained subjects , smokers scored more poorly on  GT  than nonsmokers ( F(1,18 ) = 5.64 , P = 0.032 ) and had more treatment failures ( 67 % heroin use during the last 30 days versus 20 % ) . The findings suggest that among opiate-dependent individuals , tobacco smoking may be a marker for a more severe form of substance abuse disorder , reflecting impaired decision-making , as modeled by GT Reinforcing properties of psychoactive substances are considered to be critically involved in the development and maintenance of substance dependence . While accumulating evidence suggests that the sensitivity to reinforcement values may generally be altered in chronic substance users , relatively little is known about the influence reinforcing feedback exerts on ongoing decision-making in these individuals . Decision-making was investigated using the Cambridge Risk Task , in which there is a conflict between an unlikely large reward option and a likely small reward option . Responses on a given trial were analyzed with respect to the outcome on the previous trial , providing a measure of the impact of prior feedback in modulating behavior . Five different groups were compared : ( i ) chronic amphetamine users , ( ii ) chronic opiate users in methadone maintenance treatment ( MMT ) , ( iii ) chronic users of illicit heroin , ( iv ) ex-drug users who had been long-term amphetamine / opiate users but were abstinent from all drugs of abuse for at least 1 year and ( v ) matched controls without a history of illicit substance use . Contrary to our predictions , choice preference was modified in response to feedback only in opiate users enrolled in MMT . Following a loss , the MMT opiate group chose the likely small reward option significantly less frequently than controls and heroin users . Our results suggest that different opiates are associated with distinctive behavioral responses to feedback . These findings are discussed with respect to the different mechanisms of action of heroin and methadone AIMS To assess the influence of methadone and buprenorphine maintenance treatment on the driving aptitude of opioid-dependent patients . DESIGN Prospect i ve , open label , outpatient maintenance , single-blind ( investigator ) study . PARTICIPANTS AND SETTING Thirty opioid-dependent patients maintained on either methadone or buprenorphine were recruited from the drug-addiction outpatient clinic in Vienna . MEASUREMENTS The traffic-relevant performance dimensions of the participants were assessed 22 h after receiving synthetic opioid maintenance therapy  , by a series of seven tests constituting the Act & React Test System ( ART ) 2020 St and ard test battery , developed by the Austrian Road Safety Board ( ARSB ) . To test for additional consumption of illicit substances , blood and urine sample s were taken at the beginning of the tests . FINDINGS The patient group only differed from control subjects in two of the ART 2020 St and ard tests . During a task to test the subject 's attention under monotonous circumstances ( Q1 test ) , patients had a significantly greater number of reactions ( p = 0.027 ) and a significantly higher percentage of incorrect reactions than control subjects . When driving in a dynamic environment ( DR2 test ) patients had a significantly longer mean decision time ( p = 0.029 ) and mean reaction time ( p = 0.009 ) compared with control subjects . Interestingly , when separated into treatment groups , the mean decision and reaction times of buprenorphine-maintained patients in the DR2 test did not differ from controls , whereas patients maintained on methadone showed significantly prolonged mean decision ( p = 0.009 ) and reaction times ( p = 0.004 ) . In this same test , patients who had consumed additional illicit drugs had a longer mean reaction time compared with control subjects ( p = 0.036 ) . CONCLUSION The synthetic opioid-maintained subjects investigated in the current study did not differ significantly in comparison to healthy controls in the majority of the ART 2020 St and ard tests Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared , together with age- and IQ-matched control subjects . The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory , spatial working memory , planning , sequence generation , visual discrimination learning , and attentional set-shifting . Many of these tests have previously been shown to be sensitive to cortical damage ( including selective lesions of the temporal or frontal lobes ) and to cognitive deficits in dementia , basal ganglia disease , and neuropsychiatric disorder . Qualitative differences , as well as some commonalities , were found in the profile of cognitive impairment between the two groups . The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task ( a core component of the Wisconsin Card Sort Test ) whereas in contrast , the heroin abusers were impaired in learning the normally easier intra-dimensional shift component . Both groups were impaired in some of tests of spatial working memory . However , the amphetamine group , unlike the heroin group , were not deficient in an index of strategic performance on this test . The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task . The two groups were profoundly , but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction . These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry Fifty-six heroin addicts and 60 age-matched controls were offered choices between monetary rewards ( $ 11-$80 ) available immediately and larger rewards ( $ 25-$85 ) available after delays ranging from 1 week to 6 months . Participants had a 1-in-6 chance of winning a reward that they chose on one r and omly selected trial .  Delay-discounting rates were estimated from the pattern of participants ' choices . The discounting model of impulsiveness ( Ainslie , 1975 ) implies that delay-discounting rates are positively correlated with impulsiveness . On average , heroin addicts ' discount rates were twice those of controls ( p = .004 ) , and discount rates were positively correlated with impulsivity as measured by self-report question naires ( p < .05 ) . The results lend external validity to the  delay-discounting rate  as a measure of impulsiveness , a characteristic associated with substance abuse BACKGROUND Slow-release oral morphine ( SROM ) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence . However , the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population . METHODS In 14 methadone maintenance patients reporting adequate ( holders , n=7 ) or inadequate ( non-holders , n=7 ) withdrawal suppression between doses , plasma drug concentrations and indices of opioid effect ( withdrawal severity , pupil diameter , and respiratory rate ) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM ( once-daily Kapanol ) using an open-label , crossover design . RESULTS Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations , which peaked later for morphine compared to (R)-methadone ( 6.5 + /- 2.3 h vs. 2.5 + /- 1.4 h , P<0.001 ) . For methadone non-holders , the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone ( 3.4 + /- 2.6 vs. 9.0 + /- 3.2 , P<0.01 ) ; for holders it was approximately equal ( 4.4 + /- 3.0 vs. 4.0 + /- 3.7 , P<0.76 ) . Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication . Twelve of the 14 subjects preferred SROM to methadone ( P=0.01 ) . CONCLUSIONS The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence , particularly for patients responding poorly to methadone maintenance treatment BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool , the Cochrane Collaboration Risk of Bias Tool ( CCRBT ) , for all review groups . However , the psychometric properties of this tool to date have yet to be described . Thus , the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity , in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ) . METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions  to improve the management of cancer pain . Each study assessment was completed independently by two review ers using each tool . We analysed the inter-rater reliability of each tool 's individual domains , as well as final grade assigned to each study . RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade . In contrast , the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade . Of interest , no agreement between the two tools was evident in their final grade assigned to each study . Although both tools were developed to assess ' quality of the evidence ' , they appear to measure different constructs . CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain . The newly introduced CCRBT assigned these studies a higher risk of bias . Its psychometric properties need to be more thoroughly vali date d , in a range of research fields , to underst and fully how to interpret results from its application Longitudinal data from a representative sample of 1,978 Black and White adolescents were used to examine the role of personality in multiple risk or problem behaviors . Results indicate that covariation among diverse behaviors ( educational underachievement , delinquent behavior , substance use , sexual behavior ) can be adequately modeled by a single higher order factor , and that impulsivity and avoidance coping serve as generalized risk factors for involvement in these behaviors . Whereas none of the personality variables examined explained change in problem behaviors once established , avoidance coping prospect ively predicted involvement among a subgroup of adolescents with little or no prior involvement . Results suggest that dysfunctional styles of regulating emotions and emotionally driven behaviors are core features of risky or problem behaviors during adolescence Cognitive impairment in drug-dependent patients receiving methadone ( MMP ) maintenance treatment has been reported previously . We assessed cognitive functioning after at least 14 days of stable substitution treatment with buprenorphine ( BUP ) or MMP and after 8 to 10 weeks . We performed a r and omized , nonblinded clinical trial in 59 drug-dependent patients receiving either BUP or MMP maintenance treatment and healthy normal controls ( n = 24 ) matched for sex , age , and educational level . Thirteen patients dropped out of the study before the second testing was performed  ( BUP , n = 22 ; MMP , n = 24 ) . A neuropsychological test battery was used to measure selective attention , 
    Output:
    