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: The aim of group fMRI studies is to relate contrasts of tasks or stimuli to regional brain activity increases . These studies typically involve 10 to 16 subjects . The average regional activity statistical significance is assessed using the subject to subject variability of the effect ( r and om effects analyses ) . Because of the relatively small number of subjects included , the sensitivity and reliability of these analyses is question able and hard to investigate . In this work , we use a very large number of subject ( more than 80 ) to investigate this issue . We take advantage of this large cohort to study the statistical properties of the inter-subject activity and focus on the notion of reproducibility by bootstrapping . We asked simple but important method ological questions : Is there , from the point of view of reliability , an optimal statistical threshold for activity maps ? How many subjects should be included in group studies ? What method should be preferred for inference ? Our results suggest that i ) optimal thresholds can indeed be found , and are rather lower than usual corrected for multiple comparison thresholds , ii ) 20 subjects or more should be included in functional neuroimaging studies in order to have sufficient reliability , iii ) non-parametric significance assessment should be preferred to parametric methods , iv ) cluster-level thresholding is more reliable than voxel-based thresholding , and v ) mixed effects tests are much more reliable than r and om effects tests . Moreover , our study shows that inter-subject variability plays a prominent role in the relatively low sensitivity and reliability of group studies Stimulant medications , such as methylpheni date , which are effective treatments for attention deficit hyperactivity disorder ( ADHD ) , enhance brain dopamine signaling . However , the relationship between regional brain dopamine enhancement and treatment response has not been evaluated . Here , we assessed whether the dopamine increases elicited by methylpheni date are associated with long-term clinical response . We used a prospect i ve design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylpheni date . Methylpheni date -induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride ( D2/D3 receptor radiolig and sensitive to competition with endogenous dopamine ) . Clinical responses were assessed using the Conners ' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylpheni date treatment . A challenge dose of 0.5 mg/kg intravenous methylpheni date significantly increased dopamine in striatum ( assessed as decreases in D2/D3 receptor availability ) . In the ventral striatum , these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment . Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylpheni date that were also associated with decreases in symptoms of inattention . Our findings indicate that dopamine enhancement in ventral striatum ( the brain region involved with reward and motivation ) was associated with therapeutic response to methylpheni date , further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD . It also provides preliminary evidence that methylpheni date -elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response The stimulant methylpheni date ( MPX ) and the nonstimulant atomoxetine ( ATX ) are the most commonly prescribed medications for attention deficit hyperactivity disorder ( ADHD ) . However , no functional magnetic resonance imaging ( fMRI ) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX . A r and omized , double-blind , placebo-controlled , crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX , ATX , and placebo during a stop task , combined with fMRI within 19 medication-naive ADHD boys , and their potential normalization effects relative to 29 age-matched healthy boys . Compared with controls , ADHD boys under placebo showed bilateral ventrolateral prefrontal , middle temporal , and cerebellar underactivation . Within patients , MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation , which correlated with enhanced inhibitory capacity . Relative to controls , both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo , while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX . The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX BACKGROUND Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood . The mechanism of action of methylpheni date , the most common treatment for attention deficit hyperactivity disorder , is unclear . In vitro , the affinity of methylpheni date for the norepinephrine transporter ( NET ) is higher than that for the dopamine transporter ( DAT ) . The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylpheni date in vivo in humans . METHODS We used (S , S)-[¹¹C ] methylreboxetine ( [¹¹C]MRB ) to determine the effective dose 50 ( ED₅₀ ) of methylpheni date for NET . In a within-subject design , healthy subjects ( n = 11 ) received oral , single-blind placebo and 2.5 , 10 , and 40 mg of methylpheni date 75 min before [¹¹C]MRB injection . Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph . The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable ( BP(ND ) ) in the thalamus and other NET-rich regions . RESULTS BP(ND ) was reduced by methylpheni date in a dose-dependent manner in thalamus and other NET-rich regions . The global ED₅₀ was estimated to be .14 mg/kg ; therefore , the average clinical maintenance dose of methylpheni date ( .35-.55 mg/kg ) produces 70 % to 80 % occupancy of NET . CONCLUSIONS For the first time in humans , we demonstrate that oral methylpheni date significantly occupies NET at clinical ly relevant doses . The ED₅₀ is lower than that for DAT ( .25 mg/kg ) , suggesting the potential relevance of NET inhibition in the therapeutic effects of methylpheni date in attention-deficit/hyperactivity disorder CONTEXT Previous studies have reported hypofunction , structural abnormalities , and biochemical abnormalities of the dorsal anterior midcingulate cortex ( daMCC ) in attention-deficit/hyperactivity disorder ( ADHD ) . Stimulant medications are effective treatments for ADHD , but their neural effects have not been fully characterized . OBJECTIVE To determine whether the methylpheni date hydrochloride osmotic-release oral system ( OROS ) would increase functional magnetic resonance imaging ( fMRI ) activation , compared with placebo , in the daMCC and other frontoparietal regions subserving attention during the Multi- Source Interference Task ( MSIT ) . DESIGN R and omized , placebo-controlled , 6-week , before-after fMRI study . SETTING Academic medical center ambulatory clinic . PATIENTS Twenty-one adults with ADHD r and omized to 6 weeks of treatment with methylpheni date OROS ( n = 11 ) or placebo ( n = 10 ) . INTERVENTIONS Patients underwent fMRI twice while performing the MSIT ( scan 1 at baseline and scan 2 at 6 weeks ) . MAIN OUTCOME MEASURES Group-averaged , r and om-effects , repeated- measures , general linear model analyses were used to compare daMCC ( and whole-brain ) fMRI activation during the MSIT . Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented . RESULTS Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups . Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylpheni date OROS group than in the placebo group ( P < 1 x 10(-4 ) , cluster corrected for multiple comparisons ) . Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response . Methylpheni date OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks . CONCLUSION Methylpheni date OROS increased daMCC activation during the MSIT and may act , in part , by normalizing daMCC hypofunction in ADHD We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing , decreased tolerance to delays , poor temporal foresight and steeper temporal discounting . A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder ( ADHD ) . Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD . We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal , cingulate , striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds , motor timing to seconds and temporal discounting of longer time intervals . Given that impulsiveness , timing abnormalities and more specifically ADHD have been related to dopamine dysregulation , we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice , methylpheni date . This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor OBJECTIVE While there has been considerable concern over possible adverse effects of psychostimulants on brain development , this issue has not been examined in a prospect i ve study . The authors sought to determine prospect ively whether psychostimulant treatment for attention deficit hyperactivity disorder ( ADHD ) was associated with differences in the development of the cerebral cortex during adolescence . METHOD Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD . The mean age at the first scan was 12.5 years , and at the second scan , 16.4 years . Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants .  Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD . RESULTS Adolescents taking psychostimulants  differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip , the left middle/inferior frontal gyrus , and the right parieto-occipital region . The group difference was due to more rapid cortical thinning in the group not taking psychostimulants ( mean cortical thinning of 0.16 mm/year [ SD=0.17 ] , compared with 0.03 mm/year [ SD=0.11 ] in the group taking psychostimulants ) . Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates . The treatment groups did not differ in clinical outcome , however . CONCLUSIONS These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle CONTEXT Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder ( ADHD ) , with varying methods , small sample s , cross-sectional design s , and without accounting for stimulant drug exposure . OBJECTIVE To compare regional brain volumes at initial scan and their change over time in  medicated and previously unmedicated male and female patients with ADHD and healthy controls . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted from 1991 - 2001 at the National Institute of Mental Health , Bethesda , Md , of 152 children and adolescents with ADHD ( age range , 5 - 18 years ) and 139 age- and sex-matched controls ( age range , 4.5 - 19 years ) recruited from the local community , who contributed 544 anatomic magnetic resonance images . MAIN OUTCOME MEASURES Using completely automated methods , initial volumes and prospect i ve age-related changes of total cerebrum , cerebellum , gray and white matter for the 4 major lobes , and cau date nucleus of the brain were compared in patients and controls . RESULTS On initial scan , patients with ADHD had significantly smaller brain volumes in all regions , even after adjustment for significant covariates . This global difference was reflected in smaller total cerebral volumes ( -3.2 % , adjusted F(1,280 ) = 8.30 , P = .004 ) and in significantly smaller cerebellar volumes ( -3.5 % , adjusted F(1,280 ) = 12.29 , P = .001 ) . Compared with controls , previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes ( overall F(2,288 ) = 6.65 ; all pairwise comparisons Bon 
    Output:
    
agent
RESULTS The fMRI analysis showed that methylpheni date significantly enhanced activation in bilateral inferior frontal cortex (IFC)/insula during inhibition and time discrimination but had no effect on working memory networks .
The meta- analysis , including 14 fMRI data sets and 212 children with ADHD , showed that stimulants most consistently enhanced right IFC/insula activation , which also remained for a subgroup analysis of methylpheni date effects alone .
A more lenient threshold also revealed increased putamen activation .
CONCLUSIONS Psychostimulants most consistently increase right IFC/insula activation , which are key areas of cognitive control and also the most replicated neurocognitive dysfunction in ADHD .
These neurocognitive effects may underlie their positive clinical effects
***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: The aim of group fMRI studies is to relate contrasts of tasks or stimuli to regional brain activity increases . These studies typically involve 10 to 16 subjects . The average regional activity statistical significance is assessed using the subject to subject variability of the effect ( r and om effects analyses ) . Because of the relatively small number of subjects included , the sensitivity and reliability of these analyses is question able and hard to investigate . In this work , we use a very large number of subject ( more than 80 ) to investigate this issue . We take advantage of this large cohort to study the statistical properties of the inter-subject activity and focus on the notion of reproducibility by bootstrapping . We asked simple but important method ological questions : Is there , from the point of view of reliability , an optimal statistical threshold for activity maps ? How many subjects should be included in group studies ? What method should be preferred for inference ? Our results suggest that i ) optimal thresholds can indeed be found , and are rather lower than usual corrected for multiple comparison thresholds , ii ) 20 subjects or more should be included in functional neuroimaging studies in order to have sufficient reliability , iii ) non-parametric significance assessment should be preferred to parametric methods , iv ) cluster-level thresholding is more reliable than voxel-based thresholding , and v ) mixed effects tests are much more reliable than r and om effects tests . Moreover , our study shows that inter-subject variability plays a prominent role in the relatively low sensitivity and reliability of group studies Stimulant medications , such as methylpheni date , which are effective treatments for attention deficit hyperactivity disorder ( ADHD ) , enhance brain dopamine signaling . However , the relationship between regional brain dopamine enhancement and treatment response has not been evaluated . Here , we assessed whether the dopamine increases elicited by methylpheni date are associated with long-term clinical response . We used a prospect i ve design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylpheni date . Methylpheni date -induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride ( D2/D3 receptor radiolig and sensitive to competition with endogenous dopamine ) . Clinical responses were assessed using the Conners ' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylpheni date treatment . A challenge dose of 0.5 mg/kg intravenous methylpheni date significantly increased dopamine in striatum ( assessed as decreases in D2/D3 receptor availability ) . In the ventral striatum , these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment . Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylpheni date that were also associated with decreases in symptoms of inattention . Our findings indicate that dopamine enhancement in ventral striatum ( the brain region involved with reward and motivation ) was associated with therapeutic response to methylpheni date , further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD . It also provides preliminary evidence that methylpheni date -elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response The stimulant methylpheni date ( MPX ) and the nonstimulant atomoxetine ( ATX ) are the most commonly prescribed medications for attention deficit hyperactivity disorder ( ADHD ) . However , no functional magnetic resonance imaging ( fMRI ) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX . A r and omized , double-blind , placebo-controlled , crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX , ATX , and placebo during a stop task , combined with fMRI within 19 medication-naive ADHD boys , and their potential normalization effects relative to 29 age-matched healthy boys . Compared with controls , ADHD boys under placebo showed bilateral ventrolateral prefrontal , middle temporal , and cerebellar underactivation . Within patients , MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation , which correlated with enhanced inhibitory capacity . Relative to controls , both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo , while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX . The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX BACKGROUND Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood . The mechanism of action of methylpheni date , the most common treatment for attention deficit hyperactivity disorder , is unclear . In vitro , the affinity of methylpheni date for the norepinephrine transporter ( NET ) is higher than that for the dopamine transporter ( DAT ) . The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylpheni date in vivo in humans . METHODS We used (S , S)-[¹¹C ] methylreboxetine ( [¹¹C]MRB ) to determine the effective dose 50 ( ED₅₀ ) of methylpheni date for NET . In a within-subject design , healthy subjects ( n = 11 ) received oral , single-blind placebo and 2.5 , 10 , and 40 mg of methylpheni date 75 min before [¹¹C]MRB injection . Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph . The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable ( BP(ND ) ) in the thalamus and other NET-rich regions . RESULTS BP(ND ) was reduced by methylpheni date in a dose-dependent manner in thalamus and other NET-rich regions . The global ED₅₀ was estimated to be .14 mg/kg ; therefore , the average clinical maintenance dose of methylpheni date ( .35-.55 mg/kg ) produces 70 % to 80 % occupancy of NET . CONCLUSIONS For the first time in humans , we demonstrate that oral methylpheni date significantly occupies NET at clinical ly relevant doses . The ED₅₀ is lower than that for DAT ( .25 mg/kg ) , suggesting the potential relevance of NET inhibition in the therapeutic effects of methylpheni date in attention-deficit/hyperactivity disorder CONTEXT Previous studies have reported hypofunction , structural abnormalities , and biochemical abnormalities of the dorsal anterior midcingulate cortex ( daMCC ) in attention-deficit/hyperactivity disorder ( ADHD ) . Stimulant medications are effective treatments for ADHD , but their neural effects have not been fully characterized . OBJECTIVE To determine whether the methylpheni date hydrochloride osmotic-release oral system ( OROS ) would increase functional magnetic resonance imaging ( fMRI ) activation , compared with placebo , in the daMCC and other frontoparietal regions subserving attention during the Multi- Source Interference Task ( MSIT ) . DESIGN R and omized , placebo-controlled , 6-week , before-after fMRI study . SETTING Academic medical center ambulatory clinic . PATIENTS Twenty-one adults with ADHD r and omized to 6 weeks of treatment with methylpheni date OROS ( n = 11 ) or placebo ( n = 10 ) . INTERVENTIONS Patients underwent fMRI twice while performing the MSIT ( scan 1 at baseline and scan 2 at 6 weeks ) . MAIN OUTCOME MEASURES Group-averaged , r and om-effects , repeated- measures , general linear model analyses were used to compare daMCC ( and whole-brain ) fMRI activation during the MSIT . Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented . RESULTS Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups . Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylpheni date OROS group than in the placebo group ( P < 1 x 10(-4 ) , cluster corrected for multiple comparisons ) . Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response . Methylpheni date OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks . CONCLUSION Methylpheni date OROS increased daMCC activation during the MSIT and may act , in part , by normalizing daMCC hypofunction in ADHD We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing , decreased tolerance to delays , poor temporal foresight and steeper temporal discounting . A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder ( ADHD ) . Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD . We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal , cingulate , striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds , motor timing to seconds and temporal discounting of longer time intervals . Given that impulsiveness , timing abnormalities and more specifically ADHD have been related to dopamine dysregulation , we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice , methylpheni date . This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor OBJECTIVE While there has been considerable concern over possible adverse effects of psychostimulants on brain development , this issue has not been examined in a prospect i ve study . The authors sought to determine prospect ively whether psychostimulant treatment for attention deficit hyperactivity disorder ( ADHD ) was associated with differences in the development of the cerebral cortex during adolescence . METHOD Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD . The mean age at the first scan was 12.5 years , and at the second scan , 16.4 years . Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants .  Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD . RESULTS Adolescents taking psychostimulants  differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip , the left middle/inferior frontal gyrus , and the right parieto-occipital region . The group difference was due to more rapid cortical thinning in the group not taking psychostimulants ( mean cortical thinning of 0.16 mm/year [ SD=0.17 ] , compared with 0.03 mm/year [ SD=0.11 ] in the group taking psychostimulants ) . Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates . The treatment groups did not differ in clinical outcome , however . CONCLUSIONS These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle CONTEXT Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder ( ADHD ) , with varying methods , small sample s , cross-sectional design s , and without accounting for stimulant drug exposure . OBJECTIVE To compare regional brain volumes at initial scan and their change over time in  medicated and previously unmedicated male and female patients with ADHD and healthy controls . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted from 1991 - 2001 at the National Institute of Mental Health , Bethesda , Md , of 152 children and adolescents with ADHD ( age range , 5 - 18 years ) and 139 age- and sex-matched controls ( age range , 4.5 - 19 years ) recruited from the local community , who contributed 544 anatomic magnetic resonance images . MAIN OUTCOME MEASURES Using completely automated methods , initial volumes and prospect i ve age-related changes of total cerebrum , cerebellum , gray and white matter for the 4 major lobes , and cau date nucleus of the brain were compared in patients and controls . RESULTS On initial scan , patients with ADHD had significantly smaller brain volumes in all regions , even after adjustment for significant covariates . This global difference was reflected in smaller total cerebral volumes ( -3.2 % , adjusted F(1,280 ) = 8.30 , P = .004 ) and in significantly smaller cerebellar volumes ( -3.5 % , adjusted F(1,280 ) = 12.29 , P = .001 ) . Compared with controls , previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes ( overall F(2,288 ) = 6.65 ; all pairwise comparisons Bon 
    Output:
    