Healthcare utilization and costs of children with attention deficit/hyperactivity disorder initiating atomoxetine versus extended-release guanfacine.

OBJECTIVES: To compare 1-year direct healthcare costs and utilization among children and adolescents initiating non-stimulant medications atomoxetine (ATX) or extended-release guanfacine (GXR). METHODS: In this retrospective, observational cohort study, children and adolescents aged 6-17 years with attention deficit/hyperactivity disorder (ADHD) who had ≥1 prescription claim for ATX or GXR between December 31, 2009 and January 1, 2011 were identified in the MarketScan Commercial or Multi-State Medicaid claims databases. The first claim was set as the index. Patients with no claims for other ADHD medications that overlapped with the days' supply for the index therapy during the post-period were classified as initiating monotherapy. All-cause and ADHD-related utilization and costs (2011 US$) and treatment patterns (adherence and persistence) were evaluated during the 12 months following index. Propensity score adjustment accounted for differences in patient characteristics, and bootstrapping was used for comparisons. RESULTS: A total of 13,239 children and adolescents with ADHD met the study criteria (4,411 ATX initiators and 8,828 GXR initiators). There were 2,699 ATX monotherapy patients. In propensity-score-adjusted analyses, mean all-cause total costs were significantly less for monotherapy ATX initiators than for GXR initiators ($7,553 vs $10,639; difference = -$3,086, p < .0001), as were mean ADHD-related total costs ($3,213 vs $4,544; difference = -$1,330, p < .0001). Monotherapy ATX initiators had significantly fewer all-cause and ADHD-related total medical visits and ∼22 days shorter persistence to index therapy (p < .0001). Results were similar for secondary analyses comparing all ATX with all GXR initiators, regardless of monotherapy or combination regimen, and comparing only monotherapy initiators. CONCLUSIONS: Children and adolescents with ADHD who initiated ATX monotherapy incurred lower all-cause and ADHD-related total healthcare costs than patients who initiated GXR. This was due in part to less healthcare resource utilization and slightly shorter persistence for ATX patients. These findings may aid decision-making and inform future studies, but must be tempered due to inherent observational research limitations.

Meta-analysis of suicide-related behavior or ideation in child, adolescent, and adult patients treated with atomoxetine.

OBJECTIVE: This meta-analysis examined suicide-related events in the acute phases of double-blind, placebo-controlled atomoxetine trials in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 3883 pediatric and 3365 adult patients were included. Potential events were identified from the adverse events database using a text-string search. Mantel-Haenszel risk ratios (MHRR) were calculated for potential suicide-related events categorized according to United States Food and Drug Administration defined codes. RESULTS: In this data set, no completed suicides were reported in the pediatric or adult populations. One pediatric (attempted suicide) (and no adult patient events) was categorized as suicidal behavior in the atomoxetine group. The frequency of combined suicidal behavior or ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo) and the risk compared with placebo was not statistically significant (MHRR=1.57; p=0.42 and MHRR=0.96; p=0.96, respectively). In pediatric patients, suicidal ideation only was reported more frequently compared with placebo (MHRR=1.63; p=0.41). CONCLUSIONS: Overall in this data set, no completed suicides and 1 pediatric patient suicidal behavior event were reported in atomoxetine-treated pediatric and adult patients. Suicidal ideation was uncommon among atomoxetine-treated pediatric and adult patients, although it was reported more frequently in atomoxetine-treated pediatric patients compared with placebo; the reporting rate difference was not statistically significant. The MHRR of suicidal ideation was consistent with a previous meta-analysis of similar design. There was no evidence of increased risk for suicidal behavior in atomoxetine-treated pediatric or adult patients. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov . The data reported are from an analysis of 23 pediatric and 9 adult clinical trials completed between 1998 and 2011. Ten pediatric (Studies HFBD, HFBK, LYAC, LYAS, LYAT, LYAW, LYAX, LYBG, LYBI, and LYBP) and two adult trials (Studies LYAA and LYAO) were conducted before the requirement to post trials at initiation (ongoing as of July 1, 2005) and, therefore, do not have a registration number. The registration numbers for the 13 pediatric trials meeting this requirement are: NCT00191698 (LYBX), NCT00486122 (LYCC), NCT00386581 (LYCZ), NCT00485459 (S010), NCT00191542 (LY15), NCT00191295 (LYBC), NCT00191906 (LYCK), NCT00192023 (LYCY), NCT00191945 (LYDM), NCT00546910 (LYDV), NCT00406354 (LYDW), NCT00380692 (S017), and NCT00607919 (LYEB). For the seven adult trials, the registration numbers are: NCT00190931 (LYBV), NCT00190957 (LYBY), NCT00190736 (LYCU), NCT00190775 (LYCW), NCT00190879 (LYDQ), NCT00510276 (LYDZ), and NCT00962104 (LYEE).

Profile of sexual and genitourinary treatment-emergent adverse events associated with atomoxetine treatment: a pooled analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that begins in childhood. Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. Several studies have demonstrated the safety and efficacy of atomoxetine in the treatment of ADHD. OBJECTIVE: The objective of this analysis was to provide additional information on the frequency, time to onset and time to resolution of sexual and genitourinary (GU) treatment-emergent adverse events (TEAEs) reported during atomoxetine treatment in clinical trials. METHODS: Data from all adult atomoxetine placebo-controlled ADHD trials were pooled for this analysis, for a total of 3,314 patients (atomoxetine, n = 1,738; placebo, n = 1,576). Additionally, data from all adolescent patients (baseline age ≥13 to <18 years) within all ADHD placebo-controlled trials were pooled for analysis, for a total of 538 patients (atomoxetine, n = 329; placebo, n = 209). Rates of sexual and GU TEAEs were summarized by sex for each age group. Time to onset and resolution of sexual and GU TEAEs were summarized and compared using Kaplan-Meier methods. RESULTS: Overall, the baseline characteristics of randomized patients in the atomoxetine and placebo groups were similar. Profiles of sexual and GU TEAEs for atomoxetine appeared clinically similar to placebo in female patients and in adolescent male patients. Adult male patients reported relatively more sexual and GU TEAEs when taking atomoxetine compared with placebo, with libido decreased (4.6 vs. 3.0 %), dysuria (3.7 vs. 1.5 %), urinary hesitation (6.9 vs. 2.4 %), urine flow decreased (2.5 vs. 0.6 %), ejaculation disorder (2.8 vs. 1.1 %) and erectile dysfunction (8.0 vs. 1.9 %) being the most common. The time to onset of the most common TEAEs in adult male patients tended to occur relatively early in dosing: within the first 2 weeks for GU TEAEs, and during the second and third week of dosing for erectile and ejaculation issues. The median time to resolution for these events ranged from around 3-8 weeks after event onset, depending on the event. While the common sexual and GU TEAEs showed numerically higher percentages of discontinuations in atomoxetine-treated patients compared with placebo, most incidences of the sexual and GU TEAEs were not considered severe. CONCLUSIONS: The sexual and GU TEAE profiles of patients taking atomoxetine were generally similar to those of patients taking placebo in the female and adolescent male populations, with greater frequency of TEAEs reported in adult males taking atomoxetine compared with placebo. The time to onset of the TEAEs tended to be shorter, and time to resolution tended to be longer in adult male patients treated with atomoxetine compared with those receiving placebo. The conclusions must be interpreted with caution because the TEAEs were likely underreported.

American Cancer Society lung cancer screening guidelines.

Findings from the National Cancer Institute's National Lung Screening Trial established that lung cancer mortality in specific high-risk groups can be reduced by annual screening with low-dose computed tomography. These findings indicate that the adoption of lung cancer screening could save many lives. Based on the results of the National Lung Screening Trial, the American Cancer Society is issuing an initial guideline for lung cancer screening. This guideline recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with low-dose computed tomography should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation.

Validation of the adult ADHD investigator symptom rating scale (AISRS).

OBJECTIVE: Validation of the Adult ADHD Investigator Symptom Rating Scale (AISRS) that measures aspects of ADHD in adults. METHOD: Psychometric properties of the AISRS total and AISRS subscales are analyzed and compared to the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) and the Clinical Global Impression-ADHD-Severity Scale using data from a placebo-controlled 6-month clinical trial of once-daily atomoxetine. RESULTS: The AISRS has high internal consistency, good convergent, and discriminant validities; modest divergent validity; and small ceiling and floor effects (

Effects of atomoxetine on attention-deficit/hyperactivity disorder in clinical pediatric treatment settings: a naturalistic study.

BACKGROUND: Observational studies involving atomoxetine hydrochloride in the treatment of attention-deficit/hyperactivity disorder (ADHD) complement randomized controlled trials by assessing treatment effects in a usual-care setting and including a more heterogeneous patient population. OBJECTIVE: To provide data on the effectiveness of atomoxetine in a naturalistic treatment setting according to both physician and parent ratings. DESIGN AND METHODS: A prospective, observational (non-interventional), longitudinal, open-label study of patients (N = 627; mean age = 11 years) with ADHD (from 60 physicians' offices in the United States and Puerto Rico) whose physicians had decided to prescribe atomoxetine either as initial treatment or after trying another ADHD treatment (e.g., stimulants, antidepressants). Patients with a baseline visit and one post-baseline visit for up to 1 year were eligible. Atomoxetine administration, dosing, and timing of follow-up visits were at each physician's discretion. Physicians evaluated the effectiveness of atomoxetine using a single-item rating scale: the Physician Global Impression: ADHD Severity (PGI-ADHD-S) scale. RESULTS: The average reported duration of treatment was 21.2 (range 0-89) weeks. Over this period, treatment significantly lowered ADHD severity compared with baseline, with a mean change of -0.91 (95% confidence interval: -1.00 to -0.82; p < 0.001) on the PGI-ADHD-S scale. Physician-rated improvement was more marked in patients with more severe ADHD at baseline (p < 0.001). Most patients (59-69%) experienced consistent symptom control at all times of the day. ADHD severity was improved similarly in patients across comorbid conditions (e.g., anxiety, depression, learning disorders), chief complaints (e.g., school problems, emotional problems), and prior treatment with stimulants or other medications. By parent reports, 49% of patients had improved grades following atomoxetine therapy while 35% stayed the same, and improvement in behavior (according to parents' ratings) occurred in 49% of patients following atomoxetine therapy, whereas 31% stayed the same. CONCLUSION: Data captured in this study support the conclusion that atomoxetine was effective in reducing symptom severity, and improving progress toward treatment goals, in children and adolescents with ADHD treated in a naturalistic treatment setting. However, given the open-label, observational (non-interventional) design of this study, certain biases cannot be excluded.

Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome.

OBJECTIVE: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). METHOD: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. RESULTS: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. CONCLUSION: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS.

Transition from methylphenidate or amphetamine to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder--a preliminary tolerability and efficacy study.

BACKGROUND: The primary treatment for attention-deficit/hyperactivity disorder (ADHD) has been psychostimulants. Recently developed nonpsychostimulant treatments have allowed certain patients to switch from a psychostimulant to a nonpsychostimulant. However, the outcomes of such switches have not been systematically studied. OBJECTIVE: The purpose of this pilot study was to assess treatment tolerance and efficacy during a cross-taper transition from methylphenidate or amphetamine to atomoxetine among children and adolescents with ADHD. METHODS: This pilot study was conducted in patients (aged 6-17 years) with incomplete responses (failure to obtain full reduction/elimination of symptoms) or intolerance of adverse events (AEs) during psychostimulant treatment. Patients continued ongoing psychostimulant treatment during the first week of the study. Transition to atomoxetine began by administering atomoxetine 0.5 mg/kg . d plus full-dose psychostimulant for 1 week, followed in the second week by 1.2 mg/kg . d atomoxetine plus half-dose psychostimulant. Patients remained on 1.2 mg/kg . d atomoxetine monotherapy for the remaining 5 weeks. This stepwise transition was enacted due to the difference in pharmacodynamics between the psychostimulants and atomoxetine. Applying a stepwise cross-titration allowed for better control of ADHD symptoms during the intervening period. Change in ADHD symptoms, as measured by the mean change in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-administered and -scored (ADHDRS-IV-Parent:Inv), was assessed from baseline to end point. RESULTS: Of the 62 subjects enrolled in the study, 39 (62.9%) were diagnosed as ADHD-combined type. Similar proportions were receiving methylphenidate (51.6%) and amphetamine (48.4%). Slightly more wished to switch due to inadequate response (53.2%) than intolerability (46.8%). Nine subjects discontinued at various times during the course of the study (patient or parent/caregiver decision [4], AE [2], protocol violation [2], and lack of efficacy [1]). Mean (SD) ADHDRS-IV-Parent:Inv total scores (n = 59, last-observation-carried-forward) improved significantly from baseline (visit 2) to an end point (32.1 [10.5] vs 22.6 [14.0]; P < 0.001). Of the 58 subjects answering in the atomoxetine monotherapy phase, 38 (65.5%) reported a preference for atomoxetine treatment over their previous psychostimulant. Tolerability results were as follows: 26 (44.1%) of 59 patients reported >or=1 AE, the most common being somnolence (4 [6.8%]), fatigue (3 [5.1%]), decreased appetite (3 [5.1%]), cough (3 [5.1%]), headache (3 [5.1%]), and contact dermatitis (2 [3.4%]). No clinically severe AEs were reported. Both mean (SD) diastolic (2.4 [7.8] mm Hg; P = 0.031) and systolic (2.4 [7.9] mm Hg; P = 0.029) blood pressures increased significantly from baseline to end point. Electrocardiography revealed a significant increase in mean (SD) heart rate (9.2 [11.6] bpm; P < 0.001) and a corresponding decrease in mean (SD) RR interval (-77.8 [98.2] ms; P < 0.001). Statistically significant, but mild, increases in diastolic pressure and heart rate were observed. CONCLUSION: These children and adolescent patients were successfully switched from methylphenidate or amphetamine to atomoxetine treatment, with resulting improvement in ADHD symptom severity from baseline in this pilot study.

Addition of atomoxetine for depression incompletely responsive to sertraline: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Despite appropriate treatment with selective serotonin reuptake inhibitors (SSRIs), many depressed patients do not attain remission. Addition of a noradrenergic intervention in patients poorly or partially responsive to SSRIs may improve outcomes, but few well-controlled studies testing this hypothesis have been reported. METHOD: Patients with major depressive disorder (confirmed by the Structured Clinical Interview for DSM-IV) were treated with sertraline at doses up to 200 mg/day in this study, conducted from June 18, 2003, to January 28, 2005. Patients who continued to experience depressive signs and symptoms after 8 weeks were randomly assigned to have atomoxetine 40 to 120 mg/day or placebo added to sertraline for a further 8 weeks. RESULTS: Of 276 patients starting the study, 146 with persistent depressive symptoms after 8 weeks of sertraline treatment (mean [SD] final sertraline dose: 161.1 [43.4] mg/day) were randomly assigned to addition of atomoxetine or placebo. After 8 additional weeks, there was no difference between treatment groups in mean change in symptom severity or in the proportion of patients whose symptoms remitted (sertraline/ atomoxetine 29/72 [40.3%], sertraline/placebo 28/74 [37.8%], p = .865). Secondary analyses that separated the subgroups with improvements in symptoms that did not reach remission (partial responders) and those with little or no improvement (nonresponders) also showed no effect of atomoxetine. The number of patients discontinuing because of adverse events did not differ between groups. CONCLUSION: In depressed patients with persistent symptoms after an initial trial of sertraline, addition of atomoxetine did not improve response more than placebo.

Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with atomoxetine.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has its onset during childhood and is estimated to affect 3% to 7% of school-aged children. Unfortunately, the disorder frequently persists into adult life. The burden of this disorder is considerable and is often characterized by academic (or occupational) impairment and dysfunction within the family and society. Despite the existence of research demonstrating the effects of ADHD on certain aspects of life, the clinical trials of treatments for this disorder have focused primarily on efficacy and safety. METHODS: Atomoxetine was approved in the United States in November 2002 for the treatment of ADHD in children, adolescents, and adults. The present study uses data from a clinical trial of atomoxetine in adult patients with ADHD that incorporated a measure of health-related quality of life (the Medical Outcomes Study 36-item short-form health survey [SF-36]) as part of the overall assessment of the success of this relatively new treatment. The primary outcome measure for ADHD symptoms was the Conners Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS) ADHD total symptom score. RESULTS: In agreement with previous studies, adult patients with ADHD treated with atomoxetine at typical doses showed significant amelioration of ADHD symptoms, as measured on the CAARS. At baseline, the measures of overall mental health (one aspect of quality of life) of adult patients with ADHD were below the average level, as measured on the SF-36. Treatment with atomoxetine significantly improved the measures of mental health and ameliorated the ADHD symptoms. In addition, the 2 measures were correlated. CONCLUSIONS: These data suggest that pharmacological intervention with atomoxetine not only ameliorates ADHD symptoms in adult patients but also improves their perceived quality of life.

Placebo-controlled study of the effects of atomoxetine on bladder control in children with nocturnal enuresis.

INTRODUCTION: Nocturnal enuresis is a condition in which children at least 5 years of age are incontinent of urine at night. Atomoxetine, a potent inhibitor of the presynaptic norepinephrine transporter, is used to treat attention-deficit/hyperactivity disorder (ADHD). This study tested the hypothesis that atomoxetine will provide significant therapeutic benefit for nocturnal enuresis in patients with the diagnosis of nocturnal enuresis. METHODS: Atomoxetine's efficacy for improving nocturnal enuresis was studied in 87 pediatric subjects using an outpatient, multicenter, randomized, double-blind, parallel, placebo-controlled study. Efficacy was determined by measuring the mean number of dry nights per week using an intent-to-treat analysis of the primary outcome measure, the Dry Night Log-Parent Report (DNL-PR), a daily parent diary. RESULTS: Baseline and end point DNL-PR data were available from 42 atomoxetine-treated and 41 placebo-treated subjects. Atomoxetine increased the average number of dry nights per week by 1.47 compared with .60 for placebo (F = 7.06; df = (1, 75); p = 0.01). Fifteen atomoxetine-treated subjects (35.7%) had an increase of at least 2 dry nights per week compared with only 6 (14.6%) placebo-treated subjects (Fisher's exact test; p = 0.042). There were no significant differences in adverse events between the groups. CONCLUSIONS: Compared with placebo, atomoxetine treatment was associated with a significant increase in dry nights in children with nocturnal enuresis.

Improvement in health-related quality of life in children with ADHD: an analysis of placebo controlled studies of atomoxetine.

Despite significant functional impairments associated with attention-deficit hyperactivity disorder (ADHD) and the growing appreciation of the importance of health-related quality of life (HRQL) assessment in children with chronic disorders, relatively few studies have examined the impact of ADHD treatment on HRQL. This investigation examines the effect of atomoxetine, a nonstimulant treatment for ADHD, on HRQL and identifies factors that are predictive of HRQL improvements. The Child Health Questionnaire (CHQ), which is a multidimensional HRQL measure, was collected during three randomized, double-blind, placebo-controlled clinical trials. Children who received atomoxetine had significantly greater improvement in psychosocial functioning compared to the placebo group. No significant differences between once-a-day and twice-a-day dosing were found. Treatment with atomoxetine, lower HRQL baseline score, no history of stimulant use, and absence of oppositional defiant disorder were all associated with improvements in psychosocial functioning. Findings demonstrate the positive impact of atomoxetine on HRQL in children with ADHD.

Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial.

OBJECTIVES: Atomoxetine seems to be as effective for treating attention-deficit/hyperactivity disorder (ADHD) when the daily dose is administered once in the morning as when the dose is divided and administered in the morning and evening. In the present study, the efficacy of atomoxetine administered once daily among children with ADHD was assessed throughout the day, including the evening and early morning. Another goal was to determine how early in treatment it was possible to discern a specific effect of the drug on ADHD symptoms. METHODS: This study was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 12 outpatient sites in the United States. A total of 197 children, 6 to 12 years of age, who had been diagnosed as having ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, were randomized to receive 8 weeks of treatment with atomoxetine or placebo, dosed once daily in the mornings. ADHD symptoms were assessed with parent and investigator rating scales. The primary outcome measure was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score. Daily parent assessments of children's home behaviors in the evening and early morning were recorded with an electronic data entry system. This instrument measures 11 specific morning or evening activities, including getting up and out of bed, doing or completing homework, and sitting through dinner. RESULTS: Seventy-one percent of the children enrolled were male, 69% met criteria for the combined subtype (both inattentive and hyperactive/impulsive symptoms), and the most common psychiatric comorbidity was oppositional defiant disorder (35%). Once-daily atomoxetine (final mean daily dose of 1.3 mg/kg) was significantly more effective than placebo in treating core symptoms of ADHD. Mean reductions in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score were significantly greater for patients randomized to atomoxetine, beginning at the first visit after the initiation of treatment and continuing at all subsequent visits. Both inattentive and hyperactive/impulsive symptom clusters were significantly reduced with atomoxetine, compared with placebo. With continued treatment and dose titrations, core symptoms of ADHD continued to decrease throughout the 8-week study. Mean reductions in the daily parent assessment total scores for patients randomized to atomoxetine were superior during the first week, beginning with the first day of dosing, and were also superior at endpoint. Efficacy outcomes for the evening hours for atomoxetine-treated patients were superior to those for placebo-treated patients, as assessed with 2 different assessment scales. Decreases in the daily parent assessment morning subscores at endpoint showed a significant reduction in symptoms that lasted into the mornings. Rates of discontinuations attributable to adverse events were <5% for both groups. Adverse events reported significantly more frequently with atomoxetine were decreased appetite, somnolence, and fatigue. CONCLUSIONS: Among children 6 to 12 of age who had been diagnosed as having ADHD, once-daily administration of atomoxetine in the morning provided safe, rapid, continuous, symptom relief that lasted not only into the evening hours but also into the morning hours. Atomoxetine treatment was safe and well tolerated.