Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute on Drug Abuse (NIDA) | NIH |
Not provided
Not provided
Not provided
The central objective of this project is to obtain proof-of-concept data demonstrating the effects of propranolol (a beta-adrenergic antagonist) on neurobiological responses to personal smoking environments and behavioral responses in a laboratory smoking behavior task. Human cigarette smokers (N = 50) will take photographs of locations where they do and do not smoke cigarettes. They will then be randomly assigned to receive either propranolol (40 mg) or placebo prior to completing: A) An MRI session assessing neural responses to personal smoking/non-smoking environments, standard smoking/non-smoking environments and proximal smoking/non-smoking cues; and B) A laboratory session examining smoking behavior in response to environmental cues.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Propranolol | Experimental | Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions |
|
| Placebo | Placebo Comparator | Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Propranolol | Drug | Participants will take one dose of Propranolol (40mg IR) on two separate occasions. |
|
| Measure | Description | Time Frame |
|---|---|---|
| BOLD Activation to Smoking Cues - Amygdala | BOLD activation in amygdala (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | MRI Scan: 2-3 hours post-administration |
| BOLD Activation to Smoking Cues - Anterior Insula | BOLD activation in Anterior Insula (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | MRI Scan: 2-3 hours post-administration |
| BOLD Activation to Smoking Cues - Anterior Hippocampus | BOLD activation in Anterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | MRI Scan: 2-3 hours post-administration |
| BOLD Activation to Smoking Cues - Posterior Hippocampus | BOLD activation in Posterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. |
| Measure | Description | Time Frame |
|---|---|---|
| Laboratory Visit - Self-Reported Craving | Self-reported craving to smoke following presentation of personal smoking environments (prior to ad-lib smoking period). Assessed using the average rating across four questions drawn from the Questionnaire on Smoking Urges: (1) While focusing on those places...nothing would have been better than smoking a cigarette; (2) While focusing on those places...I had the urge for a cigarette; (3) While focusing on those places...all I wanted right then was a cigarette; (4) While focusing on those places...I craved a cigarette. Participants rated each item on an 11-point scale ranging from 0 (Do not agree) to 100 (Strongly agree) in 10-point intervals. These ratings were averaged across items for analysis. higher values represent greater craving. Tiffany, S. T., & Drobes, D. J. (1991). The development and initial validation of a questionnaire on smoking urges. British Journal of addiction, 86(11), 1467-1476. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Note that the above criteria reflect general guidelines for decision-making, but ultimate determinations are left to the discretion of the study physician. Presence of minor (e.g. asymptomatic bradycardia in the range of 50-60 in an otherwise healthy adult) or transient (e.g. electrolyte imbalance readily addressed via changes in fluid intake) may still be deemed eligible to participate.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Jason A Oliver, PhD | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University School of Medicine | Durham | North Carolina | 27705 | United States |
Detailed protocols, datasets and additional information will be available from the Principal Investigator and research team upon request. In order to maintain compliance with HIPAA requirements (as well as university data security policies), all data will be de-identified according to HIPAA guidelines prior to being shared. Personal images themselves will not be made publicly available due to privacy concerns. However, a brief description of each image (e.g. "Front porch of home") will be made available. Data would be provided in widely accessible formats (e.g. csv/xls), along with a detailed data dictionary describing all elements and coding and study protocols.
We anticipate making data available within six months of study completion. It will be available for an indefinite period of time.
Contact PI for details
Not provided
Not provided
Participants were enrolled in a laboratory setting at Duke University School of Medicine during a period ranging from January 2018 to June 2019.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Propranolol | Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions Propranolol: Participants will take one dose of Propranolol (40mg IR) on two separate occasions. |
| FG001 | Placebo | Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions Placebo: Participants will take one dose of Placebo on two separate occasions. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Participants who completed the study.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Propranolol | Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions Propranolol: Participants will take one dose of Propranolol (40mg IR) on two separate occasions. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | BOLD Activation to Smoking Cues - Amygdala | BOLD activation in amygdala (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | Percent Signal Change | MRI Scan: 2-3 hours post-administration | Trial Type, MRI Run, Brain Hemisphere | Trial Type, MRI Run, Brain Hemisphere |
|
This is an acute administration study with an approved medication with a well-established safety profile. Adverse events were assessed over the 1-3 month period in which participants were engaged in the project, primarily for purposes of ensuring new contraindications did not emerge prior to drug administration vs concerns about adverse events related to the drug itself.
Participants abstain from smoking for 24 hours before the MRI visit and 6 hours before the laboratory visit. Symptoms of nicotine withdrawal are assessed but are not considered adverse events. Participant self-report of any newly-onset or worsening medical problems during their time of participation are considered adverse events. Repeat blood draws were occasionally necessary but are also not considered adverse events.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Propranolol | Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions Propranolol: Participants will take one dose of Propranolol (40mg IR) on two separate occasions. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dog Bite | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Participant reported having been bitten by a dog prior to their MRI visit. |
This was a pilot study with a small sample size. A between-subjects design was used with no baseline scan for comparison. No clinical endpoints were examined - results are limited to neuroimaging and behavioral task outcomes.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jason A. Oliver, Ph.D. | Duke University School of Medicine | (919) 668-0093 | Jason.A.Oliver@duke.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Apr 30, 2019 | Jun 23, 2020 | ICF_000.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 11, 2019 | Jun 23, 2020 | Prot_SAP_001.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D000073865 | Cigarette Smoking |
| ID | Term |
|---|---|
| D000073869 | Tobacco Smoking |
| D012907 | Smoking |
| D001519 | Behavior |
| D064424 | Tobacco Use |
Not provided
Not provided
| ID | Term |
|---|---|
| D011433 | Propranolol |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
Not provided
Not provided
Participants will be randomly assigned to receive propranolol (40 mg) or placebo
Not provided
Not provided
Double-blind
| Placebo | Drug | Participants will take one dose of Placebo on two separate occasions. |
|
| MRI Scan: 2-3 hours post-administration |
| BOLD Activation to Smoking Cues - Medial Prefrontal Cortex | BOLD activation in Medial Prefrontal Cortex (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | MRI Scan: 2-3 hours post-administration |
| fMRI BOLD Connectivity | Connectivity with right amygdala when viewing proximal smoking images, using a right anterior hippocampus seed region (psychophysiological interaction analysis; PPI). Larger values represent greater connectivity between these regions while viewing proximal smoking images. | MRI Scan: 2-3 hours post-administration |
| Cue-Provoked Craving - Proximal Cues | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | MRI Scan: 2-3 hours post-administration |
| Cue-Provoked Craving - Standard Environment Images | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | MRI Scan: 2-3 hours post-administration |
| Cue-Provoked Craving - Personal Environment Cues | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | MRI Scan: 2-3 hours post-administration |
| Lab Task: 2-3 hours post-administration |
| Laboratory Visit - # Cigarette Puffs | Number of cigarette puffs taken during ad lib smoking period while participants view images of their personal smoking environment. Smoking was video recorded and puffs were coded by two raters. | Lab Task: 2-3 hours post-administration |
Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions
Placebo: Participants will take one dose of Placebo on two separate occasions.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Cigarettes Per Day | Self-reported average number of cigarettes smoked per day at screening (baseline) visit | Mean | Standard Deviation | Cigarettes/day |
|
| Fagerstrom Test for Cigarette Dependence | Fagerstrom Test for Cigarette Dependence - This is an established self-report measure used to characterize the severity of nicotine dependence. Yes/no items are scored as 0 or 1 and multiple-choice items are scored from 0 to 3. These are summed to yield a total score ranging from 0 (no/minimal nicotine dependence) to 10 (severe nicotine dependence). | Mean | Standard Deviation | units on a scale |
|
| Contemplation Ladder (Motivation to Quit) | Contemplation Ladder - An established single-item measure of motivation to quit smoking. Participants rate themselves on a scale ranging from 0 (No thought of quitting) to 10 (Currently taking action to quit). | Mean | Standard Deviation | units on a scale |
|
| Number of Previous Quit Attempts | Self-reported number of previous quit attempts based on a smoking history form collected at baseline (screening) visit. | Mean | Standard Deviation | quit-attempts |
|
| Education | Self-reported educational attainment | Count of Participants | Participants |
|
| Income | Self-reported USUAL annual household income. | Count of Participants | Participants |
|
Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions Propranolol: Participants will take one dose of Propranolol (40mg IR) on two separate occasions. |
| OG001 | Placebo | Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions Placebo: Participants will take one dose of Placebo on two separate occasions. |
|
|
|
| Primary | BOLD Activation to Smoking Cues - Anterior Insula | BOLD activation in Anterior Insula (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | Percent Signal Change | MRI Scan: 2-3 hours post-administration | Trial Type, MRI Run, Brain Hemisphere | Trial Type, MRI Run, Brain Hemisphere |
|
|
|
|
| Primary | BOLD Activation to Smoking Cues - Anterior Hippocampus | BOLD activation in Anterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | Percent Signal Change | MRI Scan: 2-3 hours post-administration | Trial Type, MRI Run, Brain Hemisphere | Trial Type, MRI Run, Brain Hemisphere |
|
|
|
|
| Primary | BOLD Activation to Smoking Cues - Posterior Hippocampus | BOLD activation in Posterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | Percent Signal Change | MRI Scan: 2-3 hours post-administration | Trial Type, MRI Run, Brain Hemisphere | Trial Type, MRI Run, Brain Hemisphere |
|
|
|
|
| Primary | BOLD Activation to Smoking Cues - Medial Prefrontal Cortex | BOLD activation in Medial Prefrontal Cortex (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | Percent Signal Change | MRI Scan: 2-3 hours post-administration | Trial Type, MRI Run, Brain Hemisphere | Trial Type, MRI Run, Brain Hemisphere |
|
|
|
|
| Primary | fMRI BOLD Connectivity | Connectivity with right amygdala when viewing proximal smoking images, using a right anterior hippocampus seed region (psychophysiological interaction analysis; PPI). Larger values represent greater connectivity between these regions while viewing proximal smoking images. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | PPI Index | MRI Scan: 2-3 hours post-administration |
|
|
|
|
| Primary | Cue-Provoked Craving - Proximal Cues | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | units on a scale | MRI Scan: 2-3 hours post-administration |
|
|
|
|
| Primary | Cue-Provoked Craving - Standard Environment Images | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | units on a scale | MRI Scan: 2-3 hours post-administration |
|
|
|
|
| Primary | Cue-Provoked Craving - Personal Environment Cues | During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving. | Participants who completed the study. Excludes two additional participants in the placebo condition who had excessive motion artifact during scanning and could not be included in neuroimaging analyses. | Posted | Mean | Standard Deviation | units on a scale | MRI Scan: 2-3 hours post-administration |
|
|
|
|
| Secondary | Laboratory Visit - Self-Reported Craving | Self-reported craving to smoke following presentation of personal smoking environments (prior to ad-lib smoking period). Assessed using the average rating across four questions drawn from the Questionnaire on Smoking Urges: (1) While focusing on those places...nothing would have been better than smoking a cigarette; (2) While focusing on those places...I had the urge for a cigarette; (3) While focusing on those places...all I wanted right then was a cigarette; (4) While focusing on those places...I craved a cigarette. Participants rated each item on an 11-point scale ranging from 0 (Do not agree) to 100 (Strongly agree) in 10-point intervals. These ratings were averaged across items for analysis. higher values represent greater craving. Tiffany, S. T., & Drobes, D. J. (1991). The development and initial validation of a questionnaire on smoking urges. British Journal of addiction, 86(11), 1467-1476. | Participants who completed the study. | Posted | Mean | Standard Deviation | units on a scale | Lab Task: 2-3 hours post-administration |
|
|
|
|
| Secondary | Laboratory Visit - # Cigarette Puffs | Number of cigarette puffs taken during ad lib smoking period while participants view images of their personal smoking environment. Smoking was video recorded and puffs were coded by two raters. | Participants who completed the study. Data from one participant in the placebo condition was lost due to technical problems with the recording. | Posted | Mean | Standard Deviation | Puffs | Lab Task: 2-3 hours post-administration |
|
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 1 |
| 22 |
| EG001 | Placebo | Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions Placebo: Participants will take one dose of Placebo on two separate occasions. | 0 | 22 | 0 | 22 | 1 | 22 |
|
| Wrist Injury | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Participant arrived to MRI appointment in a wrist brace and reported they had sprained their wrist two days prior to the appointment. |
|
Not provided
Not provided
| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D011083 | Polycyclic Compounds |
| Non-Smoking Standard Environments |
|
| Smoking Standard Environments |
|
| Non-Smoking Proximal |
|
| Smoking Proximal |
|
| Non-Smoking Standard Environments |
|
| Smoking Standard Environments |
|
| Non-Smoking Proximal |
|
| Smoking Proximal |
|
| Non-Smoking Standard Environments |
|
| Smoking Standard Environments |
|
| Non-Smoking Proximal |
|
| Smoking Proximal |
|
| Non-Smoking Standard Environments |
|
| Smoking Standard Environments |
|
| Non-Smoking Proximal |
|
| Smoking Proximal |
|