In their Week 2 home-opener against AFC South rival Houston, Indianapolis continued its offensive dominance by starting the game with a 10-yard touchdown pass from QB Peyton Manning to WR Brandon Stokley and a 21-yard touchdown pass from Manning to rookie running back Joseph Addai. In the second quarter, kicker Adam Vinatieri successfully converted a 39-yard field goal attempt to push the Colts' lead to 17-0. The Texans responded with a field goal of their own, but the Colts tacked on another field goal as time expired to end the half. The third quarter witnessed more scoring as Peyton Manning completed a touchdown drive on the first possession of the half, this one a 15-yard touchdown pass to TE Bryan Fletcher. Five minutes later, Adam Vinatieri converted another field goal for Indianapolis, this time from 38 yards out. Houston showed signs of life in the fourth quarter as QB David Carr completed a 33-yard touchdown pass to TE Owen Daniels. Indianapolis would respond, however, with a 2-yard touchdown run by RB Dominic Rhodes. The Texans answered on Carr's 1-yard touchdown pass to TE Mark Bruener, but the Colts scored yet again, this time on a 3-yard TD run by RB Ran Carthon. Houston scored one more time in the final moments as David Carr completed a 10-yard touchdown pass to WR Andre Johnson, but the game was never as close as the final score indicated. This victory improved the Colts' record against the Texans to 9-0. Also noteworthy, QB Peyton Manning surpassed Johnny Unitas for the most pass completions in franchise history. Manning accomplished this feat on his third completion of the game. Peyton Manning finished the game 26 of 38 with 400 yards passing and three touchdowns. David Carr finished with 219 passing yards on 22 of 26 passes completed and also had three touchdown passes as well. Neither quarterback threw an interception, but Carr did fumble the football three times. Colts RB Joseph Addai finished the game with a career-high 82 rushing yards, and also had a touchdown reception. Peyton Manning was sacked twice in this game, and David Carr was sacked four times.

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