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Colts (0 3) welcomed back Pro Bowl receiver Reggie Wayne.
Luck's interception then set up a 39 yard field goal from Shayne Graham, and Graham hit a 24 yarder late to give the Saints a 20 7 lead.
The Saints' top two quarterbacks made sure the Colts didn't get many chances in the first half.
Brees looked as sharp as ever Saturday night.
10 of 18 for 103 yards with one touchdown pass and one interception on a night the Nike Air Vapormax Pure Platinum On Feet
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It was so lopsided that Luck played into the third quarter and still couldn't match Brees' numbers. Indy's starting quarterback was Nike Vapormax Black On Black
Brees capped a game opening 80 yard drive with a 3 yard TD pass to Austin Johnson. Brees later responded to Luck's 21 yard TD pass to Coby Fleener with a Nike Vapormax Black Womens 13 yarder to Marques Colston to make it 14 7 late in the first period.
Adam Vinatieri closed the half with a 20 yard field goal, but the Colts couldn't get any closer until Chandler Harnish threw a 22 yard TD pass to Josh Lenz with 13:39 left in the game.
But he did not show a hint of rustiness against the winless Colts. He went 9 of 15 for 128 yards with two touchdown passes, no interceptions and no sacks against a starting defense that had only allowed 91 yards in roughly 2 1/2 quarters during the first two preseason games. And Brees played so well that coach Sean Payton pulled him out before the end of the first quarter.
"It felt good, everything felt normal, and that's what I expected," Wayne said during a first half television interview. "You know, coach tells you that you've got about eight to 10 plays and you feel like that's the perfect number. But once you get out there, start playing, get involved, you feel like that's not enough."
Brees Sharp in Return as Saints Beat Colts
He had plenty of help, too. In the first half, New Orleans (3 0) rushed for 124 yards, piled up 288 total yards, and ran nearly twice as many plays (48) as the Colts (26).
The 35 year old Wayne hadn't suited up for a game since tearing the ACL in his right knee last October. Wayne received loud ovations from the fans when he ran onto the field after being announced as a starter during pregame introductions, and after making two catches. Both were wiped out by penalties, but Wayne did get tackled twice and bounced right up both times.
Six days after returning to practice, the Pro Bowl quarterback threw two touchdown passes in the first quarter and led the still unbeaten Saints to a 23 17 preseason victory at Indianapolis.
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